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CA3151322A1 - Combination therapy with immune stimulatory conjugates - Google Patents

Combination therapy with immune stimulatory conjugates Download PDF

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CA3151322A1
CA3151322A1 CA3151322A CA3151322A CA3151322A1 CA 3151322 A1 CA3151322 A1 CA 3151322A1 CA 3151322 A CA3151322 A CA 3151322A CA 3151322 A CA3151322 A CA 3151322A CA 3151322 A1 CA3151322 A1 CA 3151322A1
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seq
independently selected
amino acid
acid sequence
antibody
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Valerie Odegard
Peter R. Baum
Peter A. Thompson
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ARS Pharmaceuticals Inc
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

Combination therapies using a conjugate comprising a TLR agonist and an antibody that binds a tumor associated antigen or liver cell antigen, and a second therapeutic agent, such as an immune checkpoint inhibitor, are provided for treating cancer or viral infections. Combination therapies using a conjugate comprising a TLR agonist and an antibody that binds HER2, and a second therapeutic agent are also provided for treating cancer.

Description

COMBINATION THERAPY WITH IMMUNE STIMULATORY CONJUGATES
STATEMENT REGARDING SEQUENCE LISTING
The Sequence Listing associated with this application is provided in text 5 format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is 860234 412W0 SEQUENCE LISTINGixt. The text file is 9 KB, was created on September 17, 2020, and is being submitted electronically via EFS-Web.
BACKGROUND
Technical Field 100011 The present application relates to combination therapies comprising immune-stimulatory conjugates and methods for treating cancer or viral infections.
Description of the Related Art 100021 One of the leading causes of death in the United States is cancer.
15 Conventional methods of cancer treatment, like chemotherapy, surgery, or radiation therapy, tend to be highly toxic and/or nonspecific to a cancer, resulting in limited efficacy and harmful side effects. The immune system has the potential to be a powerful, specific tool in fighting cancers. This observation has led to the development of immunotherapeutics as drug candidates for clinical trials.
Immunotherapeutics can 20 act by boosting a specific immune response and have the potential to be a powerful anti-cancer treatment. Such immunotherapeutics may comprise benzazepine compounds, which in some instances, act as toll-like receptor (e.g., TLR8) agonists.
INCORPORATION BY REFERENCE
100031 All publications, patents, and patent applications mentioned in this 25 specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF SUMMARY
[0004] The present disclosure provides tumor-associated antigen- or liver cell antigen-dependent uptake of a Toll-like receptor (TLR) agonist, which allows for systemic delivery of an innate immune agonist that generates tumor- or liver-localized 5 immune cell activation while avoiding systemic toxicity. In some embodiments, a method of treating cancer or viral infection is provided, comprising administering to a subject with cancer or viral infection a conjugate comprising a TLR agonist and an antibody that binds a tumor-associated or liver cell antigen, and an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor inhibits PD-1 and/or 10 PD-L1. In some embodiments, the TLR agonist is a TLR8 agonist.
[0005] In certain embodiments, a method of treating cancer or viral infection is provided, comprising administering to a subject with cancer or viral infection a conjugate and an immune checkpoint inhibitor that inhibits PD-1 and/or PD-L1;
wherein the conjugate is represented by Formula (I):
= 4> Dx (0;
wherein:
A is an antibody that binds a tumor associated antigen or a liver cell antigen, L is a linker;
Dx is a TLR8 agonist, wherein the TLR8 agonist is a benzazepine compound;
20 n is selected from 1 to 20; and z is selected from 1 to 20.
[0006] In further embodiments, a method of treating a HER2-expressing cancer is provided, comprising administering to a subject with a HER2-expressing cancer a conjugate and an additional therapeutic agent comprising a HER2-targeted agent such 25 as a kinase inhibitor, a therapeutic agent comprising an anti-RER2 antibody, or both;
wherein the conjugate is represented by Formula (I):
2 4) = Dõ 1 ]
(0;
wherein:
A is an antibody that binds HER2, L is a linker;
5 Dx is a TLR8 agonist, wherein the TLR8 agonist is a benzazepine compound;
n is selected from 1 to 20; and z is selected from 1 to 20.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] Certain features of the disclosure are set forth with particularity in the 10 appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative aspects, in which the principles of the disclosure are utilized, and the accompanying drawings of which:
[0008] FIGS. IA-1B show increased expression levels of CD86 (FIG. 1A) and 15 PD-Li (FIG. 1B) in dendritic cells following exposure to HER2-TLR8 in the presence of HER2-expressing tumor cells, as described in Example 1.
[0009] FIG. 2 shows IFN-y expression in human PBMCs co-cultured with 5IC-BR-3 (3+ HER2+ tumor cell line), MDA-MB-453 (2+ HER2+ tumor cell line), or MDA-MB-468 (HER2- tumor cell line) in the presence of HER2-TLR8 for 24 hours, as 20 described in Example 2.
[0010] FIG. 3 shows the similarity in expression between TLR7 in mouse and TLR8 in human dendritic cells and macrophages, as described in Example 3.
[0011] FIGS. 4A-4K show single agent efficacy of a HER2-TLR7 (mouse surrogate for human HER2-TLR8) in an in vivo xenograft mouse model, as described in 25 Example 4. The arrows indicate the day a dose was administered to the mice. Slopes of growth curves contrasting unconjugated HER2 mAb against HER2-TLR7 are significantly different (p < 0.001) at each dose level.
3
4 [0012] FIGS. SA-5B show the upregulation of PD-Li on the surface of HER2-expressing tumor cells following treatment with the HER2-TLR8 surrogate, HER2-TLR7, 48 hours after: (FIG. 5A) a single dose or (FIG. 5B) the third of three doses, as described in Example 5.
5 100131 FIGS. 6A-6C show (FIG. 6A) 1P10 expression and 1FN-y expression at day 2 (FIG. 6B) and day 7 (FIG. 6C) in EMT6 tumors from mice treated once with HER2-TLR7 mouse surrogate at 10mg/kg, unconjugated anti-HER2 antibody at 10mg/kg, isotype control antibody at 10mg/kg, each alone or in combination with anti PD-1 antibody, as described in Example 6.
10 [0014] FIGS. 7A-7F show spider plots of the anti-tumor response in mice with HER2+ tumors after treatment with (FIG. 7F) HER2-TLR7 in combination with an anti-PD1 antibody, as compared to treatment with (FIG. 7A) combinations of isotype control antibodies (r1gG2a and mIgG2a, (FIG. 7B) mIgG2a/HER2 mAb, (FIG. 7C) mIgG2a/HER2-TLR7, (FIG. 7D) anti-PD1/mIgG2a, or (FIG. 7E) anti-PDI/HER2 mAb, 15 as described in Example 7.
00151 FIGS. 8A-8B show the interactions of HER2-TLR8 and hz4D5 with monomeric human HER2 ECD were evaluated using Octet Red 96TM in 2 orientations FIG. 8A shows monomeric human HER2 ECD with 10x histidine tag immobilized to penta-his sensor used to capture HER2-TLR8 until saturation and then tested for 20 additive binding against itself, HER2-TLR8 (solid line), or hz4D5 (broken line).
Increased signal of hz4D5 is observed after ITER2-TLR8 has saturated HER2 ECD
indicates HER2-TLR8 and hz4D5 occupy different epitopes on HER2 EGO_ FIG. 8B
is the same assay set-up as in FIG. 8A, except with hz4D5 captured until saturation and then tested for additive binding against itself, hz4D5 (broken line), or HER2-25 (solid line). Increased signal of HER2-TLR8 is observed after hz4D5 has saturated HER2 ECD additionally indicates HER2-TLR8 and hz4D5 occupy different epitopes on HER2 ECD.
[0016] FIG. 9 shows that the HER2-TLR8 agonist conjugate does not impede the function of the trastuzumab-like antibody, hz4D5, of reducing tumor cell viability in 30 vitro, as described in Example 9.

[0017] FIGS. 10A-10F. FIGS. 10A-10D show TNF-a production in co-cultures of various HER2+ (FIGS. 10A-10C) or HER2- (FIG. 10D) tumor cell lines and PBMCs contacted with HER2-TLR8, unconjugated trastuzumab-like anti-HER2 antibody, and a combination of both, as described in Example 10. FIGS. 10E-10F
show 5 IFN-y expression in co-cultures of a HER2+ (FIG. 10E) or HER2- (FIG. 10F) tumor cell line and PBMCs contacted with HER2-TLR8, unconjugated trastuzumab-like anti-HER2 antibody, and a combination of both, as described in Example 10.
[0018] FIGS. 11A-11F show spider plots of an anti-tumor response in SC1D
mice with HER2+ NCI N87 tumors following treatment with 10 mg/kg HER2-TLR7, 10 matched unconjugated HER2 mAb, or isotype control antibody, alone or in combination with the trastuzumab-like antibody, hz4D5. The arrows indicate dose administration.
[0019] FIGS. 12A-12F show that HER2-TLR7 surrogate in combination with trastuzumab-like monoclonal antibody, hz4D5, results in enhanced efficacy over the 15 single agents alone, as described in Example 12. Arrows indicate day dose was administered.
DETAILED DESCRIPTION
[0020] Immune checkpoint inhibition therapy has been largely ineffective as single agent therapies in tumors, in part due to the absence of a T cell infiltrate. An 20 abundant myeloid cell population within checkpoint refractory tumors provides an attractive target with the potential to expand and recruit tumor-specific cytotoxic T
lymphocytes (CTLs). Single agent therapies for chronic viral infections, such as Hepatitis B virus (HBV) and Hepatitis C virus (HCV), have been equally ineffective.
The present disclosure demonstrates for the first time that in vivo treatment with a 25 TLR8 agonist, when conjugated to an antibody, drives anti-tumor or anti-viral immunity, which in turn results in PD-Li upregulation, a negative regulator of T cell activation. This PD-Li induction is expected to be in the tumor microenvironment or in infected liver. The combination of immune checkpoint inhibitor and TLR8 agonist antibody conjugate results in a more profound T cell response as demonstrated by 30 enhanced 1FN-y production and ultimately enhanced efficacy compared to either agent alone. In addition, in the context of an immune competent tumor-bearing mouse, a TLR7 agonist (used as a TLR8 agonist surrogate) conjugated to an anti-HER2 antibody caused an expansion in intra-tumoral, neo-antigen specific CD8+ T cells and robust myeloid cell activation. In the case of HER2+ disease and given the current standard of 5 care for patients with HER2+ disease often includes HER2-directed agents that show clinical benefit, the ability of a TLR8 agonist conjugated to an anti-HER2 antibody to combine with HER2 directed agents to further lower tumor burden, as provided in the present disclosure, is expected to be clinically useful.
[0021] Additional aspects and advantages of the present disclosure will become 10 apparent to those skilled in this art from the following detailed description, wherein illustrative aspects of the present disclosure are shown and described. As will be appreciated, the present disclosure is capable of other and different aspects, and its several details are capable of modifications in various respects, all without departing from the disclosure. Accordingly, the descriptions are to be regarded as illustrative in 15 nature, and not as restrictive.
[0022] As used herein, a "tumor associated antigen" or "tumor antigen" refers to an antigen present on a cancer cell that can be recognized by an antibody and is preferentially present on a cancer cell as compared to normal (non-cancerous) cells.
[0023] As used herein, the term "antibody" refers to an immunoglobulin 20 molecule that specifically binds to, or is immunologically reactive toward, a specific antigen The portion of the antibody that binds a specific antigen may be referred to as an "antigen binding domain." The term antibody can include, for example, polyclonal, monoclonal, genetically engineered, and antigen binding fragments thereof An antibody can be, for example, murine, chimeric, humanized, a heteroconjugate, 25 bispecific, diabody, triabody, or tetrabody. An antigen binding fragment can include, for example, a Fab', F(a13')2, Fab, Fv, rIgG, scFv, hcAbs (heavy chain antibodies), a single domain antibody, Vim, VNAR, sdAbs, or nanobody.
[0024] As used herein, "recognize" refers to the specific association or specific binding between an antigen binding domain and an antigen. Specific association or 30 specific binding does not require that the antigen binding domain does not associate
6 with or bind to any other antigen, but rather that it preferentially associates with or binds to the antigen, as compared to association with or binding to an unrelated antigen.
[0025] As used herein, "specifically binds" and the like refers to the specific association or specific binding between the antigen binding domain and the antigen, as 5 compared with the interaction of the antigen binding domain with a different antigen (i.e., non-specific binding). In some embodiments, an antigen binding domain that recognizes or specifically binds to an antigen has a dissociation constant (ICD) of <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g. 104 M or less, e.g.
from M to 10' M, e.g., from 104 M to 1043 M). Specific binding does not require that 10 the antigen binding domain does not associate with or bind to any other antigen, but rather that it preferentially associates with or binds to the antigen, as compared to association with or binding to an unrelated antigen.
[0026] As used herein, an "Fc domain" refers to a domain from an Fc portion of an antibody that can specifically bind to an Fc receptor, such as a Fcgamma receptor or 15 an FcRn receptor.
00271 As used herein, a "myeloid cell" refers to a dendritic cell, a macrophage, a monocyte, a myeloid derived suppressor cell (VIDSC).
[0028] As used herein, an "antigen presenting cell" or "APC" refers to a cell that can present antigen to a T-, or B-cell, in a productive manner leading to activation 20 and/or expansion of T-, or B-cell clones specific for said antigen.
Nonlimiting exemplary APCs include dendritic cells, macrophages, monocytes, and B cells.
In some embodiments, an antigen presenting cell is a dendritic cell, a macrophage, or a monocyte.
[0029] As used herein, an "immune stimulatory compound" is a compound that 25 activates or stimulates an immune cell, such as a myeloid cell or an APC.
[0030] As used herein, a "myeloid cell agonist" refers to a compound that activates or stimulates an immune response by a myeloid cell.
[0031] As used herein, a "benzazepine compound" refers to small molecule chemical compound comprising a benzazepine moiety, where the benzazepine moiety is 30 a benzene ring fused to a 7-membered ring that comprises one or two nitrogen ring members. In addition to the bond where the ring is fused to the benzene ring, the 7-
7 membered ring includes two double bonds (e.g., an azepine or diazepine ring), one double bond (e.g., a dihydroazepine or dihydro-diazepine ring), or no double bonds (e.g., a tetrahydroazepine, azepane, tetrahydrodiazepine, or diazepane ring).
The benzazepine moiety is optionally substituted. In some embodiments, the benzazepine 5 moiety is an optionally substituted 4,5-dihydro-3H-benzo[b]azepine. In some embodiments, the benzazepine moiety has the structure:

wherein = is a double bond or a single bond;
L2 is selected from -X2-, -X2-CI-6 alkylene-X2-, -X2-C24 alkenylene-X2-, and -10 X2-C24 alkynylene-X2-, each of which is optionally substituted on alkylene, alkenylene or alkynylene with one or more Itn;
X2 at each occurrence is independently selected from a bond, -0-, -S-, -N(R10)-, -C(0)-, -C(0)0-, -0C(0)-, -0C(0)0-, -C( ) _ C(0)N(R1 )C(0)-, -C(0)N(Rio)C(o)N(aio), _ ty) N(R1 )C(0)N(R1 )-, -N(R1 )C(0)0-, 15 -0C(0)N(Rio)Th _0(NRio)-, ) -C(NR")N(R1 )-, -N(IVIC(NWIN(R1 )-, -S(0)2-, -0S(0)-, -S(0)0-, -S(0), -OS(0)2-, -S(0)20, -N(R")S(0)2-, -S(0)2N(10 )-, -N(RnS(0)-, -S(0)N(R")-, -N(11.1 )S(0)2N(R1 )-, and le2 is independently selected at each occurrence from halogen, -OR", -SR", 20 -N(R1 )2, -C(0)R1 , -C(0)N(R1 )2, -N(R1 )C(0)R", -C(0)0R", -0C(0)R", -S(0)R", -S(0)210 , -P(0)(0R1 )2, -0P(0)(010 )2, -NO2, =0, =S, =N(R"), and -CN; Ci.-to alkyl, C2-10 alkenyl, C2-lo alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR", -SR", -N(R10)2, -C(0)10 , -C(0)N(12.1 )2, -N(R")C(0)R1 , -C(0)011", -0C(0)R1 , -S(0)11.1 , -S(0)211.1 , 25 -P(0)(oRich2 ), -0P(0)(010 )2, -NO2, =0, =S, =N(R"), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle in R12 is optionally substituted with one or more substituents independently selected from halogen, -OR", -S111 , -N(R1 )2, -C(0)R10, -C(0)N(12.10)2, -N(11.1 )C(0)R", -C(0)011", -0C(0)11.1 ,
8 -S(0)Rm, -S(0)2R10, -P(0)(0111 3)2, -0P(0)(012.1 )2, -NO2, =0, =S, =N(Rm), -CN, CI-6 alkyl, C2-6 alkenyl, C2.6 alkynyl;
R4 is selected from: -OW , -N(Rto)2, _c(0)N(R10)2, _goAto, _C(0)0R1 , -S(0)11.1 , and -S(0)2R1 ; Ct-to alkyl, C2-10 alkenyl, C2-to alkynyl, each of which is 5 optionally substituted with one or more substituents independently selected from halogen, -ORm, -C(0)N(R1 )2, -N(11.1 )C(0)Rm, -N(Rm)C(0)N(R1 )2, -Nita 0)2, -C(0)R1 , -C(0)0R1 , -0C(0)R1 , -NO2, =0, =S, =N(R10), -CN, C3-12 carbocycle, and 3-to 12-membered heterocycle; and C3-12 carbocycle, and 3-to 12-membered heterocycle, wherein each C3-12 carbocycle, and 3- to 12-membered heterocycle in le is 10 optionally substituted with one or more substituents independently selected from halogen, -Ole , -Ste , -C(0)N(R111)2, -N(le )C(0)R10, -N(Rm)C(0)N(Rm)2, -Ni(Ro)2, -C(0)R1 , -C(0)0R1 , -0C(0)R1 , -NO2, =0, =S, =N(R10), -CN, C2-6 alkenyl, and C2-6 alkynyl; and le is independently selected at each occurrence from hydrogen, -N112, 15 -C(0)0CH2C6H5; and Ci-to alkyl, C2-10 alkenyl, C2-to alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, -C(0)0C1tC6H5, -NHC(0)0CH2C6H5, Ci-to alkyl, -Ct-to haloalkyl, -0-C1-to alkyl, C2-to alkenyl, C2-to alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and haloalkyl;
20 and the moiety is optionally substituted at any position.
[0032] A "small molecule" is an organic compound with a molecular weight of less than 1500, or 100, or 900, or 750, 01 600, or 500 Daltons. In some embodiments, a small molecule agonist has an octanol-water partition coefficient (logP) in the range of from 3 to 6, or from 4 to 5, or from 2 to 4. In some embodiments, a small molecule 25 agonist has a polar surface area of less than 200, or less than 150 A2 In some embodiments, the small molecule agonist has not more than five, or not more than three, hydrogen bond donors, and not more than 10, or not more than three hydrogen bond acceptors. A small molecule myeloid cell agonist is not a protein, a polysaccharide, or a nucleic acid. In some embodiments, a small molecule is an 30 immune checkpoint inhibitor, such as a PD-1 or PD-Li inhibitor, or a HER2 inhibitor.
9 100331 As used herein, the term "conjugate" refers to a polypeptide attached to at least one compound, optionally via a linker(s). In some embodiments, the polypeptide is an antibody or antigen binding fragment thereof.
100341 As used herein, an "immune-stimulatory conjugate" refers to a conjugate 5 that activates or stimulates the immune system or a portion thereof, as determined by an in vitro or in vivo assay.
100351 As used herein, an "immune cell" refers to a T cell, B cell, MC cell, NKT cell, or an antigen presenting cell. In some embodiments, an immune cell is a T
cell, B cell, NK cell, or NKT cell. In some embodiments, an immune cell is an antigen
10 presenting cell. In some embodiments, an immune cell is not an antigen presenting cell.
100361 The terms "salt" or "pharmaceutically acceptable salt" refer to salts derived from a variety of organic and inorganic counter ions well known in the art.
Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, 15 hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, 20 salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary 25 amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
30 100371 The term "Cx-y" when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term "CL-6 alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term ¨Cx-y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For 5 example ¨Ci-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

100381 The terms "Cx-y alkenyl" and "Cx-y alkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, 10 respectively. The term ¨Cx-y alkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, ¨C24 alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term 15 ¨C1-y alkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain. For example, ¨C2-6 alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.
20 100391 "Alkylene" refers to a divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a 25 single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. In other embodiments, an alkylene comprises one to five carbon atoms (i.e., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C t-alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., 30 Ci-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom
11 (i.e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (1.e., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms C2-05 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (La, C3-CS alkylene). Unless stated otherwise specifically in the 5 specification, an alkylene chain is optionally substituted by one or more substituents such as those substituents described herein.
100401 "Alkenylene" refers to a divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon 10 atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. In other embodiments, an alkenylene comprises two to five carbon atoms (La, C2-05 alkenylene). In other embodiments, an alkenylene 15 comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (La, C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (La, C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms 20 (i.e., C3-05 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more substituents such as those substituents described herein.
[0041] "Alkynylene" refers to a divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at 25 least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. In other embodiments, an alkynylene comprises two to 30 five carbon atoms (La, C2-Cs alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (La, C2-C4 alkynylene). In other embodiments, an
12 alkynylene comprises two to three carbon atoms (La, C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (La, C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., Cs-Cs alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms 5 (i.e., C3-05 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more substituents such as those substituents described herein.
[0042] "Heteroalkylene" refers to a divalent hydrocarbon chain including at least one heteroatom in the chain, containing no unsaturation, and preferably having 10 from one to twelve carbon atoms and from one to 6 heteroatoms, e.g., -0-, -NH-, -S-.
The heteroalkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the heteroalkylene chain to the rest of the molecule and to the radical group are through the terminal atoms of the chain. In other embodiments, a heteroalkylene comprises one to 15 five carbon atoms and from one to three heteroatoms. In other embodiments, a heteroalkylene comprises one to four carbon atoms and from one to three heteroatoms In other embodiments, a heteroalkylene comprises one to three carbon atoms and from one to two heteroatoms. In other embodiments, a heteroalkylene comprises one to two carbon atoms and from one to two heteroatoms. In other embodiments, a 20 heteroalkylene comprises one carbon atom and from one to two heteroatoms. In other embodiments, a heteroalkylene comprises five to eight carbon atoms and from one to four heteroatoms. In other embodiments, a heteroalkylene comprises two to five carbon atoms and from one to three heteroatoms. In other embodiments, a heteroalkylene comprises three to five carbon atoms and from one to three heteroatoms. Unless stated 25 otherwise specifically in the specification, a heteroalkylene chain is optionally substituted by one or more substituents such as those substituents described herein.
[0043] The term "carbocycle" as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle includes 3-to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered 30 bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g.,
13 phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. A bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. A
bicyclic carbocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems.
Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. The term "unsaturated carbocycle" refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles.
Examples 10 of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.
100441 The term "heterocycle" as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, 0, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings.
A
15 bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-20 6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. The term "unsaturated heterocycle" refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine.
25 100451 The term "heteroaryl" includes aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two 30 adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic. Heteroaryl groups
14 include, for example, pyrrole, fman, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
[0046] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., -NH-, of the 5 structure. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, 10 substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched,
15 carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
20 [0047] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N-NH2), -Rb-011.a, -11.11-0C(0)-1e, -RP-OC(0)-0W, -1e-OC(0)-N(Ra)2, -PP-N(Ril)2, -le-C(0)1e, 4e-C(0)01e, -Rb-C(0)N(R12, -Rb-O-Itc-C(0)N(Ra)2., -Rb-N(Ra)C(0)0Ra, -R1-25 N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -ltb-S(0),Ra (where t is 1 or 2), -Rb-S(0),011a (where t is 1 or 2), and -R1'-S(0)iN(Ita)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalky1, 30 haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N-NH2), -Rb-011.a, -Rb-OC(0)-1e, -Rb-OC(0)-01ta, -11.6-0C(0)-N(R12, -170-N(R12, -Rb-C(0)W, -Rb-C(0)0170, -Rb-C(0)N(1112, -Rb-O-Itc-C(0)N(Ra)2, -Rb-N(RIC(0)01e, -Rb-N(RIC(0)re, -Rb-NatiS(0)tRa (where t is 1 or 2), -R1'-S(0)rita (where t is 1 or 2), -Rb-S(0)rOW (where t is 1 or 2) and -Rb-S(0)tN(W)2 (where t is 1 or 2); wherein each 11.3 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each W, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-011), hydrazine (=N-NH2), -Rb-OW, -Rb-OC(0)-W, -Rb-OC(0)-011.a, -Rb-OC(0)-N(W)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -10-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-O-Re-C(0)N(Ra)2, -Rb-N(W)C(0)0Ra, -Rb-N(W)C(0)10, -le-N(10)8(0)tR' (where t is 1 or 2), -Rb-S(0)rR3 (where t is 1 or 2), -Rb-S(0)tOR3 (where t is 1 or 2) and RP-S(0)tN(Ra)2 (where t is 1 or 2); and wherein each Itb is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each RC is a straight or branched alkylene, alkenylene or alkynylene chain.
100481 It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as "unsubstituted,"
references to chemical moieties herein are understood to include substituted variants.
For example, reference to a "heteroaryl" group or moiety implicitly includes both substituted and unsubstituted variants.
[0049] In addition, it should be understood that the individual compounds (e.g., proteins), or groups of compounds, derived from the various combinations of the structures and substituents (e.g., domains, regions or peptide components) described herein, are disclosed by the present application to the same extent as if each compound or group of compounds was set forth individually. Thus, selection of particular structures or particular substituents is within the scope of the present disclosure.
100501 Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.
16 [0051] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The 5 exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include.
v ar1; \AAA 9 H H
µ3, H
\ NH 2 \ NH \NA H
\CA-NA
H
cr's tie --- :ra N I
N,N
HN¨Nõ1\1---1 NH
N
,sst N '1/41 s e`r4 t e E
OH

[0052] The phrases "intravenous administration" and "administered intravenously" as used herein refer to injection or infusion of a conjugate into a vein of a subject.
[0053] The phrases "intravenous slow infusion" and "IV slow infusion" as used here refer to an intravenous infusion that results in a Tmax of about 4 hours or more.
[0054] The phrases "subcutaneous administration," "subcutaneously administering" and the like refer to administration of a conjugate into the subcutis of a 15 subject. For clarity, a subcutaneous administration is distinct from an intratumoral injection into a tumor or cancerous lesion located in the subcuta.
[0055] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human
17 beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
[0056] As used herein, "identical" or "identity" refer to the similarity between a DNA, RNA, nucleotide, amino acid, or protein sequence to another DNA, RNA, 5 nucleotide, amino acid, or protein sequence. Identity can be expressed in terms of a percentage of sequence identity of a first sequence to a second sequence.
Percent (%) sequence identity with respect to a reference DNA sequence can be the percentage of DNA nucleotides in a candidate sequence that are identical with the DNA
nucleotides in the reference DNA sequence after aligning the sequences. "Percent (%) sequence 10 identity with respect to a reference amino acid sequence can be the the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. The 15 percentage sequence identity values can be generated using the NCBI
BLAST 2.0 software as defined by Altschul et a/. (1997) "Gapped BLAST and PSI-BLAST. a new generation of protein database search programs," Nucleic Acids Res. 25:3389-3402, with the parameters set to default values.
[0057] The term "about" as used herein in the context of a number refers to a 20 range centered on that number and spanning 10% less than that number and 10% more than that number. The term "about" used in the context of a range refers to an extended range spanning 10% less than that the lowest number listed in the range and 10% more than the greatest number listed in the range.
[0058] In the present description, any concentration range, percentage range, 25 ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness, are to be understood to include any integer within the recited range, unless 30 otherwise indicated. It should be understood that the terms "a" and "an"
as used herein refer to "one or more" of the enumerated components. The use of the alternative (e.g.,
18 "of') should be understood to mean either one, both, or any combination thereof of the alternatives. As used herein, the terms "include" and "comprise" are used synonymously.
100591 The phrase "at least one of" when followed by a list of items or 5 elements refers to an open ended set of one or more of the elements in the list, which may but does not necessarily include more than one of the elements.
Exemplary Antibodies [0060] In some embodiments, a conjugate as described herein comprises an antibody. In some such embodiments, the antibody comprises one or more antigen 10 binding domains and an Fc domain, wherein each antigen binding domain specifically binds to an antigen. An antibody can have, for example, a first antigen binding domain that specifically binds to a first antigen, a second antigen binding domain that specifically binds to a second antigen, and an Fc domain. In various embodiments, an antibody can include two antigen binding domains, in which each antigen binding 15 domain recognizes the same epitope on the antigen. An antibody can include two antigen binding domains in which each antigen binding domain recognizes a different epitope of the same antigen. An antibody can include two antigen binding domains in which each antigen binding domain recognizes different antigens. In various embodiments, an antibody has one antigen binding domain. In various embodiments, 20 an antigen binding domain may comprise, for example, a heavy chain variable domain (VH) and a light chain variable domain (VL), or in the case of a heavy-chain only antibody, a VHH
[0061] Nonlimiting exemplary tumor antigens that may be bound by a polypeptide, such as an antibody, include CD5, CD25, CD37, CD33, CD45, BCMA, 25 CS-1, PD-L1, 87-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUD, folate-binding protein (FOLR1), A33, G250 (carbonic anhydrase IX), prostate-specific membrane antigen (PSMA), G02, GD3, GM2, Ley, CA-125, CA19-9 (MUC1 sLe(a)), epidermal growth factor, HER2, IL-2 receptor, EGFRvIll (de2-7 EGFR), fibroblast activation protein (FAP), a tenascin, a 30 metalloproteinase, endosialin, avB3, LMP2, EphA2, PAP, AFP, ALK, polysialic acid,
19 TRP-2, fucosyl GM1, mesothelin (MSLN), PSCA, sLe(a), GM3, BORIS, Tn, TF, GloboH, STn, CSPG4, AKAP-4, SSX2, Legumain, Tie 2, Tim 3, VEGFR2, PDGFR-B, ROR2, TRA1L1, MUC16, EGFR, CMET, HER3, MUC1, MUC15, CA6, NAPI2B, CLDN182, RON, LY6E, FRAlpha, DLL3, PTK7, LIV1, ROR1, CLDN6, GPC3, 5 ADAM12, LRRC15, CDH6, TMEFF2, TMEM238, GPNMB, ALPPL2, UPK1B, UPK2, LAMP-1, LY6K, EphB2, STEAP, ENPP3, CDH3, Nectin4, LYPD3, EFNA4, GPA33, SLITRK6, and HAVCRL
[0062] In certain embodiments, the tumor antigen is selected from HER2, Nectin4, MSLN, LIV-1, MUC16, CEACAM1, CEACAM3, CEACAM4, CEACAM5, CEACAM6, CEACAM7, CEACAM8, CEACAM16, CEACAM18, CEACAM19, CEACAM20, CEACAM21, VEGFR1, VEGFR2, MUC1, PSMA, PSA, M1JC-2, and [0063] In certain embodiments, a polypeptide, such as an antibody, specifically binds to a non-proteinaceous or glycoantigen, such as GD2, GD3, GM2, Ley, polysialic 15 acid, fucosyl GM1, GM3, Tn, STn, sLe(animal), or GloboH.
[0064] In certain embodiments, a polypeptide, such as an antibody, specifically binds to a solid tumor antigen. In some embodiments, the solid tumor antigen is preferentially present on sarcoma or carcinoma cell(s). In some embodiments, the solid tumor antigen is preferentially present on a sarcoma cell(s). In some embodiments, the
20 solid tumor antigen is preferentially present on a carcinoma cell(s).
[0065] In some embodiments, the solid tumor antigen is present on cells of a brain, breast, lung, liver, kidney, pancreatic, colorectal, ovarian, head and neck, bone, skin, mesothelioma, bladder, stomach, prostate, thyroid, uterine or cervical/endometrial cancer.

[0066] In some embodiments, the solid tumor antigen is an antigen present on breast cancer, such as HER2, LIV-1, CDH3 (p-cadherin), MUC1, Sialo-epitope CA6, PTX.7, GPNMB, LAMP-1, LRRC15, ADAM12, EPHA2, TNC, LYPD3, EFNA4, Nectin-4, and CLDN6.
[0067] In some embodiments, the solid tumor antigen is an antigen present on 30 brain cancer, such as EGFRAII, TNC and DLL-3.

[0068] In some embodiments, the solid tumor antigen is an antigen present on lung cancer, such as mesothelin, HER2, EGFR, PD-L1, MSLN, LY6K, CD56, PTK7, FOLR1, DLL3, SLC34A2, CECAM5, MUC16, LRRC15, ADAM12, EGFRAII, LYPD3, EFNA4, Nectin-4, and MUCl.

[0069] In some embodiments, the solid tumor antigen is an antigen present on liver cancer, such as GPC3, EPCAM, and CECAM5.
[0070] In some embodiments, the solid tumor antigen is an antigen present on kidney cancer, such as HAVCR1, ENPP3, CDH6, CD70, and cMET.
100711 In some embodiments, the solid tumor antigen is an antigen present on 10 pancreatic cancer, such as PTK7, MUC16, MSLN, LRRC15, ADAM12, EFNA4, MUC5A, Nectin-4, and MUCl.
[0072] In some embodiments, the solid tumor antigen is an antigen present on colorectal cancer, such as EPHB2, TMEM238, CECAM5, LRRC15, Nectin4, ADAM12, EFNA4 and GPA33.

[0073] In some embodiments, the solid tumor antigen is an antigen present on ovarian cancer, such as M1JC16, MUC1, MSLN, FOLR1, sTN, VTCN1, HER2, PTK7, FAP, TMEM238, LRRC15, CLDN6, SLC34A2 and EFNA4.
[0074] In some embodiments, the solid tumor antigen is an antigen present on head and neck cancer, such as LY6K, PTK7, LRRC15, ADAM12, LYPD3, Nectin4, 20 EFNA4 and TNC.
[0075] In some embodiments, the solid tumor antigen is an antigen present on bone cancer, such as EPHA2, LRRC15, ADAM12, GPNMB, TP-3 and CD248.
[0076] In some embodiments, the solid tumor antigen is an antigen present on mesothelioma, such as MSLN.

[0077] In some embodiments, the solid tumor antigen is an antigen present on bladder cancer, such as LY6K, PTK7, UPK1B, UPK2, TNC, Nectin4, SLITRK6, LYPD3, EFNA4 and HER2.
[0078] In some embodiments, the solid tumor antigen is an antigen present on stomach/gastric cancer, such as HER2, EPHB2, TMEM238, CECAM5 and EFNA4.
21 [0079] In some embodiments, the solid tumor antigen is an antigen present on prostate cancer, such as PSMA, FOLH1, PTK7, STEAP, T1M-EFF2 (TENB2), 0R51E2, SLC30A4 and EFNA4.
100801 In some embodiments, the solid tumor antigen is an antigen present on 5 thyroid cancer, such as PTK7.
[0081] In some embodiments, the solid tumor antigen is an antigen present on uterine cancer, such as present on uterine cancer such as LY6K, PTK7, EPHB2, FOLR1, ALPPL2, M1JC16, Nectin-4, and EF1sTA4.
[0082] In some embodiments, the solid tumor antigen is an antigen present on 10 cervical/endometrial cancer, such as LY6K, PTK7, MUC16, LYPD3, EFNA4, Nectin-4, and MUCl.
[0083] In some embodiments, the solid tumor antigen is an antigen present on a sarcoma, such as LRRC15.
[0084] In some embodiments, the tumor antigen is HER2. In some aspects, the 15 HER2 antigen is expressed for example, on a lung, colorectal, ovarian, bladder, stomach/gastric, or breast cancer cell.
[0085] In some aspects, the antigen is a liver cell antigen. In some aspects, the liver cell antigen is expressed on a canalicular cell, Kupffer cell, hepatocyte, or any combination thereof. In some aspects, the liver cell antigen is a hepatocyte antigen. In 20 some aspects, the liver cell antigen is selected from the group consisting of ASGR1 (asialoglycoprotein receptor 1), ASGR2 (asialoglycoprotein receptor 2), TRF2, UGT1A1, SLC22A7, SLC13A5, SLC22A1, and C9. In some aspects, the liver cell antigen is selected from the group consisting of ASGR1, ASGR2, and TRF2. In some aspects, the liver cell antigen is expressed on a liver cell infected with a virus selected 25 from the group consisting of HBV and HCV.
[0086] In some aspects, the antigen is a viral antigen from a virus selected from the group consisting of HBV and HCV. In some aspects, the viral antigen is an HBV
antigen. In some aspects, the viral antigen is HBsAg, HBcAg, or HBeAg. In some aspects, the viral antigen is HBsAg.
30 100871 In some embodiments, an antibody comprises an antigen binding domain and an Fc domain. In some embodiments, an antibody comprises two light chain
22 polypeptides (light chains) and two heavy chain polypeptides (heavy chains), held together covalently by disulfide linkages. The heavy chain typically comprises a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CHI, CH2, and CH3. An Fc domain 5 typically comprises heavy chain CH2 and CH3 domains. The light chain typically comprises a light chain variable region (VL) and a light chain constant region_ The antigen-recognition regions of the antibody variable domains typically comprise six complementarity determining regions (CDRs), or hypervariable regions, that lie within the framework of the heavy chain variable region and light chain variable region at the 10 N-terminal ends of the two heavy and two light chains. The constant domains provide the general framework of the antibody and may not be involved directly in binding the antibody to an antigen, but can be involved in various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity (ADCC).
100881 An antibody can be any class, e.g., IgA, IgD, IgE, IgG, and Ig.M.
15 Certain classes can be further divided into isotypes, e.g., IgGl, IgG2, IgG3, IgG4, IgAl , and IgA2. The heavy-chain constant regions that correspond to the different classes of immunoglobulins can be a, 6, e, y, and p., respectively. The light chains can be either kappa (or K) or lambda (or X).
100891 In some embodiments an antigen binding domain comprises a light chain 20 complementary determining region 1 (LCDRI), a light chain complementary determining region 2 (LCDR2), a light chain complementary determining region 3 (LCDR3), a heavy chain complementary determining region 1 (HCDR1), a heavy chain complementary determining region 2 (HCDR2), and a heavy chain complementary determining region 3 (HCDR3). In some embodiments, an antibody may be a heavy-25 chain only antibody, in which case the antigen binding domain comprises HCDRI, HCDR2, and HCDR3, and the antibody lacks a light chain. Unless stated otherwise, the CDRs described herein can be defined according to the 'MGT (the international ImMunoGeneTics information) system.
100901 An antibody can be chimeric or humanized. Chimeric and humanized 30 forms of non-human (e.g., murine) antibodies can be intact (full length) chimeric immunoglobulins, immunoglobulin chains or antigen binding fragments thereof (such
23 as Fv, Fab, Fab', F(abl2 or other target-binding subdomains of antibodies), which can contain sequences derived from non-human immunoglobulin. In general, the humanized antibody can comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to 5 those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence. A humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), an Fc domain, typically that of a human immunoglobulin sequence.
[0091] An antibody described herein can be a human antibody. As used herein, 10 "human antibodies" can include antibodies having, for example, the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or from animals transgenic for one or more human immunoglobulins and that typically do not express endogenous immunoglobulins.
Human antibodies can be produced using transgenic mice which are incapable of 15 expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. Completely human antibodies that recognize a selected epitope can be generated using guided selection. In this approach, a selected non-human monoclonal antibody, e.g., a mouse antibody, is used to guide the selection of a completely human antibody recognizing the same epitope 20 100921 An antibody described herein can be a bispecific antibody or a dual variable domain antibody (DVD). Bispecific and DVD antibodies are monoclonal, often human or humanized, antibodies that have binding specificities for at least two different antigens.
[0093] An antibody described herein can be derivatized or otherwise modified.
25 For example, derivatized antibodies can be modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, or the like.
[0094] An antibody described herein can specifically bind to a cancer antigen.

An antibody can specifically bind to a solid tumor antigen.
30 100951 In some embodiments, the antibody may comprise the CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to thellVIGT
24 system), antigen binding fragment (e.g., the variable regions), or the entire heavy and light chains of an antibody selected from trastuzumab, cetuximab, panitumumab, ofatumumab, belimumab, ipilimumab, pertuzumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, MDX-1105 (PCT Publication No. WO 2007/005874), 5 dacetuzumab, urelumab, MPDL3280A, lambroliz-umab, blinatumomab, nimotuzumab, zalutumumab, onartuzumab, patritumab, clivatuzumab, sofituzumab, edrecolomab, adecatumumab, anetumab, huDS6, lifastuzumab, PRI A3, humanized PRI A3, humanized Ab2-3, claudiximab, AMG595, ABT806, sibrotuzumab, DS-8895a variant 1, DS-8895a variant 2, MEDI-547, namatumab, RG7841, farletuzumab, mirvetuximab, 10 J591 variant 1, J591 variant 2, rovalpituzumab, PF-06647020, ladiratuzumab, cirmtuzumab, ladiratuzumab, huLiv1-14 (PCT Publication No. WO 2012/078688), Liv1-1.7A4 (US Patent Publication No. 2011/0117013), huLiv1-22 (PCT
Publication No. WO 2012078688), 4H11 (US Patent Publication No. 2013/0171152), 4115 (US
Patent Publication No. 2013/0171152), glembatumumab, oportuzumab, enfortumab, 15 depatuxizumab, the antibody of ASG-15ME, huM25 (PCT Publication No.
W02017/095808A1), and codrituzumab.
100961 In some embodiments, the antibody may comprise the CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to the [MGT
system), the antigen binding fragment (e.g., variable regions), or the entire heavy and 20 light chains of an antibody selected from pertuzumab, trastuzumab, and ladiratuzumab, or biosimilar thereof.
100971 In some such embodiments, the anti-HER2 antibody of the conjugate comprises heavy chain (LC)-CDR1, HC-CDR2, HC-CDR3, light chain (LC)-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 1-6, respectively. In further embodiments,
25 the anti-HER2 antibody of the conjugate comprises a heavy chain and light chain, wherein: (a) the heavy chain comprises HC-CDR1, HC-CDR2, and HC-CDR3 of SEQ
ID NOs: 1-3, respectively, and comprises a heavy chain variable region (VH) having an amino acid sequence that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 30 99.5%, or 100% identity to the VH amino acid sequence of SEQ ID NO: 7;
and (b) the light chain comprises LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ED NOs: 4-6, respectively, and a light chain variable region (VI.) having an amino acid sequence that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100%
identity to the VL amino acid sequence of SEQ ID NO: 8. In still further embodiments, the anti-5 HER2 antibody of the conjugate comprises a Vir comprising or consisting of the amino acid sequence of SEQ ID NO: 7 and a N/L, comprising or consisting of the amino acid sequence of SEQ ID NO: 8. In yet further embodiments, the anti-HER2 antibody of the conjugate comprises a heavy chain and light chain, wherein: (a) the heavy chain comprises HC-CDR1, HC-CDR2, and HC-CDR3 of SEQ ID NOs: 1-3, respectively, 10 and comprises an amino acid sequence that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100% identity to the heavy chain amino acid sequence of SEQ
ID NO: 9; and (b) the light chain comprises LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 4-6, respectively, and an amino acid sequence that has at least 90%, at 15 least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100% identity to the light chain amino acid sequence of SEQ ID NO: 10. In more embodiments, the anti-HER2 antibody of the conjugate comprises a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 9 and a light chain comprising or consisting of the 20 amino acid sequence of SEQ ID NO: 10.
100981 In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a 25 light chain comprising the amino acid sequence of SEQ ID NO: 10.
00991 In some embodiments, an antibody specifically binds to a breast cancer antigen. In some such embodiments, the antibody may comprise the CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to the IMGT
system), antigen binding fragment (e.g., the variable regions), or the entire heavy and 30 light chains of an antibody selected from trastuzumab, pertuzumab, ladiratuzumab, huLiv1-14 (PCT Publication No. WO 2012/078688), Liv1-1,7A4 (US Patent
26 Publication No. 2011/0117013), huLiv1-22 (PCT Publication No. WO 2012078688), huDS6, glembatumumab, PF-0664720, MEDI-547, DS-8895a variant 1, and DS-08895a variant 2.
101001 In some embodiments, an antibody specifically binds to an antigen 5 present on brain cancer cells. In some such embodiments, the antibody may comprise the CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to the IMGT system), antigen binding fragment (e.g., the variable regions), or the entire heavy and light chains of an antibody selected from 4MG595, A8T806, rovalpituzumab or depatuxizumab.
10 01011 In some embodiments, an antibody specifically binds to an antigen present on lung cancer cells. In some such embodiments, the antibody may comprise the CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to the IMGT system), antigen binding fragment (e.g., the variable regions), or the entire heavy and light chains of an antibody selected from panitumumab, cetuximab, 15 pembrolizumab, nivolumab, atezolizumab, nimotuzumab, lifastuzumab, anetumab, PF-0664720, farletuzumab, rovalpituzumab, lifastuzumab, sofituzumab, huDS6, ABT806, AMG595, and huM25 (PCT Publication No. W02017/095808A1).
[0102] In some embodiments, an antibody specifically binds to an antigen present on liver cancer. In some such embodiments, the antibody may comprise the 20 CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to the IMGT system), antigen binding fragment (e.g., the variable regions), or the entire heavy and light chains of an antibody selected from codrituzumab, oportuzumab, and humanized PR1A3.
[0103] In some embodiments, an antibody specifically binds to an antigen 25 present on kidney cancer. In some such embodiments, the antibody may comprise the CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to the IMGT system), antigen binding fragment (e.g., the variable regions), or the entire heavy and light chains of an antibody selected from AGS-16M8F, AGS-16C3, the antibody of CDX-014, and onartuzumab.
30 101041 In some embodiments, an antibody specifically binds to an antigen present on pancreatic cancer. In some such embodiments, the antibody may comprise
27 the CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to the IMGT system), antigen binding fragment (e.g., the variable regions), or the entire heavy and light chains of an antibody selected from PF-0664720, clivatuzumab, 4HI1 (US Patent Publication No. 2013/0171152), 4H5 (US Patent 5 Publication No. 2013/0171152), anetumumab, huDS6, sofituzumab, huM25 (PCT
Publication No. W02017/095808A1), and RG7841.
101051 In some embodiments, an antibody specifically binds to an antigen present on colorectal cancer. In some such embodiments, the antibody may comprise the CDRs (such as LCDRI, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, 10 according to the IMGT system), antigen binding fragment (e.g., the variable regions), or the entire heavy and light chains of an antibody selected from huM25 (PCT
Publication No. W02017/095808A1), PR1A3, humanized PR1A3, pantumumab, cetuximab, nimotuzumab, and zalutumumab.
[0106] In some embodiments, an antibody specifically binds to an antigen 15 present on ovarian cancer. In some such embodiments, the antibody may comprise the CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to the IMGT system), antigen binding fragment (e.g., the variable regions), or the entire heavy and light chains of an antibody selected from sofituzumab, 41111 (U.S.
Patent Publication No. 2013/0171152, 4H5 (U.S. Patent Publication No. 2013/0171152), 20 huDS6, farletuzumab, anetumab, trastuzumab, pertuzumab, PF-0664720, sibrotuzumab, huM25 (PCT Publication No. W02017/095808A1), and lifastuzumab.
[0107] In some embodiments, an antibody specifically binds to an antigen present on head and neck cancer. In some such embodiments, the antibody may comprise the CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, 25 according to the IMGT system), antigen binding fragment (e.g., the variable regions), or the entire heavy and light chains of an antibody selected from cetuximab, panitumumab, nimtuzumab, PF-0664720, pantumumab, cetuximab, nimotuzumab, and zalutumumab.
[0108] In some embodiments, an antibody specifically binds to an antigen present on bone cancer. In some such embodiments, the antibody may comprise the 30 CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to the IMGT system), antigen binding fragment (e.g., the variable regions), or the entire
28 heavy and light chains of an antibody selected from huM25 (PCT Publication No.

W02017/095808A1), DS-8895a variant 1, DS-8895a variant 2, and glembatumab.
[0109] In some embodiments, an antibody specifically binds to an antigen present on skin cancer.
5 [0110] In some embodiments, an antibody specifically binds to an antigen present on mesothelioma.
[0111] In some embodiments, an antibody specifically binds to an antigen present on cervical/endometrial cancer. In some such embodiments, the antibody may comprise the CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, 10 according to the IMGT system), antigen binding fragment (e.g., the variable regions), or the entire heavy and light chains of an antibody selected from PF-0664720, anetumumab, 4H11(US Patent Publication No. 2013/0171152), 4H5 (US Patent Publication No. 2013/0171152), huDS6, and sofituzumab.
[0112] In some embodiments, an antibody specifically binds to an antigen 15 present on bladder cancer. In some such embodiments, the antibody may comprise the CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to the IMGT system), antigen binding fragment (e.g., the variable regions), or the entire heavy and light chains of an antibody selected from enfortumab, trastuz-umab, pertuzumab and SLITRK6.
20 [0113] In some embodiments, an antibody specifically binds to an antigen present on stomach/gastric cancer. In some such embodiments, the antibody may comprise the CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to the [MGT system), antigen binding fragment (e.g., the variable regions), or the entire heavy and light chains of an antibody selected from sofituzumab, anetumab, 25 pertuzumab, trastuzumab, and humanized PR1A3.
[0114] In some embodiments, an antibody specifically binds to an antigen present on prostate cancer. In some such embodiments, the antibody may comprise the CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to the [MGT system), antigen binding fragment (e.g., the variable regions), or the entire 30 heavy and light chains of an antibody selected from mirvetuximab, J591 variant 1, and J591 variant 2.
29 [0115] In some embodiments, an antibody specifically binds to an antigen present on thyroid cancer.
[0116] In some embodiments, an antibody specifically binds to an antigen present on uterine cancer. In some such embodiments, the antibody may comprise the 5 CDRs (such as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3, according to the IMGT system), antigen binding fragment (e.g., the variable regions), or the entire heavy and light chains of an antibody selected from PF-0664720, farletuzumab, sofituzumab, 41111(US Patent Publication No. 2013/0171152, and 4115 (US Patent Publication No. 2013/0171152).
10 [0117] In some embodiments, an antibody specifically binds to an antigen present on a sarcoma, [0118] In some embodiments, an antibody specifically binds to an antigen present on a liver cell and the subject has a viral infection (e.g., HBV or HCV). The antibody can be, for example, an antibody that binds to ASGR1 or ASGR2.
15 Exemplary Fc domains [0119] A polypeptide, such as a fusion protein or an antibody, may comprise an Fc domain. An Fc domain is a structure that can bind to one or more Fe receptors (FcRs). In various embodiments, an Fc domain is from an IgG antibody, such as an IgGl, IgG2, or IgG4 antibody. An Fc domain typically comprises CH2 and CH3 20 domains of a heavy chain constant region, but may comprise more or less of the heavy chain constant region as well.
[0120] An Fc domain can be a domain of an antibody that can bind to an FcR(s). FcRs are organized into classes (e.g., gamma (y), alpha (a) and epsilon (H)) based on the class of antibody that the FcR recognizes The FcaR class binds to IgA
25 and includes several isoforms, Fecal (CD89) and Fca R. The FcyR class binds to IgG
and includes several isoforms, FcyRI (CD64), Fc-yRIIA (CD32a), FcyRIIB
(CD32b), FcyRIIIA (CD16a), and FcyRIBB (CD16b). An Fc-yRIIIA (CD16a) can be an FcyRIRA
(CD16a) F158 variant or a V158 variant. FcRs also can be FcRn receptors.
[0121] Each FcyR isoform can differ in binding affinity to the Fc domain of the
30 IgG antibody. For example, FcyRI can bind to IgG with greater affinity than FcyRII or FcyRIII. The affinity of a particular FeyR isoform to an IgG can be controlled, in part, by a glycan (e.g., oligosaccharide) at position CH2 84.4 of the IgG antibody.
For example, fucose containing CH2 84.4 glycans can reduce IgG affinity for FeyRBIA. In addition, GO glucans can have increased affinity for FcyRIIIA due to the lack of 5 galactose and terminal GIcNAc moiety.
101221 Binding of an Fc domain to an Felt can enhance an immune response.
FcR-mediated signaling that can result from an Fc domain binding to an FcR and can lead to the maturation of immune cells. FcR-mediated signaling that can result from an Fc domain binding to an FcR can lead to the maturation of dendritic cells (DCs). FcR-10 mediated signaling that can result from an Fc domain binding to an FcR
can lead to antibody dependent cellular cytotoxicity. FcR-mediated signaling that can result from an Fc domain binding to an FcR can lead to more efficient immune cell antigen uptake and processing. FcR-mediated signaling that can result from an Fc domain binding to an FcR can promote the expansion and activation of T cells. FcR-mediated signaling 15 that can result from an Fc domain binding to an FcR can promote the expansion and activation of CD8-F T cells FcR-mediated signaling that can result from an Fc domain binding to an FcR can influence immune cell regulation of T cell responses.
FcR-mediated signaling that can result from an Fc domain binding to an FcR can influence dendritic cell regulation of T cell responses. Felt-mediated signaling that can result 20 from an Fc domain binding to an FcR can influence functional polarization of T cells (e.g., polarization can be toward a THI cell response).
01231 An Fc domain can be modified, such as by a modification of the amino acid sequence, to alter the recognition of an FcR for the Fc domain. Such modification(s) may still allow for Felt-mediated signaling, depending on the 25 modification. A modification can be a substitution of an amino acid at a residue of an Fc domain for a different amino acid at that residue. A modification can be an insertion or deletion of an amino acid at a residue of an Fc domain. A modification can permit binding of an FcR to a site on the Fc domain to which the FcR may not otherwise bind.
A modification can increase binding affinity of an FcR to the Fe domain. A
30 modification can decrease binding affinity of an FcR to the Fc domain.
31 101241 An Fe domain can be a variant of a naturally occurring Fc domain (e.g., a wild type Fc domain) and can comprise at least one amino acid change as compared to the sequence of a wild-type Fc domain. An amino acid change in an Fc domain can allow the antibody or conjugate to bind to at least one Fc receptor with greater affinity 5 compared to a wild-type Fc domain. An amino acid change in an Fc domain can allow the antibody or conjugate to bind to at least one Fc receptor with lessor affinity compared to a wild-type Fc domain.
101251 In some embodiments, an Fc domain exhibits increased binding affinity to one or more Fc receptors. In some embodiments, an Fc domain exhibits increased 10 binding affinity to one or more Fcgamma receptors. In some embodiments, an Fc domain exhibits increased binding affinity to FcRn receptors. In some embodiments, an Fc domain exhibits increased binding affinity to Fcgamma and FcRn receptors.
In other embodiments, an Fc domain exhibits the same or substantially similar binding affinity to Fcgamma and/or FeRn receptors as compared to a wild-type Fc domain from an IgG
15 antibody (e.g., IgG1 antibody).
101261 In some embodiments, an Fc domain exhibits decreased binding affinity to one or more Fc receptors. In some embodiments, an Fe domain exhibits decreased binding affinity to one or more Fcgamma receptors. In some embodiments, an Fc domain exhibits decreased binding affinity to FcRn receptors. In some embodiments, 20 an Fc domain exhibits decreased binding affinity to Fcgamma and FcRn receptors. In some embodiments, an Fc domain is an Fc null domain. In some embodiments, an Fc domain exhibits decreased binding affinity to FcRn receptors, but exhibits the same or increased binding affinity to one or more Fcgamma receptors as compared to a wildtype Fe domain. In some embodiments, an Fc domain exhibits increased binding affinity to 25 FeRn receptors, but exhibits the same or decreased binding affinity to one or more Fcgamma receptors.
01271 An Fc domain may have one or more, two or more, three or more, or four or more amino acid substitutions that decrease binding of the Fc domain to an Fc receptor. In certain embodiments, an Fc domain has decreased binding affinity for one 30 or more of FeTRI (CD64), FeyRIIA (CD32), FeyRIIIA (CD16a), FeyRuIB
(CD16b), or any combination thereof. In order to decrease binding affinity of an Fc domain to an Fc
32 receptor, the Fc domain may comprise one or more amino acid substitutions that reduces the binding affinity of the Fc domain to an Fc receptor. In other embodiments, an Fc domain exhibits the same or substantially similar binding affinity to one or more of Fc7RI (CD64), FcyRIIA (CD32), FcyRIIIA (CD16a), (CD16b), or any 5 combination thereof as compared to a wild-type Fc domain from an IgG
antibody (e.g., IgG1 antibody). In some embodiments, an Fc domain can comprise a sequence of an IgG isoform that has been modified from the wild-type IgG sequence. In some embodiments, the Fc domain can comprise a sequence of the IgG1 isoform that has been modified from the wild-type IgG1 sequence. In some embodiments, the 10 modification comprises substitution of one or more amino acids that reduce binding affinity of an IgG Fe domain to all Fey receptors.
[0128] A modification can be substitution of E233, L234 and L235, such as E233P/L234V/L235A or E233P/L234V/L235A1AG236, according to the EU index of Kabat. A modification can be a substitution of P238, such as P238A, according to the 15 EU index of Kabat. A modification can be a substitution of D265, such as D265A, according to the EU index of Kabat. A modification can be a substitution of N297, such as N297A, according to the EU index of Kabat. A modification can be a substitution of A327, such as A327Q, according to the EU index of Kabat. A
modification can be a substitution of P329, such as P239A, according to the EU
index 20 of Kabat.
[0129] In some embodiments, an IgG Fc domain comprises at least one amino acid substitution that reduces its binding affinity to Fc7R1, as compared to a wild-type or reference IgG Fc domain. A modification can comprise a substitution at F241, such as F241A, according to the EU index of Kabat. A modification can comprise a 25 substitution at F243, such as F243A, according to the EU index of Kabat.
A
modification can comprise a substitution at V264, such as V264A, according to the EU
index of Kabat. A modification can comprise a substitution at D265, such as according to the EU index of Kabat.
101301 In some embodiments, an IgG Fc domain comprises at least one amino 30 acid substitution that increases its binding affinity to FeyR1, as compared to a wild-type
33 or reference IgG Fc domain. A modification can comprise a substitution at A327 and P329, such as A327Q/P329A, according to the EU index of Kabat.
[0131] In some embodiments, the modification comprises substitution of one or more amino acids that reduce binding affinity of an Igo Fe domain to FcyRII
and 5 FcyRIIIA receptors. A modification can be a substitution of D270, such as D270A, according to the EU index of Kabat. A modification can be a substitution of Q295, such as Q295A, according to the EU index of Kabat. A modification can be a substitution of A327, such as A237S, according to the EU index of Kabat.
[0132] In some embodiments, the modification comprises substitution of one or 10 more amino acids that increases binding affinity of an IgG Fe domain to FcyRII and FcyRIIIA receptors. A modification can be a substitution of T256, such as T256A, according to the EU index of Kabat. A modification can be a substitution of K290, such as K290A, according to the EU index of Kabat.
[0133] In some embodiments, the modification comprises substitution of one or 15 more amino acids that increases binding affinity of an IgG Fe domain to FicyRII
receptor. A modification can be a substitution of R255, such as R255A, according to the EU index of Kabat. A modification can be a substitution of E258, such as E258A, according to the EU index of Kabat. A modification can be a substitution of S267, such as S267A, according to the EU index of Kabat. A modification can be a substitution of 20 E272, such as E272A, according to the EU index of Kabat. A modification can be a substitution of N276, such as N276A, according to the EU index of Kabat. A
modification can be a substitution of D280, such as D280A, according to the EU
index of Kabat. A modification can be a substitution of 11285, such as H285A, according to the EU index of Kabat. A modification can be a substitution of N286, such as N286A, 25 according to the EU index of Kabat. A modification can be a substitution of T307, such as T307A, according to the EU index of Kabat. A modification can be a substitution of L309, such as L309A, according to the EU index of Kabat. A modification can be a substitution of N315, such as N3 15A, according to the EU index of Kabat. A
modification can be a substitution of K326, such as K326A, according to the EU
index 30 of Kabat. A modification can be a substitution of P331, such as P33 IA, according to the EU index of Kabat. A modification can be a substitution of S337, such as S337A,
34 according to the EU index of Kabat. A modification can be a substitution of A378, such as A378A, according to the EU index of Kabat. A modification can be a substitution of E430, such as E430, according to the EU index of Kabat.
101341 In some embodiments, the modification comprises substitution of one or 5 more amino acids that increases binding affinity of an IgG Fc domain to FicyRII
receptor and reduces the binding affinity to FcyRIIIA receptor. A modification can be a substitution of H268, such as H268A, according to the EU index of Kabat. A
modification can be a substitution of R301, such as R301A, according to the EU
index of Kabat. A modification can be a substitution of K322, such as K322A, according to 10 the EU index of Kabat.
101351 In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc domain to Fcy11.11 receptor but does not affect the binding affinity to FcyRIIIA receptor. A
modification can be a substitution of R292, such as R292A, according to the EU index of Kabat. A
15 modification can be a substitution of K414, such as K414A, according to the EU index of Kabat.
[0136] In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc domain to FcyRII

receptor and increases the binding affinity to FcyRIIIA receptor. A
modification can be 20 a substitution of S298, such as S298A, according to the EU index of Kabat. A
modification can be substitution of S239, 1332 and A330, such as A modification can be substitution of S239 and 1332, such as S239D/I332E.
[0137] In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc domain to FcyRIIIA
25 receptor. A modification can be substitution of F241 and F243, such as or F241I/F2431, according to the EU index of Kabat.
[0138] In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc domain to FcyRIIIA
receptor and does not affect the binding affinity to FcyRII receptor. A
modification can 30 be a substitution of S239, such as S239A, according to the EU index of Kabat. A
modification can be a substitution of E269, such as E269A, according to the EU
index of Kabat. A modification can be a substitution of E293, such as E293A, according to the EU index of Kabat. A modification can be a substitution of Y296, such as Y296F, according to the EU index of Kabat. A modification can be a substitution of V303, such as V303A, according to the EU index of Kabat. A modification can be a 5 substitution of A327, such as A327G, according to the EU index of Kabat.
A
modification can be a substitution of K338, such as K338A, according to the EU
index of Kabat. A modification can be a substitution of D376, such as D376A, according to the EU index of Kabat.
[0139] In some embodiments, the modification comprises substitution of one or 10 more amino acids that increases binding affinity of an IgG Fc domain to FcyRITEA
receptor and does not affect the binding affinity to FcyRII receptor. A
modification can be a substitution of E333, such as E333A, according to the EU index of Kabat.
A
modification can be a substitution of K334, such as K334A, according to the EU
index of Kabat. A modification can be a substitution of A339, such as A339T, according to 15 the EU index of Kabat. A modification can be substitution of S239 and 1332, such as 5239D/1332E.
[0140] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc domain to FcyRIIIA
receptor. A modification can be substitution of L235, F243, R292, Y300 and P396, 20 such as L235V/F243L/R292P/Y300L/P396L (IgG1VLPLL) according to the EU
index of Kabat. A modification can be substitution of S298, E333 and K334, such as 5298A/E333A/K334A, according to the EU index of Kabat. A modification can be substitution of K246, such as K246F, according to the EU index of Kabat.
[0141] Other substitutions in an IgG Fc domain that affect its interaction with 25 one or more Fey receptors are disclosed in U.S. Patent Nos. 7,317,091 and 8,969,526 (the disclosures of which are incorporated by reference herein).
[0142] In some embodiments, an IgG Fc domain comprises at least one amino acid substitution that reduces the binding affinity to FcRn, as compared to a wild-type or reference IgG Fc domain. A modification can comprise a substitution at H435, such 30 as H435A according to the EU index of Kabat. A modification can comprise a substitution at 1253, such as I253A according to the EU index of Kabat. A
modification can comprise a substitution at H310, such as H310A according to the EU index of Kabat. A modification can comprise substitutions at 1253, H310 and H435, such as I253A/H310A/H435A according to the EU index of Kabat.
[0143] A modification can comprise a substitution of one amino acid residue 5 that increases the binding affinity of an IgG Fc domain for FcRn, relative to a wildtype or reference IgG Fc domain. A modification can comprise a substitution at V308, such as V308P according to the EU index of Kabat. A modification can comprise a substitution at M428, such as M428L according to the EU index of Kabat. A
modification can comprise a substitution at N434, such as N434A according to the EU
10 index of Kabat or N43411 according to the EU index of Kabat. A
modification can comprise substitutions at T250 and M428, such as T250Q and M428L according to the EU index of Kabat. A modification can comprise substitutions at M428 and N434, such as M428L and N434S, N434A or N434H according to the EU index of Kabat_ A
modification can comprise substitutions at M252, S254 and T256, such as 15 M252Y/S254T/T256E according to the EU index of Kabat. A modification can be a substitution of one or more amino acids selected from P257L, P257N, P2571, V279E, V279Q, V279Y, A281S, E283F, V284E, L306Y, T307V, V308F, Q311V, D376V, and N434H. Other substitutions in an IgG Fc domain that affect its interaction with FeRn are disclosed in U.S. Patent No. 9,803,023 (the disclosure of which is incorporated by 20 reference herein).
[0144] In some embodiments, an antibody is a human IgG2 antibody, including an IgG2 Fc region. In some embodiments, the heavy chain of the human IgG2 antibody can be mutated at cysteines at positions 127, 232, or 233. In some embodiments, the light chain of a human IgG2 antibody can be mutated at a cysteine at position 214. The 25 mutations in the heavy and light chains of the human IgG2 antibody can be from a cysteine residue to a serine residue.
Immune-Stimulatory Compounds [0145] The antibodies are attached to immune stimulatory compounds, typically via a linker(s) to form immune-stimulatory conjugates. An antibody can be attached to one or more immune-stimulatory compounds, typically from about 1 to about 10 compounds per antibody.
[0146] In some embodiments, an immune stimulatory compound activates human immune cells, including but not limited to dendritic cells, macrophages, 5 monocytes, myeloid-derived suppressor cells, NK cells, B cells, T cells, or tumor cells, or a combination thereof. In some embodiments, an immune-stimulatory compound is a myeloid cell agonist. A myeloid cell agonist is a compound that activates or stimulates an immune response by a myeloid cell. For example, a myeloid cell agonist can stimulate an immune response by causing the release of cytokines by myeloid cells, 10 which results in the activation of immune cells. The stimulation of an immune response by a myeloid cell agonist can be measured in vitro by co-culturing immune cells (e.g., peripheral blood mononuclear cells (PBMCs)) with cells targeted by the conjugate and measuring cytokine release, chemokine release, proliferation of immune cells, upregulation of immune cell activation markers, ADCC, or any combination thereof.
15 Exemplary assays are described in the Examples. ADCC can be measured by determining the percentage of remaining target cells in the co-culture after administration of the conjugate with the target cells and PBMCs.
[0147] In general, an immune stimulatory compound acts on toll like receptors (TLRs), nucleotide-oligomerization domain-like receptors (NOD), RIG-I-Like receptors 20 (RLR), C-type lectin receptors (CLR), or cytosolic DNA Sensors (CDS), or a combination thereof.
[0148] In some embodiments, an immune stimulatory compound comprises a ligand of one or more TLRs selected from the group consisting of: TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR7/TLR8, TLR9, and TLR10.

[0149] In some embodiments, an immune-stimulatory compound is a myeloid cell agonist. In some embodiments, a myeloid cell agonist is a ligand of TLR2 selected from the group consisting of: (a) a heat killed bacteria product, preferably HKAL, HKEB, HK_HP, HKLM, HKLP, HKLR, HKMF, HKPA, HKPG, or HKSA, HKSP, and (b) a cell-wall components product, preferably LAM, LM, LPS, LIA, LIA, PGN, FSL, 30 Pam2CSK4, Pam3CSK4, or Zymosan.

101501 In some embodiments, a myeloid cell agonist is a ligand of TLR3 selected from the group consisting of: rintatolimod, poly-ICLC, RIBOXXONO, Apoxxim, RIBOXXIMO, MCT-465, MCT-475, and ND-1.1.
101511 In some embodiments, a myeloid cell agonist is a ligand of TLR4 5 selected from the group consisting of LPS, MPLA or a pyrimido[5,4-b]indole such as those described in PCT Publication No. WO 2014/052828 (U of Cal).
101521 In some embodiments, the myeloid cell agonist is a ligand of TLR5 selected from the group consisting of: FLA and Flagellin.
101531 In some embodiments, the myeloid cell agonist is a ligand of TLR6.
10 101541 In certain embodiments, a myeloid cell agonist is a TLR7 agonist and/or a TLR8 agonist. In certain embodiments, the myeloid cell agonist is a TLR7 agonist.
In certain embodiments, the myeloid cell agonist is a TLR8 agonist. In some embodiments, the myeloid cell agonist selectively agonizes TLR7 and not TLR8.
In other embodiments, the myeloid cell agonist selectively agonizes TLR8 and not TLR7.
15 101551 In certain embodiments, a myeloid cell agonist is a TLR7 agonist. In certain embodiments, the TLR7 agonist is selected from an imidazoquinoline, an imidazoquinoline amine, a thiazoquinoline, an aminoquinoline, an aminoquinazoline, a pyrido[3,2-d]pyrimidine-2,4-diamine, a pyrimidine-2,4-diamine, a 2-aminoimidazole, an 1-alkyl-1H-benzimidazol-2-amine, a tetrahydropyridopyrimidine, a 20 heteroarothiadiazide-2,2-dioxide, a benzonaphthyridine, a thieno[3,2-d]pyrimidine, a 4-amino-imidazoquinoline, an imidazo-ppidinone, an imidazo-pyrimidinone, a purine, a fused pyrimidine-lactam, an imidazo[4,5-c]quinoline-4-amine, an imidazo[4,5-c]quinoline, a pyrimidine, a ben7.a7epine, an imidazo-pyridine, a pyrrolo-pyrimidine, a 2-amino-quinazoline, a guanosine analog, an adenosine analog, a thymidine 25 homopolymer, an ssRNA, CpG-A, PolyG10, and PolyG3. In certain embodiments, the TLR7 agonist is selected from an imidazoquinoline, an imidazoquinoline amine, a thiazoquinoline, an aminoquinoline, an aminoquinazoline, a pyrido[3,2-d]primidine-2,4-diamine, a pyrimidine-2,4-diamine, a 2-aminoimidazole, a 1-alky1-1H-benzimidazol-2-amine, a tetrahydropyridopyrimidine, a heteroarothiadiazide-2,2-30 dioxide, a benzonaphthyridine, a thieno[3,2-d]pyrimidine, a 4-amino-imidazoquinoline, an imidazo-pyridinone, an imidazo-pyrimidinone, a purine, a fused pyrimidine-lactam, an imidazo[4,5-c]quinoline-4-amine, an imidazo[4,5-c]quinoline, a pyrimidine, a benzazepine, an imidazo-pyridine, a pyrrolo-pyrimidine, and a 2-amino-quinazoline, but is other than a guanosine analog, an adenosine analog, a thymidine homopolymer, an ssRNA, CpG-A, PolyG10, and PolyG3. In some embodiments, a TLR7 agonist is a 5 non-naturally occurring compound. Examples of TLR7 modulators include GS-9620, GSK-2245035, imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, and the TLR7 modulator compounds disclosed in US Patent Publication No.
2016/0168164 (Janssen, thieno[3,2-d]pyrimicline derivatives), US Patent Publication 10 No. 2015/0299194 (Roche, 4-amino-imidazoquinoline derivatives), US
Patent Publication No. 2011/0098248 (Gilead Sciences, imidazo-pyridinone, imidazo-pyrimidinone, and purine derivatives), US Patent Publication No. 2010/0143301 (Gilead Sciences, fused pyrimidine-lactam derivatives), and US Patent Publication No.
2009/0047249 (Gilead Sciences, purine derivatives), and these publications are 15 incorporated by reference herein. Further examples of TLR7 modulators include compounds disclosed in PCT Publication No. W02018/009916 (Stanford University/Bolt Biotherapeutics, imidazo[4,5-c]quinolin-4-amine derivatives), PCT
Publication No. W02018/112108 (Bolt Biotherapeutics, imidazo[4,5-c]quinoline, pyrimidine, benzazepine, imidazo-pyridine, pyrrolo-pyrimidine, and purine 20 derivatives), US Patent Publication No. 2019/0055247 (Bristol-Myers Squibb, purine derivatives), PCT Publication No. PCT Publication No. W02018/198091 (Novartis, pyrrolo-pyrimidine derivatives), US Patent Publication No. 2017/0121421 (Novartis, pyrrolo-pyrimidine derivatives), US Patent No. 10,253,003 (Janssen, 2-amino-quinazoline derivatives), and US Patent No. 10,233,184 (Roche, imidazo-pyrimidinone 25 derivatives), and these publications are incorporated by reference herein. In some embodiments, a TLR7 agonist has an EC50 value of 500 nM or less by PBMC assay measuring TNFalpha or IFNgammaproduction. In some embodiments, a TLR7 agonist has an EC50 value of 100 nM or less by PBMC assay measuring TNFalpha or IFNgamma production. In some embodiments, a TLR7 agonist has an EC50 value of 30 50 TIM or less by PBMC assay measuring TNFalpha or IFNgamma production.
In some embodiments, a TLR7 agonist has an EC50 value of 10 tiM or less by PBMC assay measuring TNFalpha or IFNgamma production.
[0156] In certain embodiments the myeloid cell agonist is a TLR8 agonist. In certain embodiments, the TLR8 agonist is selected from the group consisting of a 5 benzazepine, an imidazoquinoline, a thiazoloquinoline, an aminoquinoline, an aminoquinazoline, a pyrido[3,2-d]pyrimidine-2,4-diamine, a pyrimidine-2,4-diamine, a 2-aminoimidazole, an 1-allcyl-1H-benzimidazol-2-amine, a tetrahydropyridopyrimidine, a pyrido[3,2-d]pyrimidine, a dihydropyrimidinyl benzazepine carboxamide, a benzo[b]azepine, benzazepine dicarboxamide derivatives with a tertiary amide, 10 benzazepine dicarboxamide derivatives with a secondary amide, a quinazoline, a pyrido[3,2-d]pyrimidine, a diamino-pyrimidine, an amino-quinazoline, a heterocyclic-substituted 2-amino-quinazoline, a diamino-pyrimidine, a piperidino-pyrimidine, an alkylamino-pyrimidine, an 8-substitued benzoazepine, an amino-diazepine, an amino-benzo-diazepine, an amido-indole, an amido-benzimidazole, a phenyl sulfonamide, a 15 dihydropteridinone, a fused amino-pyrimidine, a quinazoline, a pyrido-pyrimidine, an amino-substituted benzazepine, a pyrrolo-pyridine, an imidazo-pyridine derivatives, an amino-benzazepine, and a ssRNA. In certain embodiments, a TLR8 agonist is selected from the group consisting of a benzazepine, an imidazoquinoline, a thiazoloquinoline, an aminoquinoline, an aminoquinazoline, a pyrido[3,2-d]pyrimidine-2,4-diamine, a 20 pyrimidine-2,4-diamine, a 2-aminoimidazole, an 1-alkyl-1H-benzimidazol-2-amine, a tetrahydropyridopyrimidine, a pyrido[3,2-d]pyrimidine, a dihydropyrimidinyl benzazepine carboxamide, a benzo[b]azepine, benzazepine dicarboxamide derivatives with a tertiary amide, benzazepine dicarboxamide derivatives with a secondary amide, a quinazoline, a pyrido[3,2-d]pyrimidine, a diamino-pyrimidine, an amino-quinazoline, a 25 heterocyclic-substituted 2-amino-quinazoline, a diamino-pyrimidine, a piperidino-pyrimidine, an alkylamino-pyrimidine, an 8-substitued benzoazepine, an amino-diazepine, an amino-benzo-diazepine, an amido-indole, an amido-benzimidazole, a phenyl sulfonamide, a dihydropteridinone, a fused amino-pyrimidine, a quinazoline, a pyrido-pyrimidine, an amino-substituted benzazepine, a pyrrolo-pyridine, an imidazo-30 pyridine derivatives, and an amino-benzazepine, and is other than a ssRNA. In some embodiments, a TLR8 agonist is a non-naturally occurring compound. Examples of TLR8 agonists include motolimod, selgantolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and the TLR8 modulator compounds disclosed in US Patent Publication No. 2018/0086755 (Gilead, pyrido[3,2-d]pyrimidine derivatives), PCT Publication No. W02017/216054 (Roche, dihydropyrimidinyl 5 benzazepine carboxamide derivatives), PCT Publication No. PCT Publication No.
W02017/190669 (Shanghai De Novo Pharmatech, benzo[b]azepine derivatives), PCT
Publication No. W02016/142250 (Roche, benzazepine dicarboxamide derivatives), PCT Publication No. W02017/202704 (Roche, benzazepine dicarboxamide derivatives with a tertiary amide), PCT Publication No. W02017/202703 (Roche, benzazepine 10 dicarboxamide derivatives with a secondary amide), US Patent Publication No.
2017/0071944 (Gilead, quinazoline and pynidop,2-d]pyrimdine derivatives), US
Patent Publication No. 2014/0045849 (Janssen, diamino-pyrimidine derivatives), US
Patent Publication No. 2014/0073642 (Janssen, amino-quinazoline derivatives), PCT
Publication No. W02014/056953 (Janssen, pyrrolo[3,2-d]pyrimidine derivatives), PCT
15 Publication No. W02014/076221 (Janssen, heterocyclic substituted 2-amino-quinazoline derivatives), PCT Publication No. W02014/128189 (Janssen, diamino-pyrimidine derivatives), US Patent Publication No. 2014/0350031 (Janssen, piperidino-pyrimidine derivatives), PCT Publication No. W02014/023813 (Janssen, alkyl-aminopyrimidine derivatives), US Patent Publication No. 2008/0234251 (Array 20 Biophanna, 8-substituted benzoazepine derivatives), US Patent Publication No.
2008/0306050 (Array Biophartna, amino-diazepine derivatives), US Patent Publication No. 2010/0029585 (VentiRx Pharma, amino-benzazepine derivatives), US Patent Publication No. 2011/0092485 (VentiRx Pharma, amino-benzazepine derivatives), US
Patent Publication No. 2011/0118235 (VentiRx Pharma, amino-benzazepine 25 derivatives), US Patent Publication No. 2012/0082658 (VentiRx Pharma, amino-benzazepine VTX-378), US Patent Publication No. 2012/0219615 (VentiRx Pharma), US Patent Publication No. 20140066432 (VentiRx Pharma, amino-benzazepine VTX-2337), US Patent Publication No. 2014/0088085 (VentiRx Pharma, amino-benzazepine and amino-benzo-diazepine derivatives), US Patent Publication No. 2014/0275167 30 (Novira Therapeutics, amido-indole and amido-benzimidazole derivatives), and US
Patent Publication No. 2013/0251673 (Novira Therapeutics, phenyl sulfonamide derivatives), and these publications are incorporated by reference herein.
Further examples of TLR8 modulators include compounds disclosed in U52016/0108045 (Gilead, dihydropteridinone derivatives), US Patent Publication No.

(Gilead, fused amino-pyrimidine derivatives), US Patent Publication No.

5 (Gilead, quinazoline and pyrido-pyrimidine derivatives), PCT Publication No.
W02017/046112 (Roche, amino-substituted benzazepine derivatives), PCT
Publication No. W02016/096778 (Roche, amino-substituted benzazepine derivatives), US
Patent Publication No. 2019/0016808 (Birdie Biopharmaceuticals, pyrrolo- or imidazo-pyridine derivatives or amino-benzazepine derivatives), and these publications are 10 incorporated by reference herein. In some embodiments, the TLR8 agonist comprises L.
1.1 ) the structure:
, wherein the structure is optionally substituted at any position other than the -NM position. In some embodiments, a TLR8 agonist has an EC50 value of 500 n.M or less by PBMC assay measuring TNFalpha production. In some embodiments, a TLR8 agonist has an EC50 value of 100 nNI or less by PBMC
15 assay measuring TNFalpha production. In some embodiments, a TLR8 agonist has an EC50 value of 50 tilvl or less by PBMC assay measuring TNFalpha production. In some embodiments, a TLR8 agonist has an EC50 value of 10 nM or less by PBMC
assay measuring TNFalpha production.
[0157] In some embodiments, a TLR8 agonist is a benzazepine selected from 20 compounds provided herein.
101581 In some embodiments, a myeloid cell agonist is a ligand of TLR9 selected from the group consisting of: ODN1585, ODN1668, ODN1826, PF-3512676 (0DN2006), 0DN2007, 0DN2216, 0DN2336, 0DN2395, BB-001, BB-006, CYT-003, IM0-2055, IM0-2125, IMO-3100, IMO-8400, IR-103, IM0-9200, agatolimod, 25 DIMS-9054, DV-1079, DV-1179, AZD-I419, leftolimod (MGN-1703), litenimod, and CYT-003-QbGl0 [0159] In other embodiments, the myeloid agonist selectively agonizes TLR9, TLR3, TLR4, TLR2, TLR5, MG-I, STING, cGAS, NOD1, NOD2, NOD1/NOD2, NRLP3, ALPK I, MDA5 AIN42,1RE1, or PERK.
30 [0160] In some embodiments, a myeloid cell agonist is a ligand of TLR10.

[0161] In some embodiments, a myeloid cell agonist is a ligand of a ligand of nucleotide-oligomerization domain (NOD)-like selected from the group consisting of:
NOD! agonist (C12-iE-DAP, iE-DAP, Tri-DAP), NOD2 agonist (L18-MDP, MDP, M-TriLYS, M-TriLYS-D-ASN, Murabutide, N-Glycolyl-MDP), and NOD1/NOD2 5 agonists (M-TriDAP, PGN).
[0162] In some embodiments, a myeloid cell agonist is a ligand of one or more RIG-I-Like receptors (RLR) selected from the group consisting of: Sippp-dsRNA, Poly (dA:dT), Poly(dG:dC), and Poly (I:C).
[0163] In some embodiments, a myeloid cell agonist is a ligand of one or more 10 C-type Iectin receptors (CLR) selected from the group consisting of:
Cnrdlan AL, RICCA, HKSC, WGP, Zymosan, and Trehalose-6,6-dibehenate.
[0164] In some embodiments, a myeloid cell agonist is a ligand of one or more Cytosolic DNA Sensors (CDS) selected from the group consisting of: ADU-S100, c-GMP, c-G-AMP, c-G-GMP, c-A-AMP, c-di-AMP, c-di-IMP, c-di-GMP, c-di-LTMP, 15 HSV-60, ISD, pCpG, Poly (dA:dT), Poly( dG:dC), Poly (dA),VACV-70 and a-mangostin and the compounds disclosed in PCT Publication No. W02018/156625 (U
of Texas), PCT Publication No. WO 2018/152453 (Eisai), PCT Publication No.
W02018/138685 (Janssen), PCT Publication No. W02018/100558 (Takeda), PCT
Publication No. W02018/098203 (Janssen), PCT Publication No. W02018/065360 20 (Biolog Life Sciences), PCT Publication No, W02018/060323 (Boehringer Ingelheim), PCT Publication No. PCT Publication No. W02018/045204 (1FM Therapeutics), PCT
Publication No. PCT Publication No. W02018/009466 (Aduro), PCT Publication No.

WO 2017/161349 (Immune Sensor), PCT Publication No. W02017/123669, PCT
Publication No. W02017/123657, PCT Publication No. W02017/027646 (Merck), 25 PCT Publication No. W02017/027645 (Merck), PCT Publication No, (GSK), PCT Publication No. W02016/096174 (InvivoGen), and US Patent Publication No. 2014/0341976 (Aduro).
[0165] In some embodiments, the myeloid cell agonist is a ligand of an inflammasome inducer selected from the group consisting of: (a) NLRP3 30 inflammasome protein complex, preferably alum Crystals, ATP, CPPD
Crystals, Hennozoin, MSU Crystals, Nano-Si 02, Nigericin, and (b) AIM2 inflammasome protein complex, such as Poly (dA:dT).
[0166] In certain aspects, a TLR8 agonist or a TLR7 agonist is selected from Category A or Category B, respectively, as further described herein. Variables and 5 Formula of the Compounds of Category A (TLR8 agonists) are described in the section entitled Compounds of Category A, and variables and Formula of the Compounds of Category B (TLR7 agonists) are described in the subsequent section, entitled Compounds of Category B. Formulas and variables of the Compounds of Category A

and the Compounds of Category B may overlap in nomenclature, e.g., Formula IA
for 10 both Compounds of Category A and Category B; however, variables and Formula descriptions are not intended to be interchangeable between the catagories.
[0167] In some aspects, the myeloid cell agonist is a benzazepine-4-carboxamide compound. In some aspects, the benzazepine-4-carboxamide compound has the structure of Formula X-1:

=
* teR4 wherein:
RE is C3-7 alkyl;
112 is C3-7 alkyl or C3-7 cycloalkyl-CI-7a1ky1;
it is hydrogen;
20 it is selected from the group consisting of Cl-7 alkyl, said C1-7 alkyl being unsubstituted or substituted by one or two groups selected from the group consisting of phenyl and heteroaryl, said heteraryl being an aromatic 5- or 6-membered ring which comprises one, two, or three atoms selected from nitrogen, oxygen, and/or sulfur;
25 C3-7 cycloalkyl, said C3-7 cycloalkyl being unsubstituted or substituted by phenyl or phenylamino-C14 alkyl, and heterocyclyl, said heterocyclyl being a saturated 3- to 7-membered ring containing one heteroatom selected from N and 0 and being unsubstituted or substituted by phenyl.
Structures of Formula X-1 are described, for example, in PCT Publication No.
W02017/202703.
101681 In some aspects, the the myeloid cell agonist is a benzazepine-dicarboxamide compound. In some aspects, the benzazepine-dicarboxamide compound has the structure of Formula X-2:

ioi R3 14-~R2 wherein:
RI is C3-7 alkyl;
R2 is C3-7 alkyl or C3-7 cycloalkyl-CI-7 alkyl;
R3 is a heterocycle selected from xi x3 ¨ise/ X \ N¨Z1 NX2 a, a) wherein Xi is (CH2)rn wherein m is 1 or 2;
X2 is (CH2)n wherein n is 1 or 2;
X3 is (CHOO wherein o is 1 or 2;
X4 is (CH2)p wherein p is 1 or 2; and Z1 is phenyl, wherein phenyl is unsubstituted or substituted by one or two groups selected from the group consisting of Ci.-7 alkyl, halogen, halogen-alkyl, CI-7 alkoxy, hydroxy-Ct-7 alkyl, amino-C1-7 alkyl, CI-7 alkyl-amino-C1-7 alkyl, and di-C1-7 alkyl-amino-C1-7 alkyl; or /X\ õed.'22 ¨N Y1 xe b) wherein X5 is (CH2)q wherein q is 1 or 2;
X6, is (CHOr wherein r is 1 or 2;
5 Y1 is a carbon or nitrogen atom;
Z2 is hydrogen; and Z3 is selected from the group consisting of hydrogen, C1-7 alkoxy, C2-7 alkenyloxy, phenyl, phenyl-C1-7 alkyl, phenyl-C1-7 alkyloxy, phenyl-C1-7 alkylamino, phenylamino-C1-7 alkyl, phenylamino, wherein phenyl is unsubstituted or substituted by 10 one or two groups selected from the group consisting of C1-7 alkyl, halogen, halogen-Ci-7 alk-yl, C1-7 alkoxy, hydroxy-CI-7 alkyl, amino-C1-7 alkyl, C1-7 alkyl-amino-C1-7 alkyl, and di-C1-7 alkyl-amino-C1-7 alkyl; or /\ki \ ______________________________________________________ wherein 15 X7 is (CH2)s wherein s is 1 or 2; and .14 is phenyl, wherein phenyl is unsubstituted or substituted by one or two groups selected from the group consisting of Ct-7 alkyl, halogen, halogen-alkyl, C1-7 alkoxy, hydroxy-Ct-7 alkyl, amino-C1-7 alkyl, CI-7 alkyl-amino-C1-7 alkyl, and di-C1-7 alkyl-amino-C1-7 alkyl; or 20 d) wherein Xs is (CH2)t wherein t is 1 or 2; and Z5 is phenyl, wherein phenyl is unsubstituted or substituted by one or two groups selected from the group consisting of C1-7 alkyl, halogen, halogen-alkyl, C1-7 alkoxy, hydroxy-Ct-7 alkyl, amino-C1-7 alkyl, C I -7 alkyl-amino-C1-7 alkyl, and di-C1-7 alkyl-amino-C1-7 alkyl.
5 Compounds of Formula X-2 are described, for example, in PCT
Publication No. W02017/202704.
101691 In some aspects, the the myeloid cell agonist is a benzazepine sulfonamide compound. In some aspects, the benzazepine sulfonamide compound has the structure of Formula X-3:

I

Re RV

wherein R' and R2 are the same or different and are selected from the group consisting of CI-7 alkyl, hydroxy-C2-7 alkyl, amino-C2-7 alkyl, C2-7 alkenyl, and C3-7 alkynyl;
R5 is hydrogen or C1-7 alkyl;
15 R6 is hydrogen or C1-7 alkyl;
one of R4 and R5 is selected from the group consisting of hydrogen, Ct-7 alkyl, halogen-C1-7 alkyl, and C1-7 alkoxy, R
if and the other one of R4 and R5 is wherein R7 and Rs are the same or different and are selected from the group 20 consisting of hydrogen, C1-7 alkyl, halogen-C1-7 alkyl, hydroxy-Ct-7 alkyl, hydroxy-Ct-7 alkoxy-CI-7 alkyl, amino-C1-7 alkyl, CI-7 alkyl-amino-C1-7 alkyl, amino-CI-7 alkoxy-CI-7 alkyl, C1-7 alkyl-amino-Ct-7 alkoxy-C1-7 alkyl, amino-C1-7 alkyl-carbonyl, and alkyl-xamino-C 1-7 alkyl-carbonyl; or R7 and Rs together with the nitrogen atom they are attached to form a 4- to 6-25 membered heterocycle which is unsubstituted or substituted with a group selected from the group consisting of amino, C1-7 alkyl-amino, hydroxy, and hydroxy-C1-7 alkyl, and which may contain an additional N-R1 group, wherein 10 is selected from the group consisting of hydrogen, amino-C1-7 alkyl, and C1-7 alkyl-amino-C1-7 alkyl; and Y is N or CR9;
5 wherein R9 is selected from the group consisting of hydrogen, C1-7 alkyl, and halogen-C1-7 alkyl.
Compounds of Formula X-3 are described, for example, in PCT Publication No.
W02016/096778.
01701 In some aspects, the myeloid cell agonist is a dihydropyrimidinyl 10 benzazepine carboxamide compound. In some aspects, the dihydropyrimidinyl benzazepine carboxamide compound has the structure of Formula X-4:
X
Re H N

õ 411 Rs RI/ n wherein RE is C3-7 alkyl;
15 R2 is C3-7 alkyl or C3-7 cycloalkyl-CI-7 alkyl;
R3 is hydrogen or C1-7 alkyl;
R4 is hydrogen or C1-7 alkyl;
R5 is selected from the group consisting of hydrogen, halogen, C1-7 alkyl, and CI-7 alkoxy;
20 Rs is selected from the group consisting of hydrogen, halogen, C1-7 alkyl, and CI-7 alkoxy; and X is N or CR7, wherein R7 is selected from the group consisting of hydrogen, halogen, CI-7 alkyl, and C1-7 alkoxy.
Compounds of Formula X-4 are described, for example, in PCT Publication No.
25 W02017/216054.

101711 In some aspects, the myeloid cell agonist is a sulfinylphenyl or sulfonimidoylphenyl benzazepine compound. In some aspects, the sulfinylphenyl or sulfonimidoylphenyl benzazepine compound has the structure of Formula X-5:
R6 X Ra -tee R

wherein X is CR' or N;
IV is C3-7alkyl or C3-7cyc10a1ky1;
R2 is selected from the group consisting of C3-7 alkyl, hydroxy-C 1-7 alkyl, alkynyl, amino-C1-7 alkoxy-Ct-7 alkoxy-C1-7 alkyl, halogen-C1-7 alkyl, and C3-0 cycloalkyl-C1-7 alkyl;

II a I a one of R3 and It4 is , and the other one of R3 and R4 is selected from the group consisting of hydrogen, C14 alkyl, and halogen;
R5, 1(6, and R" are independently from each other selected from hydrogen, C1-7 alkyl, and halogen;
15 R.8 is C1-7 alkyl; and R9 is absent or is =N-R' , wherein 1(10 is selected from the group consisting of hydrogen, C14 alkyl, halogen-CI-7 alkyl, hydroxy-C1-7 alkyl, and hydroxy-C1-7 alkoxy-C 1-7 alkyl.
Compounds of Formula X-5 are described, for example, in PCT Publication No, 20 W02017/046112.
101721 In some aspects, the myeloid cell agonist is a TLR modulator compound that has the structure of Formula X-6:

() itz So113 ...-, :

Rb wherein (1) is a double bond or a single bond;
= (2) is a single bond or is double bond and RI is absent;
5 R2 and R3 are independently selected from H and lower alkyl, or R2 and 1(3 are connected to form a saturated carbocycle haying from 3 to 7 ring members;
I N X
one of R7 and Rs is -NRfRg, 0 ,or , and the other is hydrogen;
where Rf and Rg are lower alkyl or Rf and Rg together with the nitrogen to which 10 they are attached form a saturated heterocyclic ring having 4 to 6 ring members;
R4 is -NReRd or -ORro;
Re and Rd are lower alkyl, where the alkyl is optionally substituted with one or more -OH;
Rio is alkyl, where the alkyl is optionally substituted with one or more -OH;
15 Z is C and = (1) is a double bond, or Z is N and = (1) is a single bond;
Ra and Rb are independently selected from H, alkyl, alkenyl, alkynyl, and Re, wherein the alkyl is optionally substituted with one or more -0R10, or Re;
W is selected from -1\11-12, -NH(alkyl), and -N(alkyl)2;
RI is absent when = (2) is a double bond, or when = (2) is a single bond, 20 W and one of W or BY are taken together with the atoms to which they are attached to form a saturated, partially unsaturated, or unsaturated heterocycle having 5-7 ring members, and the other of W or Rb is hydrogen or is absent as necessary to accommodate ring unsaturation.
[0173] In some aspects, the myeloid cell agonist is a TLR modulator compound 25 that has the structure of Formula X-7:

P.Sv los le NFL, wherein Y is CF2CF3, CF2CF7R6, or an aryl or heteroaryl ring, wherein said aryl and heteroaryl rings are substituted with one or more groups independently selected from 5 alkenyl, alkynyl, Br, CN, OH, N1161V, C(3)R8, NR6S02R7, (CI-C6 alkyl)amino, R60C(=0)CH=CH2¨, SR6 and 50211.6, and wherein the aryl and heteroaryl rings are optionally further substituted with one or more groups independently selected from F, Cl, CF, CF30-, HCF20-, alkyl, heteroalkyl and Ar0-;
RI-, R3 and R4 are independently selected from H, alkyl, alkenyl, alkynyl, 10 heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, F, Cl, Br, I, CN, OR6, NR6R7, C(=0)R6, C(0)0R6, OC(=0)R6, C(=0)NR6117, (C t-C6 alkyl)amino, CH3OCH20-, R60C(0)CH=CH2-, 15 NR6S02R7, SR6 and SO2R6, or R3 and le together with the atom to which they are attached form a saturated or partially unsaturated carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, F, Cl, Br, I, CN, OR6, NR6R7, C(0)R6, C(=0)0R6, OC(3)R6, 20 C(=O)NR6R7, (Ci-Cis alkyl)amino, CH3OCH20¨,11.60C(=0)CHH2-, NR6S02R7, SR6 and S02R6;
1(2 and 1(8 are independently selected from H, OR6, NR6R7, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, 25 heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, F, Cl, Br, I, CN, 01(6, NR6R7, 4C(3)R6, g=0)0R6, OC(3)1;t6, C(0)NR61e, (Ci-C6 alkyl)amino, CH3OCH20-, R60C(3)CHH2-, NR6S02R7, SR6 and SO2R6;
R5a, R51', and R5' are independently H, F, Cl, Br, I, OMe, CH3, CH2F, CHF2 or CF3; and 5 R6 and le are independently selected from H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, F, Cl, Br, I, CN, OR6, NR6117, CD)R6, 10 C(3)0R6, OC(3)1t6, C(3)NR6R7, (CI-C6 alkyeamino, CH3OCH20-, R60C(0)CHH2-, NR6S02Ie, SR6 and SO2R6, or R6 and IV together with the atom to which they are attached form a saturated or partially unsaturated heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from alkyl, alkenyl, 15 alkynyl, F, Cl, Br, I, CN, OW, NR6R7, C(=0)1e, C(=0)0R6, OC(3)R6, C(D)NR6R7, (Ci-C6alkyl)amino, CH3OCH20-, R6OC(=D)CHCH2-, NR6S02R7, SR6 and SO2R6.
[0174] In some aspects, the myeloid cell agonist is a TLR modulator compound that has the structure of Formula X-8:
ay_ R4 N,N' twin-.N

wherein W is -C(0)-;
Z is H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ole or NR6F2, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, 25 heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl. F, Cl, Br, I, CN, OR', NR6R7, 4C(3)R6, g=0)0R6, OC(3)1;t6, C(3)NR61e, (Ci-C6 alkyl)amino, CH30CH20-, R6OCCD)CHH2-, NR6S021V, SR6 and SO2R6;
RI, R2, R3 and R4 are independently selected from H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, wherein 5 said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, F, CI, Br, I, CN, OR', NR6R7, C(D)R6, C(3)0R6, OC(3)116, C(3)NR6R7, (CI-C6 alkyl)amino, CH3OCH20-, R60C(C)CHH2-, NR6S02117, 51(6 and 502R6, 10 or le and R2 together with the atom to which they are attached form a saturated Of partially unsaturated carbocyclic ring, wherein said carbocyclic ring is optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, F, Cl, Br, I, CN, OR6, NR6R7, C(=0)R6, C(=0)0R6, OC(=3)R6, OHLONR6R7, (C1-C6 alkyl)amino, CH3OCH20-, R60C(=0)CHH2-, NR6S02R7, 15 SR6 and 502R6, or R3 and R4 together are oxo;
R5 is H, F, Cl, Br, I, OMe, CH3, CH2F, CHF2, CF3 or CF2CF3;
re and R7 are independently selected from H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, wherein 20 said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, F, Cl, Br, I, CN, OR', NR612.7, C(3)R6, C(:)0126, OC(1)R6, C(1)NR6R7, (CI-C6 alkyl)amino, CH3OCH20-, R60C(=0)CHH2-, NR6S021C, SR6 and SO2R6;
25 or R6 and R7 together with the atom to which they are attached form a saturated or partially unsaturated heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, F, Cl, Br, I, CN, OR6, NR6R7, C(=0)1e, C(=0)0R6, OC(3)R6, C(=0)NR6R7, (Ci-C6 alkyl)amino, CH3OCH20-, R60C(1)CHC112-, NR6S02R7, 30 SR6 and SO2R6; and n is 0, 1, 2,3 or 4.

101751 Compounds of Formula X-6, X-7, and X-8 are described, for example, in U.S. Publication Nos. US2019/0016808 and U.S. Publication No. 2014/0088085.
[0176] In some aspects, the myeloid cell agonist is a TLR modulator compound that has the structure of Formula X-9:

we Al N,R2 wherein RI is C3-7alkyl or C3-7cycloalkyl;
R2 is selected from the group consisting of C1-7a1ky1, hydroxy-C1-7alkyl, C2-7a1keny1, C3-7a11cyny1, amino-C1-7alkoxy-C1-7alkyl, amino-C1-7alkoxy-C1-7alkoxy-Ci-10 7a1ky1, halogen-C1-7allcyl, C3-7cycloalkyl-CL-7alkyl, and phenyl-CL-7alkyl, wherein phenyl is unsubstituted or substituted by amino-C1-7alkyl;
R3 is hydrogen;
le is selected from the group consisting of phenyl, said phenyl being unsubstituted or substituted by one or two groups 15 selected from the group consisting of C1-7alkyl, halogen, halogen-C1-7alkyl, C1-7a1k0xy, hydroxy-Ci_7alkyl, amino-C1-7a1ky1, CE-7a1ky1-amino-C1-7a1ky1, amino-C2-7alkenyl, Ci-7alkyl-amino-C2-7alkenyl, di-C1-7alkyl-amino-C2-7alkenyl, amino-C2-7alkynyl, C1-7alkyl-amino-C2-7alkynyl, di-C1-7alkyl-amino-C2-7alkynyl, benzyloxycarbonylamino-C1-7alkyl, amino-C1-7a1k0xy, amino-C1-7alkoxy-C1-7alkoxy, 20 amino-C1-7alkoxy-C1-7alkyl, amino-C1-7alkoxy-C1-7alkoxy-C1-7alkyl, Cialkylsulfonyl, heterocyclylcarbonyl, and phenyl-C1-7alkyl, wherein phenyl is unsubstituted or substituted by Ci-7alkoxy or amino-C1-7alkyl; or heteroaryl, said heteroaryl being a 5- or 6-membered aromatic ring containing one, two, or three heteroatoms selected from N, 0, or S. and being unsubstituted or 25 substituted by one or two groups selected from the group consisting of C1-7 alkyl, halogen, halogen-C1-7 alkyl, C1-7 alkoxy, hydroxy-C1-7 alkyl, amino-C1-7 alkyl, C1-7 alkyl-amino-C1-7 alkyl, di-C1-7 alkyl-amino-Ci-7 alkyl, amino-C2-7 alkenyl, C1-7 alkyl-amino-C2-7 alkenyl, alkyl-amino-C2-7 alkenyl, amino-C2-7 alkynyl, 0-7 alkyl-amino-C2-7 alkynyl, di-C1-7 alkyl-amino-C2-7 alkynyl, benzyloxycarbonylamino-0-alkyl, amino-0-7 alkoxy, amino-C1-7 alkoxy-0-7 alkoxy, amino-CI-7 alkoxy-C1-7 alkyl, amino-C1-7 alkoxy-0-7 alkoxy-C1-7 alkyl, CI-7 alkylsulfonyl, heterocyclylcarbonyl, and 5 phenyl-CI-7 alkyl, wherein phenyl is unsubstituted or substituted by CI-7 alkoxy or amino-C14 alkyl.
Compounds of Formula X-9 are described, for example, in PCT Publication No.
W02016/142250.
Compounds of Category A, TLR8 Agonists 10 101771 In some aspects, the present disclosure provides a TLR8 agonist represented by the structure of Formula (IA):

N
Li , (IA) or a pharmaceutically acceptable salt thereof, wherein:
¨ represents an optional double bond;
15 LIO is _xl0-;
L2 is selected from -X2-, -X2-CI-6alkylene-X2-, -X2-C2-6alkenylene-X2-, and -X2-C2-&alkynylene-X2-, each of which is optionally substituted on alkylene, alkenylene or alkynylene with one or more R12;
X10 is selected from -C(0)-, and -C(0)N(10 )-*, wherein * represents where X1 20 is bound to Its;
X2 at each occurrence is independently selected from a bond, -0-, -S-, -N(R10)-, -C(0)-, -C(0)0-, -0C(0)-, -0C(0)0-, -C(0)N(10 )-, -C(0)N(R1 )C(0)-, C(0)N(R1 )C(0)N(Rio), _Nazto-Kok, _N(io)c(0)mai0) _N(IC )n% 10, C(0)0-, -0C(0)N(Rio)_, _c(NRio)_, 44-Rio)c(NRio,_, ) -C(NR1 )N(R.1 )-, 25 -N(R1 )C(NR1 )N(R1 )-, -S(0)2-, -0S(0)-, -S(0)0-, -S(0), -OS(0)2-, -S(0)20, -N(10)S(0)2-, -S(0)2N(Rio)-, _N(zio)s(0)_, -S(0)N(Rm)-, -N(RnS(0)2N(10)-, and -N(R1 )S(0)N(10)-;
R' and 11.2 are independently selected from hydrogen; and Ci-io alkyl, C2-11) alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more 5 substituents independently selected from halogen, -OR', -C(0)N(10)2, -N(10)2, -S(0)10, -S(0)210, -C(0)10, -C(0)0R' , -0C(0)10, -NO2, =0, =S, =N(R1 ), and -CN;
is selected from: -OR lo, _ N(10)2, -C(0)N(R1 )2, -C(0)10 , -C(0)0R' , -S(0)R1 , and -S(0)2R1 ; Ci-io alkyl, C2-lo alkenyl, C2-lo alkynyl, each of which is 10 optionally substituted with one or more substituents independently selected from halogen, -OR', = -C(0)N(Rt )2, -N(10 )C(0)R10, -N(10)C(0)N(R1 )2, -N(R1 )2, -C(0)R' , -C(0)0R1 , -0C(0)R1 , -NO2, =0, =S, =N($1 ), -CN, C3-12 carbocycle, and 3-to 12-membered heterocycle; and C3-12 carbocycle, and 3-to 12-membered heterocycle, wherein each C3-12 carbocycle, and 3- to 12-membered heterocycle in fe is 15 optionally substituted with one or more substituents independently selected from halogen, -OR', = -C(0)N(10)2, -N(10)C(0)R' , -N(R1 )C(0)N(R1 )2, -N(R10)2, -C(0)R1 , -C(0)0R10, -0C(0)R' , -NO2, =0, =S, =N(F0), -CN, C1-6alkyl, C24alkenyl, and C2-6 alkynyl;
12.5 is selected from unsaturated C4-8 carbocycle; bicyclic carbocycle; and fused 20 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle, wherein R5 is optionally substituted and wherein substituents are independently selected at each occurrence from:
halogen, -OR', -S10, -C(0)N(10)2, -N(10)C(0)R10 , -N(R1 )C(0)N(R1 )2, -N(10)2, -C(0)10, -C(0)0R1 , -0C(0)10, -NO2, =S, =N(Rm), and -CN;

Ci-to alkyl, C2-10 alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -010, -SW , -C(0)N(Rio)2, -N(R10)C(0)R10, 2 4,4(Rio)ceD0A-Rto,), _ NOV12, -C(0)10, -C(0)0R' , -0C(0)10, -NO2, =0, =S, =N(10), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle;

and C3-I2 carbocycle, and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle, and 3- to 12-membered heterocycle in R5 is optionally substituted with one or more substituents independently selected from halogen, -0R1 , -SR1 , -C(0)N(R10)2, _N(Rio),c(o)Rto, -N(R10)C(c)N(R10)2, -iNkicen1 )2, -C(0)R1 , -C(0)0R1 , 5 -0C(0)R' , -NO2, =0, =S, =N(Rw), -CN, CI-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
le is independently selected at each occurrence from hydrogen, -NH2, -C(0)0CH2C6H5; and Ci-to alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, 10 -C(0)0CH2C6H5, -NHC(0)0CH2C6H5, C1-10 alkyl, -Ci-io haloalkyl, -0-C 1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and haloalkyl;
and R12 is independently selected at each occurrence from halogen, -OW', Nio _sr, to, _(t)2,-C(0)R1 , -C(0)N(R10)2, -N(R1 )C(0)R1 , -C(0)0R1 , -0C(0)R1 , 15 -S(0)R1 , -S(0)2Rto, _p(0)(OR to)2, -0P(0)(0R1 )2, -NO2, =0, =S, =N(Rm), and -CN;
Ci-io alkyl, C2-10 alkenyl, C2-to alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OW , -SRm, -N(Rm)2, -C(0)Rm, -C(0)N(R10)2, )1.(0)R10, -C(0)0R1 , -0C(0)R10, -S(0)Rm, -S(0)2R10 , _p(0)(oRio)2, -0P(0)(010 )2, -NO2, =0, =S, =N(R1 ), -CN, C3-10 carbocycle and 3- to 20 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle in R12 is optionally substituted with one or more substituents independently selected from halogen, -ORm, -SW , -N(R10)2, -C(0)R1 , -C(0)N(R10)2, -N(Rm)C(0)R1 , -C(0)0R1 , -0C(0)R1 , _s(0)Rto, _s(0)2Rto, _p(0)(oRto)2, OP(0)(0R1 )2, -NO2, =0, =S, =N(Rm), -CN, 25 Ct-o alkyl, C2-6 alkenyl, C2-6 alkynyl;
wherein any substitutable carbon on the benzazepine core is optionally substituted by a substituent independently selected from Ry or two substituents on a single carbon atom combine to form a 3- to 7- membered carbocycle.
101781 In some embodiments, the compound of Formula (HA) is represented by 30 Formula (HB):

n. 42 ,1 (IIB) or a pharmaceutically acceptable salt thereof, wherein:
R20, 1(21, n22, lc and R23 are independently selected from hydrogen, halogen, -OW , -SRP, -N(Rw)2, -S(0)R' , -S(0)2111 , -C(0)R1 , -C(0)010 , 5 -0C(0)R1 , -NO2, =0, =S, =N(R1 ), -CN, C,-to alkyl, C2-10 alkenyl, and C2-10 alkynyl;
and R24 and Kn25 are independently selected from hydrogen, halogen, -OR', -SR10 , -N(Rm)2, -S(0)11.1 , -S(0)2R10, -C(0)R1 , -C(0)011.1 , -0C(0)R1 , -NO2, 0, =S, =Novo.% -CN, Ci-to alkyl, C2-to alkenyl, and C2-10 aIkynyl; or 1(24 and R25 taken together 10 form an optionally substituted saturated C3-7 carbocycle.
[0179] In some embodiments, R20, R21, R22, and tc. n 23 are independently selected from hydrogen, halogen, -OH, -0R' , -NO2, -CN, and Ct-to alkyl. R20, R21, R22, and R23 may be each hydrogen. In certain embodiments, R21 is halogen. In certain embodiments, 1(21 is hydrogen. In certain embodiments, 1(21 is -0R10. For example, 15 R21 may be -OCH3.
[0180] In some embodiments, R24 and R25 are independently selected from hydrogen, halogen, -OH, -NO2, -CN, and Ci-to alkyl, or R24 and R25 taken together form an optionally substituted saturated C3-7 carbocycle. In certain embodiments, R24 and R25 are each hydrogen. In other embodiments, 1(24 and R25 taken together form an 20 optionally substituted saturated C3-5 carbocycle, wherein substituents are selected from halogen, -010, -SR1 , 2 -C(0)N(R1o),, N(R1 )C(0)R1 , -N(R15C(0)N(R1 )2, -N(R10)2, -C(0)R1 , -C(0)0R' , -0C(0)R' , -NO2, =0, =S, =N(R1 ), and -CN; and Ci-to alkyl, C2-alkenyl, C2-10 alkynyt, each of which is independently optionally substituted with one or more substituents independently selected from halogen, -0R1 , -C(0)N(R1 )2, 25 -N(Rio)cor _ N(Rm)C(0)-N(R1 )2, - t-tAR ) _ C(0)R1 , -0(0)0RE , -0C(0)R10 , -NO2, =0, =S, =WW1, -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0181] In some embodiments, Ri is hydrogen. In some embodiments, R2 is hydrogen. In some embodiments, R2 is¨C(0)-.
[0182] In some embodiments, LI is selected from -C(0)N(R1 )-*. In certain embodiments, Rif) r _ or C(0)N(10 )-* is selected from hydrogen and CI-6 alkyl. For 5 example, 12 may be -C(0)NH-t.
[0183] In some embodiments, 11.5 is an optionally substituted bicyclic carbocycle. In certain embodiments, R5 is an optionally substituted 8- to 12-membered bicyclic carbocycle. R5 may be an optionally substituted 8- to 12- membered bicyclic carbocycle substituted with one or more substituents independently selected from 10 halogen, -OR', -N(Rw)2, -C(0)R' , -C(0)0R1", -0C(0)10- , -NO2, =0, =S, -CN, CL-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In certain embodiments, 12.5 is an optionally substituted 8- to 12- membered bicyclic carbocycle substituted with one or more substituents independently selected from -OR', -N(R1 )2, and =O. In some embodiments, R5 is an optionally substituted indane, and optionally substituted 15 tetrahydronaphthalene. R5 may be selected from:
and , any one of which is optionally substituted. For example, the R5 is selected from:

OH

OH
41141:1 =140 , and CbzHN
[0184] In some embodiments, R5 is an optionally substituted unsaturated C4-8 20 carbocycle. In certain embodiments, le is an optionally substituted unsaturated C4-6 carbocycle. In certain embodiments, leis an optionally substituted unsaturated carbocycle with one or more substituents independently selected from optionally substituted C342 carbocycle, and optionally substituted 3- to 12-membered heterocycle.
It..5 may be an optionally substituted unsaturated C4-6 carbocycle with one or more 25 substituents independently selected from optionally substituted phenyl, optionally substituted 3-to 12- heterocycle, optionally substituted Ci-to alkyl, optionally substituted C2-ioalkenyl, and halogen.

101851 In some embodiments, 11.5 is selected from an optionally substituted fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle. In certain embodiments, R5 is an optionally substituted fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle with one or more substituents independently selected from -C(0)0R' , Nit 1)2, -OW , and 5 optionally substituted Ci-io alkyl. In certain embodiments, le is an optionally substituted fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle substituted with -C(0)0R' . In certain embodiments, R5 is an optionally substituted fused 6-6 bicyclic heterocycle. For example, the fused 6-6 bicyclic heterocycle may be an optionally substituted pyridine-piperidine. In some embodiments, is bound to a carbon atom 10 of the pyridine of the fused pyridine-piperidine. In certain embodiments, Rs is selected from tetrahydroquinoline, tetrahydroisoquinoline, tetrahydronaphthyridine, cyclopentapyridine, and dihydrobenzoxaborole, any one of which is optionally substituted. Pi may be an optionally substituted tetrahydronaphthyridine. In some embodiments, R5 is selected from:

Olt FIN

craiN gal so N 411 Cbz, N

NHCbz Cbze N
_3/4., .ra)y N
I
H

1411:1 C bre LI
N
I I
N
"====., H2N...3/4õ.."-..N
N
ratIsai H2W-...)CN
F F H
HO
c :LAIN
CbzHN-Ca H2N CbzHN
and CbzHN
101861 In some embodiments, when R5 is substituted, substituents on R5 are independently selected at each occurrence from: halogen, -OR"), -SR1 , -C(0)N(R1 )2, _mato-icor K _ Witt )C(C)MRIC)2, _N(t10)2, _c(0)R10, -C(0)0R1 , -0c(c)R10 , -NO2, =0, =S, =N(R1 ), and -CN; Ci-to alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORM, _sr.K 10, _ C(0)N(Rio)2, _malaK(0)R10 , p.,(0)N(R1 )2, -N(R1 )2, -C(0)R1 , -C(0)010 , -0C(0)10, -NO2, =0, =S, =N(I0), -CN, C3-12 carbocycle, and 3-to 12-membered heterocycle; and C3-12 carbocycle, and 3-to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R10, _SRIO, _c(c)N(Rto)2, _matoie, (0)R1 , -N(R1 )C(0)N(R1 )2, -N(R1 )2, -C(0)R1 , -C(0)0111 , -0C(0)11.1 , -NO2, 0,=S, =N(R1 ), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In certain embodiments, the substituents on R5 are independently selected at each occurrence from:
halogen, -ORm, -SR1 , -C(0)N(R10)2, -N(10)C(0)R10, -N(R10)C(0)N(R10)2, -N(10)2, -C(0)10, -C(0)010, -0C(0)R1 , -NO2, =0, =S, =N(R1 ), and -CN; Ci-to alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R' , -C(0)N(11.10)2, -N(R1 )C(0)R1 , -N(R1 )C(0)N(Rio)2, _Nc-R10)2, _cor _ C(0)010, -0C(0)11.10, -NO2, =0, =S, =N(R1 ), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle. In certain embodiments, the substituents on R5 are independently selected at each occurrence from: halogen, -0R10, -C(0)N(11.10)2, -N(Rto)c(0)Rio, _N(R10)2, _c(o)Rio, -C(0)010, -0C(0)R1 , -NO2, =0, and -CN; and Ci-m alkyl optionally substituted with one or more substituents independently selected from halogen, -OR', -N(I0)2, -C(0)R' , -C(0)011.10, -NO2, =0, and -CN. In some embodiments, R5 is not substituted.

[0187] In some embodiments, L2 is selected from -C(0)-, and -C(0)NR`o_. In some embodiments, 0 is -C(0)-. In some embodiments, L2 is selected from -C(0)NR1t. R1 of -C(0)NRIo_ may be selected from hydrogen and C1-6 alkyl. For example, L2 may be -C(0)NH-.
5 [0188] In some embodiments, le is selected from: -01t1 , -N(R1 )2, -C(0)N(R1 )2, -C(0)R1 , -C(0)0111 , -S(0)R1 , and -S(0)2R1 .; Ct-to alkyl, C2-to alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R' , -SR1 , _c (c)N(Rto)2, 4.4(R1 )C(0)111 , -N(Rw)C(0)N(Rto)2, _N(t10)2, -C(0)R1 , -C(0)0R1 , -0C(0)R1 , -NO2, :), =S, 10 =N(1410), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and carbocycle and 3- to 12-membered, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R10, -SR1 , -C(0)N(R10)2, -N(Rw)C(0)10 , -N(R1 )C(0)N(Rto)2, _ in )2 1,,(R__,, _ C(0)R1 , -C(0)0R' , -0C(0)R1 , -NO2, =0, =S, =N(R1 ), -CN, Ct-6alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some 15 embodiments, R.4 is selected from: -0R1 , and -N(R1")2; and CLAD alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR', -SR1 , - N(R1 )2, -S(0)R10, -S(0)211.10, -C(0)12.1 , -C(0)0100 , -0C(0)R1 , -NO2, =0, =S, =N(R1 ), -CN, Ct-to alkyl, C2-10 alkenyl, and C2-to alkynyl.
20 In certain embodiments, R4 is _Ts(R10)2. .tc, n10 of -N(R10)2 may be independently selected at each occurrence from optionally substituted C1-6 alkyl. In certain embodiments, R1 of -N(R1 )2is independently selected at each occurrence from methyl, ethyl, propyl, and tveN 1 butyl, any one of which is optionally substituted. For example, R4 may be CH3.
rcH3 A.,ii_NI.._ In certain embodiments, -L2-R4 is cH3.
25 [0189] In some embodiments, R12 is independently selected at each occurrence from halogen, -0R10, _SR10, _ma10)2, _ C(0)1e , -C(0)N(Rio)2, _N(Rto)cowto, -C(0)0R' , -0C(0)R10, -S(0)R10, -S(0)2R1 , -P(0)(0R10)2, -0P(0)(0R1 )2, -NO2, =0, =S, =N(R1- ), and -CN; Ct-io alkyl, C2-10 alkenyl, C2-lo alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OW , -SR ' , _ N(Rw)2, -C(0)Rio, -C(0)N(R10)2, -N(RP)C(0)R1 , -C(0)0111 , 5 -0C(0)R' , -S(0)Rt0, -S(0)2R10, -P(0)(0R1 )2, -0P(0)(010- )2, -NO2, =0, =S, =N(R10), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR', -SR', -N(R10)2, -C(0)Rio, -C(0)N(R1 )2, -N(R1 )C(0' - )K 1 , C(0)0R1 , -0C(0)R1 , -S(0)11.1 , 10 -S(0)2R1 , 13(0)(0R1 )2, -0P(0)(0R1 )2, -NO2, =0, =S, -N(R1 ), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In certain embodiments, R'2 is independently selected at each occurrence from halogen, -ORlo, _SR10, -MR10)2, -C(0)R10, -C(0)N(R10)2, -N(R1 )C(0)R1 , -C(0)0R1 , -0C(0)R1 ., -S(0)R1 , -S(0)2R1 , -13(0)(0R1 )2, -0P(0)(0R1 )2, -NO2, =0, =S, =N(R1 ), and -CN; and Ct-io alkyl, C2-to alkenyl, 15 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R' , _sty , _JAREN, _0(0)Rio, _c(c)mRio)2, -N(RE )C(0)R10, -C(0)0R10, -0C(0)R' , -S(0)R"), -S(0)21e, -P(0)(ORE )2, -0P(0)(0RE0)2, -NO2, =0, =S, =N(R1 ), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle.
20 101901 In some embodiments, the compound of Formula (IIB) is a compound of Formula (TC).
IR:

Rs- 0 L2_.4 (iic) or a pharmaceutically acceptable salt thereof, wherein:
10- and R2 are hydrogen;
25 L2 is -C(0)-;
IV is -N(R1 )2;
RI is independently selected at each occurrence from hydrogen, -NI-12, -C(0)0CH2C6H5.; and Ci-to alkyl, C2-to alkenyl, Ca-to alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, -C(0)0CH2C6H5, -NHC(0)0CH2C6H5, Ct-to alkyl, -C I- to haloalkyl, -0-Ci-to alkyl, C2-io 5 alkenyl, C2-10alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and haloalkyl;
is _c(o)N(Rto)_*, wherein * represents where 1,1 is bound to R5; and R5 is a fused 5-5, fused 5-6, or fused 6-6 bicyclic heterocycle, wherein R5 is optionally substituted and wherein substituents are independently selected at each occurrence from:
10 halogen, -0R10, -S100, -C(0)N(R1 )2, -N(W1C(0)R1 , -N(R1 )C(0)N(10 )2, -N(1012, -C(0)10- , -C(0)01013, -0C(0)10 , -NO2, =0, =S, =N(10 ), and -CN;
CI-toalkyl, C2-to alkenyl, C2-to alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR', 15 -SR1 , -C(0)N(P..1 )2, -N(10 )C(0)Rw, -N(10 )C(0)N(R1 )2, -N(R112, -COW), -C(0)0R' , -0C(0)10 , -NO2, =0, =S, =N(101, -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from 20 halogen, OW , -S111 , -C(0)N(1012, -N(11.1 )C(0)10 , -mitto)c(0)N-Rio)2, _N(Rto)2, -C(0)R1 , -c(o)aRi , -0C(0)R' , -NO2, =0, =S, =N(Rw), -CN, C1-6alkyl, C2-6alkertyl, and C2-6alkynyl.
[0191] In certain embodiments, 10 of -N(I0 )2is independently selected at each occurrence from methyl, ethyl, propyl, and butyl, any one of which is optionally 25 substituted, and/or 10 of -C(0)N(10 )-* is hydrogen.
[0192] In certain embodiments, R4 is -N(C14 alky1)2 and 1,1 is -C(0)N(H)-*.

[0193] In certain embodiments, R4 is CH3; and/or R1 of -C(0)N(Rlo)_*
is hydrogen.
[0194] In some embodiments, the compound is selected from:

N, no N..... NH2 ----- re-\
iii *
N 0 --- Nre\

o \---\
o , , O. o N, Nõ
N N
H
H
---- r---\ OH
---- is--\
N
N
OH
H
O.

* 0 N, N, N
* N
H
H
N
N

NH2 , HN

, N., )LcN
N
* N
H
H
--- rTh --- /Th N
N
, 0 , *

= N,H2 N.õ 4.
N N
N

0 \Th A
* ON * 0 N, 11 * ....-rms\
N
0 \---\
go% , 40) 0 ,N N, Cbz N Ili N
H fei\ NH2 H ---- r"\
N
N

czill cLii 0 , N., Nõ
N *NHCbz r__\ H2N ...õ f---\
N N
0 \Th 0 \Th N, NH2 40 te 0 cOs, I0 N, N ..
N
CbzHN H
H
r-\ H2N
Ac - r-\
N N
N

100 Nia.,-1 N._ NH2 N
N
HN% H
H
Cbz --- 11----S\ /---\
N
0 \----\ 0 \--\
H
o uN

Cbz,, N co...N

I
N..... NH2 HN --N., N, N
N
H
H
--- r---\
--- Nf----\
N
, HN

/ -41%,cu N, Cbz N
H
N
0 \--\
, H
0 0_.?
0 , * 0 N
B N
----r H
HO
N
, 0 0 ....n,ACUN N 0 N
II H *

__.- r \
N
, CbzHN
A.tri 40 ouN 0 N -------r--\
N

1 * rouN 0 HcI
N, -% 0 0 =
40) N,N

0 \Th 0 \Th H2N------CN it r-Dao F F ^ N
N, N
r-\
and and a salt of any one thereof.
5 101951 In some aspects, the present disclosure provides a compound represented by the structure of Formula (IIIA):

N¨R2 N

(IlIA) or a pharmaceutically acceptable salt thereof, wherein:
¨ represents an optional double bond;
10 L" is -X"-;
L2 is selected from -X2-, -X2-C1-6 alkylene-X2-, -X2-C2-6 alkenylene-X2-, and -X2-C2-6 alkynylene-X2-, each of which is optionally substituted on alkylene, alkenylene or alkynylene with one or more Rn;
X" is selected from -C(0)- and -C(0)N(11')-*, wherein * represents where X"
15 is bound to R6;

X2 at each occurrence is independently selected from a bond, -0-, -S-, -N(Rm)-, -C(0)-, -C(0)0-, -0C(0)-, -0C(0)0-, -C(0)N(R10)-, -C(0)N(R1 )C(0)-, C(0)N(R1 )C(0)N(R1 )-, -N(R1 )C(0)-, -N(R1 )C(0)N(R1 )-, -tm-R ow(0)0_, OC(0)N(R1 )-, -C(NRm)-, -mato)c(NRio)_, _0(NRio)N(Rto)_, _mktonNRtox,4(Rio)_, -S(0)2-, -0S(0)-, -S(0)0-, -S(0)-, -OS(0)2-, -S(0)20-, -N(1tm)S(0)2-, -S(0)2N(Rm)-, -N(144 )S(0)-, -S(0)N(141 )-, -N(141 )S(0)2N(Rm)-, and -N(1410)S(0)N(R1 )-;
141 and R2 are independently selected from hydrogen; Chi alkyl, C2-10 alkenyl, and C2-to alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OW , -SR'', -C(0)N(14.1 )2, -11,w o)2, _s(D)Rto, -S(0)2141 , -C(0)R10, -C(0)0141 , -OC(0)141 , -NO2, =0, =S, =N(R1 ), and -CN;
R4 is selected from: -Ole , -N(R1 )2, -C(0)N(R1 )2, -C(0)10 , -C(0)0R1 , -S(0)R1 , and -S(0)2R1 ; Ci-to alkyl, C2-to alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OW , -SRI , -C(0)N(14.1 )2, -N(R1 )C(0)R1 , -N(R1 )C(0)N(R1 )2, -N(R10)2, -C(0)R' , -C(0)0R10, -0C(0)R' , -NO2, =0, =S, =N(Rm), -CN, C3-12 carbocycle, and 3-to 12-membered heterocycle; and C3-12 carbocycle, and 3--to 12-membered heterocycle, wherein each C3-12 carbocycle, and 3- to 12-membered heterocycle in R4 is optionally substituted with one or more substituents independently selected from halogen, -OW , -SRI , -C(0)N(R1 )2, -N(R1 )C(0)R1 , -N(R1 )C(0)N(R1 )2, -N(R
112, -C(0)141 , -C(0)0R10, -0C(0)14.1 , -NO2, =0, =S, =N(R10), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6alkynyl;
146 is selected from phenyl and 5- or 6- membered heteroaryl, any one of which is substituted with one or more substituents selected from R7 and R6 is further optionally substituted by one or more additional substituents independently selected from R12;
R7 is selected from -C(0)NIINH2, -C(0)NH-CI-3alkylene-NH(R1 ), -C(0)CH3, -C1-3 alkylene-NHC(0)01411, -C1-3 alkylene-NHC(0)141 , -C1-3 alkylene-NHC(0)NHRto, -Ct-3a1ky1ene-NHC(0)-C 1-3 alkylene-1410, and a 3- to 12-membered heterocycle optionally substituted with one or more substituents independently selected from R12;
Rm is independently selected at each occurrence from hydrogen, -NH2, -C(0)0CH2C6H5; and Ci-io alkyl, C2-io alkenyl, Ca-to alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, -C(0)0CH2C6H5, -NHC(0)0CH2C6H5, -Ci-io alkyl, -Ci-to haloalkyl, -0-C i-to alkyl, 5 C2-m alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle;
R" is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from R12; and R12 is independently selected at each occurrence from halogen, -0R1 , -N(R1 )2, -C(0)R10, -C(0)N(R)2, -N(R.1 )C(Ort , -C K
(0)0R10, _oc(0oR10, _s(o)RlO, _s(0)2n _ P(0)(0R1 )2, -0P(0)(01V0)2, -NO2, =0, =S, =N(R1 ), and -CN; Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR', -N(R1 )2, -C(0)R1 , 2 -C(0)N(R1 0)µ, _ N(R1 )C(0)1t1 , -C(0)0R1 , -0C(0)11.1 , -S(0)R1 , -S(0)210 , 15 -P(0)(0R1 )2, -0P(0)(01:0 )2, -NO2, =0, ,s, _N(Rio), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle in R12 is optionally substituted with one or more substituents independently selected from halogen, -OR', am, _mRich2 _ ), C(0)100, -C(0)N(R10)2, - N(R1 )C(0)101, -C(0)0R1 , -0C(0)R10 , -S(0)R1 , -S(0)2Rio, P(0)(01;012, -0P(0)(0111 )2, -NO2, =0, =S, =N(R10), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; and wherein any substitutable carbon on the benzazepine core is optionally substituted by a substituent independently selected from R12 or two substituents on a single carbon atom combine to form a 3- to 7- membered carbocycle.

101961 In some embodiments, the compound of Formula (IIIA) is represented by Formula (MB):

N¨R2 n. 42 ,1 (IIIB) or a pharmaceutically acceptable salt thereof, wherein:
it20, 1(21, lc n22, and R23 are independently selected from hydrogen, halogen, -0R' , -SR10, -N(R1 )2, -S(0)R' , -S(0)21e , -C(0)R' , -C(0)011.1 , -0C(0)R' , -NO2, 5 =S, =N(R1 ), -CN, Ct-to alkyl, C2-10 alkenyl, and C2-10 alkynyl; and R24 and R25 are independently selected from hydrogen, halogen, -OR', -SRI', -N(Rn2, -S(0)11.1 , -S(0)2R1 , -Maw, -C(0)0R1 , -0C(0)11.1 , -NO2, =0, =S, =N(10), -CN, Ci-to alkyl, C2-to alkenyl, and C2-10 alkynyl; or R24 and R25 taken together form an optionally substituted saturated C3-7 carbocycle.
10 [0197] In some embodiments, R20 ., R21, R22, and R23 are independently selected from hydrogen, halogen, -OH, -NO2, -CN, and Ci-io alkyl. In certain embodiments, R20, R2i, Kn22, and R23 are each hydrogen. In some embodiments, RN and R25 are independently selected from hydrogen, halogen, -OH, -NO2, -CN, and C1-10 alkyl, or R24 and R25 taken together form an optionally substituted saturated C3-7 carbocycle. In 15 certain embodiments, R24 and R25 are each hydrogen. In certain embodiments, R24 and R25 taken together form an optionally substituted saturated C3-5 carbocycle.
[0198] In some embodiments, R1 is hydrogen. In some embodiments, R2 is hydrogen.
[0199] In some embodiments, L" is selected from ¨C(0)N(R1 )- *. In some 20 embodiments, 12.1 of -C(0)N(Rw)-* is selected from hydrogen and C1-6 alkyl. For example, L11 may be ¨C(0)NH-t.
[0200] In some embodiments, 12.6 is phenyl substituted with R7 and R6 is further optionally substituted with one or more additional substituents independently selected from R12. In some embodiments, 11.6 is selected from phenyl substituted with one or 25 more substituents independently selected from -C(0)NI-INH2, -C(0)NH-C1-3 alkylene-mwo%
) C 1-3 alkylene-NHC(0)R1 , and -C(0)CH3; and 3- to 12-membered heterocycle, which is optionally substituted with one or more substituents selected from ¨OH, -N(R10)2, ¨NHC(0)(Rt ), -NHC(0)0(R1 ), -NHC(0)N(R10)2, -C(0)R10 , -C(0)N(R1 )2, -C(0)2R1 , and -CL-3 alkyleneaw) and R6 is further optionally substituted with one or more additional substituents independently selected from Rn.
5 For example, le may be selected from:
HO
H2NHN HOLD 40) Si meo2c.

H 140 H 4111 CbzHNN

,CO2Me Olt 0 , and =
10 102011 In some embodiments, 11.6 is selected from a 5- and 6-membered heteroaryl substituted with one or more substituents independently selected from R7, and R6 is further optionally substituted with one or more additional substituents selected from 102. In certain embodiments, R6 is selected from 5- and 6-membered heteroaryl substituted with one or more substituents independently selected from -C(0)CH3, -C1-3 15 alkylene-NHC(0)0Rt , -CI-3 alkylene-NHC(0)Rt , -CI-3 alkylene-NHC(0)NHR10, and -C1-3 alkylene-NHC(0) -C1-3 alkylene-(R' ); and 3- to 12-membered heterocycle, which is optionally substituted with one or more substituents selected from ¨OH, -N(R1 )2, , ¨NHC(0),(Rio), NHC(0)0(R1 ), -NHC(0)N(R10)2, -C(0)R' , -C(0)N(RE )2, -C(0)2R' , and -C1-3 allcylene-(R' ), and PP is optionally further substituted with one or 20 more additional substituents independently selected from R12. R6 may be selected from substituted pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, oxazole, thiazole, imidazole, pyrazole, oxadiazole, oxathiazole, and triazole, and R6 is optionally further substituted with one or more additional substituents independently selected from R12.
In some embodiments, le is substituted pyridine and re is optionally further substituted with one or more additional substituents independently selected from Rn. 116 may be .....N1 70.1 represented as follows: R or N-LIMI
. In some embodiments, R6 is substituted pyridine, and wherein 117 is -CI-3 alkylene-NHC(0)-Ci-3 alkylene-r. In certain embodiments, le is -Ci alkylene-NHC(0)-Ci alkylene-10 . In certain embodiments, R7 is -Ci alkylene-NHC(0)-Ci alkylene-NH2. In some embodiments, 4 N oiN *
H H H N
N.......,.N......Xj.,"
I I
is selected from: 0 , cp , N
H %%a 4 NH He...,..ni N 4%....
N
N
H

N N
00) NH2 H .......ni 4 NH2 H .fil 2 N --...
N N., N
....14 --- , iio aior NHõ..L1, IL 411 ri.....õ0.1 CbzHN -'....tliN
I
-....

il Cbzhl , 0 JON N
0 .o.N
-laN H2N i i iji \ I

oxiiN
N
H3Cit,.... CjI
õ.õ..,-..NACINUI
I
\

N
OS
H2XH..,._ I H
,.._ .ir N."--"Lie)-)ss C bz H 4-Ntire N...."---"9-11/4" ebzHN

Cbz 0 , and 0 . In certain embodiments, le is Jcio,N
H2N-Thr [0202] In some embodiments, L2 is selected from -C(0)-, and -C(0)NR1 -. In some embodiments, L2 is selected from -C(0)NRio_. Rio of _c(o)NRio_ may be 5 selected from hydrogen and Cho alkyl. For example, 12 may be -C(0)NH-. In some embodiments, L2 is -C(0)-.
[0203] In some embodiments, 11.4 is selected from: -OR', -N(R1 )2, -C(0)N(R10)2, -C(0)R1 , -C(0)011.1 , -S(0)R' , and -S(0)2R1'; Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents 10 independently selected from halogen, -0R' , -SRn, -C(0)N(Rn)2, _N(Rio)c(0)R10 , -N(Rt )C(C)N(Rm)2, - (), FT Rio,2 _ C(0)R1 , -C(0)0R' , -0C(0)R1 , -NO2, =S, =N(R1 ), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle and 3- to 12-membered, each of which is optionally substituted with one or more substituents independently selected from halogen, -Ole , -SRI , -C(0)N(RI0)2, 15 -N(Rio)C(or _ N(Rm)C(0)N(Rw)2, _maio)2, _c(0)Rio, -0(0)01?-m, -0C(0)R10, -NO2, 0,=S, =N(Rw), -CN, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl_ In some embodiments, 10 is selected from: -OR' and -N(RE )2; and Ci-io alkyl, C2-10 alkenyl, C2-alkynyl, C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents 20 selected from halogen, -010, -N(RE )2, -S(0)11"), -S(0)2R10 _c(D)Rio, _ C(0)0R' , -0C(0)R1 , -NO2, =0, =S, =N(R1 ), -CN, Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl. In certain embodiments, R4 is _Is(R10)2 R10 of _N(tc.. n-- io )2 may be independently selected at each occurrence from optionally substituted Ci-6 alkyl. In some embodiments, RI of -N(R10)2 is independently selected at each occurrence from methyl, 25 ethyl, propyl, and butyl, any of which are optionally substituted. For example, R4 may ('CH3 (CH3 EVe ArNI

be CH3 In some embodiments, -L2-le is 102041 In some embodiments, R12 is independently selected at each occurrence from halogen, -ORth, -SR1 , -N(R10)2, _coy.n -C(0)N(R10)2,-N(Rt )C(0)R1 , -C(0)0R' , -0C(0)R1 , -S(0)R1 , -S(0)2R1 , -P(0)(0R1 )2, -0P(0)(0R1 )2, -NO2, =0, =S, =N(R1 ), and -CN; Ct-to alkyl, C2-10 alkenyl, C2-to alkynyl, each of which is 5 independently optionally substituted at each occurrence with one or more substituents selected from halogen, -01e , -S11.1 , -N(11.1 )2, -C(0)11.10, -C(0)N(R1 )2, -N(R1 )C(0)R1 , -C(0)0R10, -0C(0)R' , -S(0)R1 , -S(0)2R10, -P(0)(0R10)2, -0P(0)(ORP)2, -NO2, =0, =S, =N(Rw), -CN, C3-to carbocycle and 3- to 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is 10 independently optionally substituted at each occurrence with one or more substituents selected from halogen, -OR', = -N(I011)2, -C(0)R' , -C(0)N(R1 )2, -N(R1 )C(0)R1 , -C(0)0R10, -0C(0)R' , -S(0)R1 , -S(0)2R10, -P(0)(01120)2, -0P(0)(0R1 )2, -NO2, =0, =S, =N(Rw), -CN, Ct-6 alkyl, C2-6 alkenyl, and C2-6 allcynyl.
In certain embodiments, R12 is independently selected at each occurrence 15 from halogen, -0R1 , -SR1 , -N(R1 )2, -C(0)12.1 , -C(0)N(Rm)2, -N(R1 )C(0)R1 , -C(0)0 R10, -0C(0)10 , -S(0)10 , -S(0)2R' , _13(0)(0R1 )2, -0P(0)(01tw)2, -NO2, =0, =S, =N(11.10), and -CN; Ct-to alkyl, C2-to alkenyl, C2-loalkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -0R1 , = -N(R1 )2, -C(0)Rw, -C(0)N(R1 )2, -N(100)C(0)R1 20 0, -C(0)0R'0, -0C(0)11.1 , -S(0)111 , -S(0)2111 , -P(0)(013.1 )2, -0P(0)(0R1 )2, -NO2, =0, =S, =N(R1 ), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle.
102051 In some embodiments, the compound is selected from:
HO
CN

0 *
*
--0 issTh 0 'NM

HOo Si N, ags Cbz,,., CIN N
r, --iu 0 ....... i 11,_ iH AO- r---\
N
0 \---\
, H2N...ON N
y ) 0 Na._. NH2 H
N

ON N

N
ril *
N
0 \----\
, H2N __ter, N

n 0 N, N (00 H
--- Nr-\

.....N
0.,%.1 0 Nõ
VI *HN
....- rm, N
0 \---\
, N . 0 N

-- r, N
, H3C N, H so0 NC\....õ
0 z, , CbzHN..õ.õ...-,N 0 H N, NH2 N
H
---- Nr- \
0 Z, HN
N, *
--- C\
N
CbzHNI"---NEI *
0 \Th , * H

o N..... NH2 N
H
N

4 H H j xN N

N......e.N "-... N., I I
*
H
raj N

le ....N N

Ic....õ..c.....1,N * N, NH2 H H

N
0 \Th , N
*
NH H ..n 0 N
N
H
N

\---\ 5 *.
H %........a NH2 N
H

--- r-1 N

N
4 NH2 H ri- ) 0 N.,.....&.õ..A..N
N, H
--- ri N
N
H re1/4.n1 0... N .õic. ...............A . I ,N

*, H

N
0 \---\
, H j lei N -,..õ
N
N, NH2 N
, CbzHN-...---till 0 --õ,.
K., N *
H
--- Nr\
ihuuN 0 N___ N *
N

to H3c 40 0 N.....
M *
N

H CAC: )1 1 N, M SI
N

ri.., IN 0 N
CbzHIXt N
H

--- CI\
N
0 \----\
, JuN 0 N
H2 ...N)Cir N
H

N/Th , N
CbzHN N
H
N
N
N
H

N
-_.
H
Cbz 0 /Th N
CO2 Me %.;
N
Me02C. 40 0 N NH2 --.
It le N , H
H
N N --- /--\
--- /Th N
N
N
tx H

H2N....õ..T.N \

--- re-\
N
, and 0 \-1\ and a salt of any one thereof.
[0206] In some aspects, the present disclosure provides a compound represented by the structure of Formula (IA):

N, (IA) or a pharmaceutically acceptable salt thereof, wherein:
- represents an optional double bond;
12 is selected from -XI-, -X2-C1-6 alkylene-X2-Ci-6 alkylene-, -X2-C2-6 5 alkenylene-X2-, and -X2-C2-6 alkynylene-X2-, each of which is optionally substituted on alkylene, alkenylene or alkynylene with one or more RP, L2 is selected from -X2-, -X2-C 1-6 alkylene-X2-, -X2-C2-6 alkenylene-X2-, and -X2-C2-e alkynylene-X2-, each of which is optionally substituted on alkylene, alkenylene or alkynylene with one or more Rt2;
10 r is selected from -S-*, -N(Rm)-*, -C(0)0-*, -0C(0)-*, -0C(0)0-*, -C(0)N(R1 )C(0)- *, -C(0)N(R1 )C(0)N(Rw)*, -N(RnC(0)-*, -CRt 2N(R1 )C (0)-*, -N(1V )C(0)N(R1 )-*, -N(1V )C(0)0-*, -0C(0)N(R15-*, -C(NR1 )-*, -N(Rt )C(NRI )-*, -C(N10 )N(R1 )-*, -N(R1 )C(NR1 )N(Rn-*, -S(0)2-*, -0S(0)-*, -S(0)0-*, -S(0), -0S(0)2-*, -S(0)20*, -N(Rw)S(0)2-*, -S(0)2N(R1 )-*, 15 -N(RnS(0)-*, -S(0)N(R1 )-*, -N(Rm)S(0)2N(R1 )-*, and -N(10 )S(0)N(R1 )-*, wherein * represents where X1 is bound to R3;
X2 is independently selected at each occurrence from -0-, -S-, -N(101)-, -C(0)-, -C(0)0-, -0C(0)-, -0C(0)0-, -C(0)N(100)-, -C(0)N(Rt )C(0)-, -C(0)N(R1 )C(0)N(R1 ), -N(R1 )C(0)-, -N(R1 )C(0)N(R1 )-, -N(Rt )C(0)0-, 20 -0C(0)N(Rm)-, -C(NRw)-, -N(R1 )C(NR1 )-, -C(N11.1 )N(Rm)-, -N(10 )C(NR1 )N(Rm)-, -S(0)2-, -0S(0)-, -S(0)0-, -S(0), -OS(0)2-, -S(0)20, -N(Rw)S(0)2-, -S(0)2N(111 )-, -N(Rt )S(0)-, -S(0)N(11.11-, -N(11.1 )S(0)2N(R1 )-, and -N(Rw)S(0)N(Rw)-;
R1 and R2 are independently selected from hydrogen; Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more substituents 25 independently selected from halogen, -01e , -SRt , -C(0)N(R10)2, -N(Rm)2, -S(0)10 , -S(0)212-1 , -C(0)10 , -C(0)0R1 , -0C(0)R' , -NO2, =0, =S, =N(R1 ), and -CN;

IV is selected from optionally substituted C3-12 carbocycle, and optionally substituted 3- to 12-membered heterocycle, wherein substituents on R3 are independently selected at each occurrence from: halogen, -OW , -SW , -C(0)N(R1 )2, -N(RP)C(0)R' , -N(R40)C(0)N(R1)2, -N(R112, -C(0)11P, -C(0)01e , -00potio, 5 -Nth, =0, =S, =N(101, and -CN; Ct-to alkyl, C2-10 alkenyl, C2-toalkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OW , -SW , -C(0)N(R40)2, -N(Rw)C(0)RP, -N(LOC(0)N(R10)2, -N(R1 )2, -C(0)R1 , -C(0)0R1 , -0C(0)11P, -NO2, =0, =S, =N(R1 ), -CN, C3-12 carbocycle, and 3-to 12-membered heterocycle; and C3-12 carbocycle, and 3-to 12-membered 10 heterocycle, wherein each C3-12 carbocycle, and 3- to 12-membered heterocycle in 112 is optionally substituted with one or more substituents independently selected from halogen, -OW , -SW , -C(0)N(R40)2, -N(Rw)C(0)R4 , -N(100)C(0)N(R10)2, -N(R10)2, -C(0)R1 , -C(0)0R1 , -0C(0)11P, -NO2, =0, =S, =N(R1 ), -CN, Ct-is alkyl, C2-6 alkenyl, and C2-6alkynyl;
15 le is selected from: -01V , -N(W12, -C(0)N(R10)2, -C(0)0R1 , -S(0)R' , and -S(0)2R1 ; Ci-to alkyl, C2-10 alkenyl, C2-loalkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OW , -SW , -C(0)N(R40)2, -N(11.1 )C(0)Rw, -N(R1 )C(0)N(R10)2, -N(R10)2, -C(0)10- , -C(0)0R10, -0C(0)R4 , -NO2, =0, =S, =N(R1"), -CN, C3-12 carbocycle, and 20 3-to 12-membered heterocycle; and C3-12 carbocycle, and 3-to 12-membered heterocycle, wherein each C3-12 carbocycle, and 3- to 12-membered heterocycle in R4 is optionally substituted with one or more substituents independently selected from halogen, -OR', -SW , -C(0)N(R4 )2, -N(R1 )C(0)Rm, -N(R1 )C(0)N(R10)2, -N(1110)2, -C(0)R1 , -C(0)0R4 , -0C(0)R4 , -NO2, =0, =S, =N(R10), -CN, C1-6 alkyl, C2-6alkenyl, 25 and C2-6alkynyl;
Itm is independently selected at each occurrence from:
hydrogen, -NH2, -C(0)0CH2C61-15; and Ci-to alkyl, C2-to alkenyl, C2-to alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -NI-12, =S, -C(0)0CH2C6H5, -NHC(0)0CH2C6H5, C1-10alkyl, C2-to alkenyl, C2-toalkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and haloalkyl; and R12 is independently selected at each occurrence from halogen, -OR", -SR", -N(R")2, -C(0)R1 , -C(0)N(R10)2, -N(Rm)C(0)1V- , -C(0)0R", -0C(0)R10, -S(0)11P, -S(0)21e , -P(0)(OR")2, -0P(0)(011.1 )2, -NO2, =0, =S, =N(R1 ), and -CN; C'4) alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more 5 substituents independently selected from halogen, -OR10, _SR", _N(RE0)2, -C(0)R' , -C(0)N(Rio)2, _mato)coynio, -C(0)0R", -0C(0)R", -s(o)Rio., _s(0)2Rto, -P(0)(0R10)2, -0P(0)(0R10)2, -NO2, =0, =S, =N(11"), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle in 111-2 is optionally 10 substituted with one or more substituents independently selected from halogen, -OR", _swop, _N(Rio)2, _icor to, _ K C(0)N(Rio)2, N(Rio)cor to, _ K
C(0)0R", -0C(0)R", -S(0)R", -S(0)2R' , P(:WOR")2, -0P(0X0R10)2, -NO2, =0, =S, =N(W-1), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; and wherein any substitutable carbon on the benzazepine core is optionally 15 substituted by a substituent independently selected from RI' or two substituents on a single carbon atom combine to form a 3- to 7- membered carbocycle 102071 In some embodiments, the compound of Formula (IA) is represented by Formula OB):
Ri R22 R-=>-n (1B) 20 or a pharmaceutically acceptable salt thereof, wherein:
R20, R21, R22, and n n 23 are independently selected from hydrogen, halogen, -OR", -sinK _ 10, WRILe)2, -S(0)R1 , -S(0)2R' , -C(0)R' , -C(0)0R1 , -0C(0)R1 , -NO2, =S, =N(Itn, -CN, Cr-to alkyl, C2-10 alkenyl, and C2-to alkynyl; and R24 and K-25 are independently selected from hydrogen, halogen, -OR', -SR", 25 -N(W1)2, -S(0)Rm, -S(0)2R", -C(0)R", -C(0)0R1 , -0C(0)RP, -NO2, =0, =S, =Noce), -CN, C1-to alkyl, C2-to alkenyl, and C2-to alkynyl; or R24 and 1125 taken together form an optionally substituted saturated C3-7 carbocycle.
[0208] In some embodiments, R20, R21, R22, and ts. r. 23 are independently selected from hydrogen, halogen, -OH, -NO2, -CN, and Ci-to alkyl. In certain embodiments, 1120 , 5 1121, 11 22, and 1123 are each hydrogen.
[0209] In some embodiments, R24 and R25 are independently selected from hydrogen, halogen, -OH, -NO2, -CN, and Ci-to alkyl, or R24 and 1125 taken together form an optionally substituted saturated C3-7 carbocycle. In some embodiments, R24 and 1125 are each hydrogen. In some embodiments, R24 and 1125 taken together form an 10 optionally substituted saturated C3-5 carbocycle.
[0210] In some embodiments, R1 is hydrogen. In some embodiments, R2 is hydrogen.
[0211] In some embodiments, is selected from -N(RO)C(0)-*, -S(0)2N(Rn-*, _cRio2N(Rto)c *and -X2-C1-6 alkylene-X2-Cl-6 alk-ylene-. In some embodiments, 15 1.2 is selected from -N(R1 )C(0)-*. In certain embodiments, le of -N(R1 )C(0)-* is selected from hydrogen and C1-6 alkyl. For example, may be -N1HC(0)-*. In some embodiments, 1,1 is selected from -S(0)2N(Rm)-*. In certain embodiments, Rio of -S(0)2N(R1 )-* is selected from hydrogen and C1-6 alkyl. For example, I2 is -S(0)2N1-I-*. In some embodiments, 12 is -CR1 2N(R10)C(0)-*. In certain embodiments, 1,1 is 20 selected from -CH2N(H)C(0)-t and -CH(CH3)N(H)C(0)-4.
[0212] In some embodiments, 10 is selected from optionally substituted C3-12 carbocycle, and optionally substituted 3- to 12-membered heterocycle, wherein substituents on R3 are independently selected at each occurrence from:
halogen, -OR', -C(0)N(R1 ) _ N(R1 )C(0)10 , -N(R1 )C(0)N(R10)2, _N(R10ftµ, _ C(0)R1 , 25 -C(0)0R1 , -0C(0)R' , -NO2, =0, ¨S, ¨114(R10), and -CN; Ci-to alkyl, C2-10 alkenyl, C2-alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R10, _c(o)N(Rto)2, _NR10),c(o)Rio, -N(12.1 )C(0)N(R 1)2, - ) _ C(0)R1 , -C(0)01011, -0C(0)100, -NO2, =S, =N(R1 ), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 30 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR', -Sltm, -C(0)N(Rlo)2, _ in Notic(0)Rto, _N(R1 )µ..`"(0)N(Rw)2, -N(Rw)2, -C(0)11.10, -C(0)0R' , -0C(0)R' , -NO2, =0, =S, =N(Rw), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In certain embodiments, R3 is selected from optionally substituted C3-12 carbocycle, and optionally substituted 3- to 12-membered heterocycle, wherein substituents on R3 are 5 independently selected at each occurrence from: halogen, 0R' ,-_snK, _ 10 C(0)N(Rw)2, -mitio)c(o)Rto, _mg.to)c onRio)2, _r,4(Rio)2, -C(0)R' , - C(0)0R1 , -0C(0)R1 , -NO2, =S, =N(Rw), and -CN; Ct-to alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR', _SRI , _C(0)N(R10)2, -N(lut)c(c)Rio, _mat )µ...7(0)N(11.192, -N(R10)2, -10 C(0)R' , -C(0)0R' , -0C(0)R' , -NO2, =0, =S, -N(Rw), -CN, C3-12 carbocycle, and 3-to 12-membered heterocycle.
[0213] In some embodiments, R3 is selected from an optionally substituted aryl and an optionally substituted heteroaryl. In some embodiments, R3 is an optionally substituted heteroaryl. R3 may be an optionally substituted heteroaryl substituted with 15 one or more substituents independently selected from halogen, -ORto, am, _N(Rio)2, _ C(0)10), -C(0)0R' , -0C(0)R' , -NO2, =0, =S, -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In certain embodiments, R3 is selected from an optionally substituted membered heteroaryl. For example, R3 may be an optionally substituted pyridine. In some embodiments, R3 is an optionally substituted aryl. In certain embodiments, R3 is 20 an optionally substituted aryl substituted with one or more substituents independently selected from halogen, -ORIO, _SR10, _NR10)2, _c(or _ 10, K C(0)0R1 , -0C(0)R' , -NO2, =0, =S, -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. R3 may be an optionally substituted phenyl. In certain embodiments, R3 is selected from pyridine, phenyl, tetrahydronaphthalene, tetrahydroquinoline, tetrahydroisoquinoline, indane, 25 cyclopropylbenzene, cyclopentapytidine, and dihydrobenzoxaborole, any one of which oisN Sop is optionally substituted. R3 may be selected from:

HN
.4111 HO
oat N
B
I col se . 0 NA 6 OP
H

, any one of which is optionally substituted. For example, IV may be selected from:

OH
N
, cl 0 0 0 all el OH
H
N, HN 40) Iii filli 5 , , , H

N
A 101 011n CAN
.--....... 1 III
CbzeN le NE-I2 * , g )011 N
I
c Ø1 N
cal 40 411 = 411 NHCbz , H2N CbzHN H2N CbzHN
, , .
HOlo HOCIN oi 0 N .µ H2NHN le --)HON le (-Tiy lir CbzHN---.N 0 H

s s s N
N
H
H H
N .,_____ -=-Ø. IMI
lie N.,,e, N.,..X.)../"....
C bzHN ---..' I:1 11. 411 I I

, , , SI N _N
NH
N
H

N 1111 1-12 H .....X.11 ilin -z N "..., Irl jt,.*ey 1t N ' N
, N

il,,,,,a 01 11,,Jai , N
N......niess H
H2Neet.MN 1 CbzHN --11 1 I -Atli CbzHN-ItrN ...--- I ...õ. 1 %,.. -.....

, , IS tuai t.,0,,es,,N
II
k4e02c.

CbzHN 0 N õ
,CO2Me N
N
i ii# . ili Cbz 0 HO,B HR C bZ
i HO
B N H
v 5 , and CbzHN
.
102141 In some embodiments, L2 is selected from -C(0)-, and -C(0)NRio_. In certain embodiments, L2 is -C(0)-. In certain embodiments, L2 is selected from -C(0)NRio_. RID of _c(0)NR10_ may be selected from hydrogen and Ci-6 alkyl.
For example, L2 may be -C(0)NH-.

102151 In some embodiments, R4 is selected from: -0R10, -N(Rw)2, -C(0)N(10)2, -C(0)R' , -C(0)0100, -S(0)R' , and -S(0)210; Ci-io alkyl, C2-10 alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -01tw, -SRM, _coysst(t10)2, _N(R1th)..."(0)R1 , -N(R1 )C(C)N(RECI)2, -N(R10)2, -C(0)R10, -C(0)0R1 , -0C(0)R10, -NO2, =0, =S, 15 =N(Rw), -CN, C3-I2 carbocycle, and 3-to 12-membered heterocycle; and C3-carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R' , -Sltw, -C(0)N(Rl0)2, _N(Rio)c(0)Rio, _ N(R1 )C(0)N(R1 )2, 'T kn..'" J-N4 1 )2, -C(0)R' , C(0)0R1 , -0C(0)R' , -NO2, =0, =S, =N(Rw), -CN, CI-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

102161 In some embodiments, 114 is selected from: -OW , -N(Rw)2, n io, -C(0)N(R10)2, -C(0)R1 , -C(0)0k -S(0)R' , and -S(0)2R' ; Ci-io alkyl, C2-10 alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R1 , _sin to, ts. -C(0)N(Rm)2, -N(R1 )C(0)R1 , -N(R1 )C(0)N(R113)2, ) _ C(0)R1 , -C(0)0R1 , -0C(0)R1 , -NO2, =0, =S, =N(10), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some 5 embodiments, 11.4 is selected from: -Ole , and -N(Rm)2; and Ci-io alkyl, C2-10 alkenyl, C2-10alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, _caw, _SRI , ) _ S(0)10 , -S(0)210, -C(0)R1 , -C(0)010 , -0C(0)R' , -NO2, =0, =S, =N(11.11), -CN, Ct-to alkyl, C2-10 alkenyl, and C2-10 alkynyl.
10 In certain embodiments, R4 is -MR10)2. tic -=-= 10 of -N(Rm)2 may be independently selected at each occurrence from optionally substituted C1-6 alkyl. In certain embodiments, IV
of-N(R10)2 is independently selected at each occurrence from methyl, ethyl, propyl, and butyl, any one of which is optionally substituted. For example, 10 may be CH3.
cscr.N1,1 0 1, In certain embodiments, L2-R4 is CH3.
15 102171 In some embodiments, R12 is independently selected at each occurrence from halogen, -OR10, _SRN, _N(R10)2, _garb 10, _ tr.
C(0)N(Rm)2, -N(11.1 )C(0)R1 , -C(0) R' , _Oc(0)Rio, _spy. io, _ S(0)2Rm, -P(0)(0R10)2, -0P(0)(0R10)2, -NO2, =0, =S, =N(Rm), and -CN; Ct-io allcyl, C2-10 alkenyl, C2-w alkynyl, each of which is optionally substituted with one or more substituents independently selected from 20 halogen, -0R' , 2 _N(Rto,), _ C(0)R1 , -C(0)N(R10)2, _We:W(0)R', -C(0)011.1 , -0C(0)11.1 , -S(0)R10, -S(0)2R10, -P(0)(0R10)2, -0P(0)(0R10)2, -NO2, =0, =s, =N(Rio), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and C3-10 carbocycle and 3-to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R10, _SRM, - N(R112, -C(0)11.1 , 25 -C(0)N(Rio, ) N(R1 )C(0)R1 ,-C(0)0R1 , -0C(0)R1 , -S(0)11.1 , -S(0)211.10 , -P(0)(0R1 )2, -0P(0)(01k10)2, -NO2, =0, =S, =N(R1 ), -CN, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl. In some embodiments, R" is independently selected at each occurrence from halogen, -ORm, -SRm, -N(R10)2, _c(o)Rto, _c(0)N(R10)2, _Nottonowto, _ C(0)0R1 , -0C(0)R1 , -S(0)1e, -S(0)2R' , -P(0)(0R1 )2, -0P(0)(011.1 )2, -NO2, =0, =S, =N(111 ), and -CN; Ct-to alkyl, C2-10 alkenyl, C2-to alkynyl, each of which is 5 optionally substituted with one or more substituents independently selected from halogen, -OR'", _N(t to)2, -C(0)11-10, -C(0)N(R10)2, -N(R.1 7)C(0)r-C(0)011."), -0C(0)11.1 , -S(0)R1 , -S(0)2100, -11(0)(01;t10)2, -0P(0)(010 )2., -NO2, =0, =S, =N(11.1 ), -CN, C3-io carbocycle and 3- to 10-membered heterocycle.
102181 In some embodiments, the compound is selected from:

cy N, NH:

r-\

,and a salt of any one thereof.
102191 In some aspects, the present disclosure provides a compound represented by the structure of Formula (IVA):
N¨R2 Ra (IVA) 15 or a pharmaceutically acceptable salt thereof, wherein:
¨ represents an optional double bond;
L12 is selected from -30-, -X3-C1-6 -V-C2-6a11eny1ene-X3-, and alkynylene-V-, each of which is optionally substituted on alkylene, alkenylene, or allcynylene with one or more substituents independently selected from 20 Rt2;
L22 is independently selected from -X4-, -X4-C1-6 alkylene-r-, -r-C2-6 alkenylene-r-, and -r-C2-6 alkynylene-r-, each of which is optionally substituted on alkylene, alkenylene, or alkynylene with one or more substituents independently selected from Rix%
X3 and X4 are independently selected at each occurrence from a bond, -0-, -S-, -N(R1 )-, -C(0)-, -C(0)0-, -0C(0)-, -0C(0)0-, -C(0)N(RIc)_r,, _ C(0)N(R1 )C(0)-, -C(0)N(R1 )C(0)N(R1 )-, -N(Rw)C(0)-, -N(R1 )C(0)N(R1 )-, -N(Rm)C(0)0-, -0C(0)N(10)-, -gmtio)_, _mitio)c(NRKI)_, _gNRio)N(Rio)-, -N(R1 )C(N10)N(Rm)-, -S(0)2-, -0S(0)-, -S(0)0-, -S(0)-, -OS(0)2-, -S(0)20-, -N(Rm)S(0)2-, _ -S(0)2N(Rio,), _ N(RnS(0)-, -S(0)N(Rm)-, -N(10)S(0)2N(Rm)-, and -N(R1 )S(0)N(R")-;
It1 and R2 are independently selected from 1,3, and hydrogen; and Ci-io alkyl, 10 alkenyl, and C2-10 alkynyl, each of which is optionally bound to 1_,3 and each of which is optionally substituted with one or more substituents independently selected from halogen, -OR', -S10, -C(0)N(Rm)2, -N(10)2, -S(0)10, -S(0)2R' , -C(0)R1 , -C(0)010, -0C(0)10, -NO2, =0, =S, =N(R"), and -CN;
le and le are independently selected from: -0R1 , -N(R1 )2, -C(0)N(10)2, -C(0)R' , -C(0)0R", -S(0)R1 , and -S(0)2R' ; Ci-to alkyl, C2-10 alkenyl, C2-to alkynyl, each of which is optionally bound to I-3 and each of which is optionally substituted with one or more substituents independently selected from halogen, -OR", -SRm, -C(0)N(R1 )2, -N(10)C(0)R1 , -N(10)C(0)N(10 )2, -N(R1 )2, -C(0)10, -C(0)010, -0C(0)10, -NO2, =0, =S, =N(R1 ), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle, and 3- to 12-membered heterocycle in 14.4 and le is optionally bound to L3 and each of which is optionally substituted with one or more substituents independently selected from halogen, -0R1 , -SRI', -C(0)N(R1 )2, - N(R1 )C(0)10, -N( 10)C(0)N(R1 )2, -N(Rm)2, -C(0)Rm, -C(0)010 , -0C(0)11.10, -NO2, =0, =S, -N(Rm), -CN, C1-6alkyl, C2-6 alkenyl, and C2-6 alkynyl;
10 is independently selected at each occurrence from 1,3, hydrogen, -Nib, -C(0)0C112C6H5; and Ci-to alkyl, C2-10 alkenyl, C2-to alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -NI-12, =0, =S, -C(0)0CH2C6H5, -NHC(0)0CH2C6H5, C i-io alkyl, C2-io alkenyl, C2-to alkynyl, C3-carbocycle, 3- to 12-membered heterocycle, and haloalkyl;
L3 is a linker moiety, wherein there is at least one occurrence of L3; and R12 is independently selected at each occurrence from halogen, -0R1 , -N(R1 )2, -C(0)R' , -C(0)N(R1 µ , - p N(R10)C(0)R1 , -C(0)0R' , _oc(D)Rio, _s(0)Rio, )2n to, _ -S(0 K P(0)(0R"))2, -0P(0)(0R1)2, -NO2, =0, =S, =N(R1 ), and -CN; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR'), ) _ C(0)R1 , -C(0)N(R10)2, -N(RIG)C(0'fttc. 1 , -C(0)0R1 , -0C(0)11.1 , -S(0)11.1 , -S(0)211.10 , -P(0)(0R152, -013(0)(010 )2, -NO2, =0, =S, -N(11.1 ), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle in R12 is optionally substituted with one or more substituents independently selected from halogen, -0R1 , am, _ C(0)R1 , -C(0)N(R1 0-.)2 _, MR1 )C(0)R1 , -C(0)0R1 ., -0C(0)R1 , -S(0)11.1 , -S(0)2Rto, _ P(OX0111 )2, -0P(OX0R1 )2, -NO2, =0, =S, =N(11.1 ), -CN, C1-6 alkyl, C2-6 alkenyl, C24 alkynyl;
wherein any substitutable carbon on the benzazepine core is optionally substituted by a substituent independently selected from R12 or two substituents on a single carbon atom combine to form a 3- to 7- membered carbocycle.
102201 In some embodiments, the compound of Formula (WA) is represented by Formula (P/13):
Ri R2o R8,L12 N' (IVB) or a pharmaceutically acceptable salt thereof, wherein:
R20, R21, R22, and R23 are independently selected from hydrogen, halogen, -OR', -sinK _ 10, MR113)2, -S(0)R1 , -S(0)2R10, -C(0)0R1 , -0C(0)R1 , -NO2, =S, =N(R1 ), -CN, Ct-to alkyl, C2-lo alkenyl, and C2-10 alkynyl; and 1&24, and R25 are independently selected from hydrogen, halogen, -OR', -SRm, -N(R1e)2, -S(0)114- , -S(0)2R10, -C(0)R' , -C(0)011410, -0C(0)R' , -NO2, =0, =S, =N(Rio), _ CN, Ci-to alkyl, C2-to alkenyl, and C2-10 alkynyl; or R24 and R25 taken together form an optionally substituted saturated C3-7 carbocycle.
5 [0221] In some embodiments, le is L3. In some embodiments, 112 is L3.
[0222] In some embodiments, 1_,12 is _c(o)mR10)_.
In some embodiments, Rrn of -C(0)N(R1 )- is selected from hydrogen, C1-6 alkyl, and L3. For example, L12 may be ¨C(0)NH-.
[0223] In some embodiments, 118 is an optionally substituted 5- or 6-membered 10 heteroaryl. le may be an optionally substituted 5- or 6- membered heteroaryl, bound to L3. In some embodiments, le is an optionally substituted pyridine, bound to L3.
[0224] In some embodiments, L22 is selected from -C(0)-, and -C(0)NR10-. In certain embodiments, L22 is -C(0)-. In certain embodiments, L22 is -C(0)Nr-.
Rw of -C(0)NRio_ may be selected from hydrogen, C1-6 alkyl, and ¨L3. For example, L22 may 15 be-C(0)NH-.
[0225] In some embodiments, R4 is selected front -010 , and -N(RI0)2; and Cl-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, aryl, and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORM, _SRM, -N(R10)2t _ S(0)1e , 20 -S(0)211m, _0(0)Rio, _ C(0)0114- , -0C(0)R' , -NO2, =0, =S, =N(R1 ), -CN, Ci-io alkyl, C2-10 alkenyl, and C2-to alkynyl and each of which is further optionally bound to L3 In some embodiments, R4 is -N(Rn2 and 124- of -N(11412 is selected from L3 and hydrogen, and wherein at least one le of -N(R1 )2 is L3.
[0226] In some aspects, the compound of Formula (IVB) is a compound of 25 Formula (IVC).

N¨R2 L12 N, (Iv.) or a pharmaceutically acceptable salt thereof, wherein:

le and R2 are hydrogen;
L22 is _c(o)_;
R4 -N(R1 )2;
RR) is independently selected at each occurrence from hydrogen, -NI-12, 5 -C(0)0C1FC6H5; and Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -NH2, =0, =S, -C(0)0C1tC6F15, -NHC(0)0CH2C6H5, Ci-io alkyl, C2-io alkenyl, C2-to alkynyl, C3-carbocycle, 3- to 12-membered heterocycle, and haloalkyl;
10 Li2 is _c(0)*Rici,_ ) *, wherein * represents where L12 is bound to Rs;
Rs is an optionally substituted fused 5-5, fused 5-6, or fused 6-6 bicyclic heterocycle bound to linker moiety, 1,3, and wherein optional substituents are independently selected at each occurrence from:
halogen, -0R1 , -C(0)N(R10)2, -N(R1 )C(0)R1 , -N(14.1 )C(0)N(R10)2, 15 -N(R11)2, -C(0)R' , -C(0)0R1 , -0C(0)R1 , -NO2, =0, =S, =N(R1 ), and -CN;
Ci-to alkyl, C2-10 alkenyl, C2-to alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -01e, -S11.1 , -C(0)N(R10)2, -N(R1 )C(0)R1 , -N(R1 )C(0)N(R10)2, -N(R10)2, -C(0)R10, -C(0)0R' , -0C(0)R1 , -NO2, =0, =S, =N(R1 ), -CN, C3-12 carbocycle, and 3- to 12-membered 20 heterocycle; and C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -010 , -SR1 , -C(0)N(R1 )2, -N(R1 )C(0)Rm, -N(R1 )C(0)N(R10)2, -N(1110)2, -C(0)1011, -C(0)0R'0, -0C(0)R1 , -NO2, =0, =S, =N(R10), -CN, C1-6alkyl, C2-6 alkenyl, 25 and C2-6alkynyl.
102271 In certain embodiments: Rl of -N(R1 )2is independently selected at each occurrence from methyl, ethyl, propyl, and butyl, any one of which is optionally substituted. In certain embodiments, le of -C(0)N(Rm)-* is hydrogen.
102281 In certain embodiments, R4 is -N(C14alkyl)2 and L12 is -C(0)N(H)-*.

veNI
102291 In certain embodiments, R4 is CH3; and/or Rm of -C(0)N(R10)_*
is hydrogen.
02301 In some embodiments, the compound is further covalently bound to a linker, L3. In some embodiments, L3 is a noncleavable linker. In some embodiments, 5 L3 is a cleavable linker. L3 may be cleavable by a lysosomal enzyme. In some embodiments, the compound is covalently attached to an antibody. In some embodiments, the antibody specifically binds to a tumor antigen. In some embodiments, the antibody comprises a target binding domain.
102311 In some embodiments, L3 is represented by the formula:

l -kto L4.--peptide-,L5-RX e We-wherein:
L4 represents the C-terminus of the peptide and L5 is selected from a bond, alkylene and heteroalkylene, wherein L5 is optionally substituted with one or more groups independently selected from R32, and RX is a reactive moiety; and 15 R32 is independently selected at each occurrence from halogen, -OH, -CN, -0-alkyl, -SH, =0, =S, -Nth, -NO2; and CI-to alkyl, C2-to alkenyl, C2-to alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -0-alkyl, -SH, =0, =S, -NH2, -NO2.
102321 In some embodiments, RX comprises a leaving group. In some 20 embodiments, RX comprises a maleimide. In some embodiments, L3 is further covalently bound to an antibody. In some embodiments, the antibody is directed against a tumor antigen. In some embodiments, the antibody comprises a target binding domain.
102331 In some embodiments, L3 is represented by the formula:

X-ILO
wherein L4 represents the C-terminal of the peptide and L5 is selected from a bond, alkylene and heteroalkylene, wherein 1.2 is optionally 5 substituted with one or more groups independently selected from R32;
Rrcomprises a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein -S. on RX* represents the point of attachment to the residue of the antibody; and, R32 is independently selected at each occurrence from halogen, -OH, -CN, 10 alkyl, -SH, =0, =S, -NH2, -NO2; and Ct-io alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -0-alkyl, -SH, =0, =S, -N112, -NO2. In some embodiments, the peptide of L3 comprises Val¨Cit or Val¨Ala.
102341 In some aspects, the present disclosure provides a compound or salt 15 selected from:

HN
o H.21-11.(11 triN

0 4i kiJ N N, o 0 \--\
H2N.f.0 HN
o H
\rENI
N
H 0 Oil N, r¨s\
o N

H
rfat ) N H2 N, ..
H
il 0 H
N

HN

, N
0 H in' N H2 y111.--'.-SN N, . 0 ..
H
ri 0 H i H
N
0 Of HN

, IIP
0 r ...i.,1 o ce.0 A.
111 Nõ NH2 0 XrrEi 0 0 0 N **--"-se .C.A.%=N
H H *
/ N ,........-..,.............A N ...N

N
H H
N
o o NH
A-_iL

, c.NO N )criii N *
o --N, N H2 H
H
rj -N
NH
='---, H2N y0 HN

*
H H

N,.,,,..,%, 0 ty N 0 niNkl H

N
N
H
-- r-=
N

H2Ny0 HN

kk_k H
0 0 *
0 = y ri 041. 0 N

H2Ny0 FIN

)LicewliNix2NkN

0 0 *

0 HAOuN 0 N, -0 \ \
H2Ny0 FIN

N

H
N

N, r¨\\

H2N tO
HN

H

re. N

N

Nr 0 \

H2Nto HN

N....}.. N
r t X ill 0 Ill 0-ITA

0 n N
NU
N
H
1k_4? N"' H2Nt0 HN
0 1-111141y1Icil N
err N N 1 0 0 0 40 0,.....eNaiN
õ

II H
0 \Th, H2Ny0 HN

11;11 J.:111(111 N
err i NI 0 s 0rais 0 0 .............õ
,,,...eN ---...i N, H N
H
N
0 \Th , o o o ON -)0 0 ouN 0 A.
cl....N.............301... "--rir rii 0 .
N._ NH2 N N
N
H H
H

--- C\
N
Hy 0 \Th.
H2N--%0 ) ic0 -1.toc ,r,i * ouN 0 ri,..............õõ. ..... a II: CR 4 0 NH2 N ..---N, N
H - H
H
0 Of --- r--\
N
HN
0 \Th H2NAo , and a salt of any one thereof [0235] In some aspects, the present disclosure provides a compound or salt selected from:

H2N y0 HN
1 \II
ARXCW11 11)LN
H

N, U
N

H --- r---\
N
40 \ ¨ \
H2N y.0 s HN

a...,....õ..y H :Lliy 11 FRX* "---f-- - N
N
H
r 1 0 NH2 H_ 0 0 , 0 .,...---....
0......e.N
N
U
H
N
N , N
ist., NH2 O
0 0 A N ry *--"-H
--- NiTh HN
H2N-e1/40 N , 0 1i,, kii 0 N, O
---rirNõ 0õ..)1.. 0 0A H 0 H N
=Tr. RW:La....,...............}1.. ....
N - N
--- r--\\
H " H
N
Of-HN
H2N'--LO
0 N , ri N.... kii N 0 O --tiry 0 is -ekri H
IC
.11r-RX.,.............õ....}..,N N

N
---- r---- \
H H
N

0 µ--- \
NH

, lie 0 0 0 * 0 N
N

H
VIV(iNJL
ri 0 - N
r---\
H E H
N
0 -.10 teN
NH

, H2N tO
HN
NFIxtt-iiirlrl 1-1:01- NN 0 0 0 . yli ......-----rii 0 r-- =ki 0 NH2 i(14....õ..-1.,N N, H
-- r---\
N
H2N ,r0 HN
H ?
tRX.WIIN Aril N. H 0 OyN.,,,.--...N 0 i.,...t.õ N,,sti 0 N
H

l!l....)-- ..N N, HLJN:- Nr\
H2N,,,r0 HN.....

Hxit__ H
15.--RX IN N N

H H

LL.,--- 0 N., N
H
-- r---\
N

yO
HN
H (311 N.:11TV' =
_ N
o " H

-Ka N
N__ NH2 r-\\
0 \Th H2N tO
HN
SH

0C.-1 N
U

reN
o \Th tO
HN

.NA\111 - N 0 0 'RI

TON

N
/Th 0 \Th H2N y0 HN

iscnyLr 11\1 0 \ 0 le 0 /Th 0 \

H2N y0 HN
H
1'14' 0 N N
ouN 0 NH2 _ 0 H H

0 \
H2W%

0 xtr.At 0 0-1-N-Th\----N =

tsi ri F F
ri N
H a H
Of rTh.

, and a salt of any one thereof, 5 wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody.
[0236] In some embodiments, L3 is represented by the formula:
Vi\1/4111:9%)101.-CL
10 n RX , wherein RX comprises a reactive moiety, and n =
0-9. In some embodiments, RX comprises a leaving group. In some embodiments, RX
comprises a maleimide. In some embodiments, I: is represented as follows:
Sag, 47.(1\ltero-N%-9 =
µ3- , wherein RX* comprises a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein -NI on 15 RX* represents the point of attachment to the residue of the antibody, and n = 0-9.

102371 In some aspects, the present disclosure provides a compound or salt selected from:
N

cfixrio isii,.õT.N N, H
---- if-j.

N

N
.sekr......01i ii\ii ........õ....õ..............j. H
_.......õU 0 NI-I2 N
"%., N, II *
-- r 0 Lnair Li H
N

N, H
----r¨\\
N

oN 0 cuN 0 H
N

.===="- N H2LjL, N
H
---r--\
N
and a salt of any one thereof 102381 In some aspects, the present disclosure provides a compound or salt o H

N, v Rxz. jai" N N
H H

--- r---N, N
\ ---- \
selected from:
0 , 4111) N
e(RXInGly ti 0 H I 1 N-_,..--.......õ----,_,AN N ,.,=.,..;ra.---**N , H H
N

o 1.--Rknair 0 )1".-CINU

r\
0 \---\
'1st-misty H 0 reõ.N..zzei I
NH
H

rTh, , and a salt of any one thereof, wherein the RX*comprises a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein -IS
on RX*
5 represents the point of attachment to the residue of the antibody.
[0239] In some embodiments, RX* comprises a succinamide moiety and is bound to a cysteine residue of an antibody. In some embodiments, RX* comprises a hydrolyzed succinamide moiety and is bound to a cysteine residue of an antibody.
[0240] In some aspects, the present disclosure provides a conjugate represented (D¨L3fAntibody 10 by the formula: IS , wherein Antibody is an antibody, D is a Category A compound or salt disclosed herein, and 1-3 is a linker moiety.
[0241] In some aspects, the present disclosure provides a conjugate represented (D¨Lal-Antibody by the formula: 1-8 , wherein Antibody is an antibody and D-1_,3 is a Category A compound or salt disclosed herein.
15 [0242] In some aspects, the present disclosure provides a pharmaceutical composition, comprising the conjugate disclosed herein and at least one pharmaceutically acceptable excipient.
[0243] In some embodiments, the average DAR of the conjugate is from about 2 to about 8, or about 1 to about 3, or about 3 to about 5.

Compounds of Category B. TLR7 Agonists 102441 In some aspects, the present disclosure provides a compound represented by the structure of Formula (IA):
(R15)w N Nõ
=-=-=

Xi N--/( ,N

---1Ati\CX2 N IA); IAC1 R6 Ri 3 R14 R9 R10 (IA), 5 or a pharmaceutically acceptable salt thereof, wherein:
R', R2, R3, R4, and R5 are independently selected from hydrogen; and Cl4 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R20, -SR20, -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20, -C(0)0R20, -0C(0)R20, -NO2, =0, =S, 10 =N(R20), and -CN; or R3 and It" taken together form a 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR', -SR20, -C(0)N(R20)2, -N(R2 )2, -S(0)R20, -S(0)2R20, -C(0)R20 , -C(0)0R20, -0C(0)R20, -NO2, =0, =S, =N(R20), and -CN;
R6 is selected from halogen, -OR", -N(R20)2, -C(0)N(R20)2, -C(0)R20 , 15 -C(0)0R20, -S(0)R20, and -S(0)2R20; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R20, -SR20, -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20 , -C(0)0R20, -0C(0)R20, -NO2, =0, =S, =N(1t20), and -CN;
R7, R8, R9, and IV are independently selected at each occurrence from hydrogen 20 and halogen; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen;
R" and 10-2 are independently selected from hydrogen, halogen, -OR', -SR20 , -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R2 , -C(0)R20, -C(0)0R20, -0C(0)R20, -NO2, and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally 25 substituted with one or more substituents independently selected from halogen, -0R20 , -SR20, -C(C)N(R20)2, -N(R20)2, _s(0)-r20, _ S(0)2R2 , -C(0)R20, -C(0)0R20, -0C(0)R20 , -NO2, =0, =S, =N(R20), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; or R11 and R12 taken together form a C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -0R20, -SR20, -C(0)N(R20)2, 5 -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20, -C(0)0R20, -0C(0)R20, -NO2, =0, =S, =N(R20), and -CN;
R13 and R14 are independently selected at each occurrence from hydrogen, halogen, -0R20, -SR20, -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20 , -C(0)0R20, -0C(0)R20, -NO2, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each 10 of which is optionally substituted with one or more substituents independently selected from halogen, -OR', -SR", -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20, -C(0)0R20, -0C(0)R20, -NO2, =0, =S, =N(R20), -CN, C3-n carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected 15 from halogen, -OR', -SR20, -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20, -C(0)0R20, -0C(0)R20, -NO2, =0, =S, =N(R20), -CN, CI-6 alkyl, C2-6 alkenyl, and alkynyl;
R15 is independently selected at each occurrence from halogen, -OR', -SR20 , -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R2 , -C(0)R20, -C(0)0R20, -0C(0)R20, -NO2, 20 0, =S, =N(R20), -CN, CI-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, -CI-6 alkyl, -C1-6 haloalkyl, -0-C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3-to 12-membered heterocycle;
25 R16 is selected from hydrogen, and CI-6 alkyl, C2-6 alkenyl, C24 alkynyl, C3-L2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, C1-6 alkyl, -C1-6 haloalkyl, -0-C1-6 alkyl, C2-6 alkenyl, C2-6 allcynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle;
30 R2 is independently selected at each occurrence from hydrogen;
and CI-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-I2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, -C(0)0CH2C6H5, -NHC(0)0CH2C6Hs, C1-6 alkyl, -C1-6 haloalkyl, -0-CE-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle;
5 X` is 0, S, or NR16;
X2 is C(0) or S(0)2;
n is 1, 2, or 3;
x is 1, 2, or 3, w is 0, 1, 2, 3, or 4; and 10 z is 0, 1, or 2.
[0245] In certain embodiments, for a compound of Formula (IA), wherein is 0. In certain embodiments, for a compound of Formula (IA), n is 2. In certain embodiments, for a compound of Formula (IA), x is 2. In certain embodiments, for a compound of Formula (IA), z is 0. In certain embodiments, for a compound of Formula 15 (IA), z is 1.
[0246] In certain embodiments, a compound of Formula (IA) is represented by Formula (113):
(R15)w N
N,R 2 I
R11 R12 R3 R9' R1 Cr .__7=1 _8.1 Izt X Xi R6 R4 R9" R10"
REr (113), or a pharmaceutically acceptable salt thereof, wherein RT, Rr, R8 Rr, R9., R9", ler, 20 and RR' are independently selected at each occurrence from hydrogen and halogen; and Ci-isalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen.
[0247] In certain embodiments, a compound of Formula (IA) is represented by Formula (IC):

(R15)w N N

Ra R11 R12 R3 R9I Rty R7õ R8õ
N--R5¨N -7\--)C LA---\CX1)C(1( R6 Ri3Ria Rg" RI
R7' Rs. (IC), or a pharmaceutically acceptable salt thereof, wherein R7I, R7", By, Ran, R9r, R9n, R10', and WIT are independently selected at each occurrence from hydrogen and halogen; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 5 one or more substituents independently selected from halogen.
[0248] In certain embodiments, for a compound or salt of any one of Formulas (LA), (B3), or (IC), le, R2, R3, n4, K and R5 are independently selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR', -SR20, -C(0)N(R20)2, _ )2 N(R20+, _ S(0)R2 , -S(0)2R20 , 10 -C(0)R20, _c(0)0R20, _oc(0)R20, -NO2, =0, =S, =N(t20), and ¨CN_ 102491 In certain embodiments, for a compound or salt of any one of Formulas (IA), (B3), or (IC), le and R2 are independently selected from hydrogen and C1-6 alkyl.
In certain embodiments, for a compound or salt of any one of Formulas (IA), (IB), or (IC), le and R2 are each hydrogen.
15 [0250] In certain embodiments, for a compound or salt of any one of Formulas (IA), (B3), or (IC), R3 is selected from hydrogen and C1-6 alkyl optionally substituted with one or more halogens.
[0251] In certain embodiments, for a compound or salt of any one of Formulas (IA), ([13), or (IC), R3 is hydrogen.
20 [0252] In certain embodiments, for a compound or salt of any one of Formulas (IA), (B3), or (IC), le is selected from hydrogen and C1-6 alkyl optionally substituted with one or more halogens.
[0253] In certain embodiments, for a compound or salt of any one of Formulas (IA), (B3), or (IC), le is hydrogen.
25 [0254] In certain embodiments, for a compound or salt of any one of Formulas (IA), (B3), or (IC), R5 is selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -0R20, -SR20, -C(0)N(R2o)2, _mR20)2, _se:01-nIt2o, _ S(0)2R2o, _c(0)-nIt2o, _ C(0)011.2 , -0C(0)12.20, -NO2, =S, =N(R20), and -CN. In certain embodiments, for a compound or salt of any one of Formulas (IA), (JIB), or (IC), R5 is hydrogen.
102551 In certain embodiments, for a compound or salt of any one of Formulas 5 (IA), (IB), or (IC), R6 is selected from halogen, -OR', and -N(R20)2; and CI-6alk-0, C2-6 alkenyl, C24allcynyl, each of which is optionally substituted with one or more substituentsindependently selected from halogen, -0R20 --_sR20, _c(o)m-R2o.) 2,N(R9n)2, _ _s(0)R20, _s(0)2R20, _C(0)R20, -C(0)0R20, -0C(0)R20, -NO2, =0, =S, =1\la20), and -CN; and 10 R2 is independently selected at each occurrence from hydrogen;
and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NW, =0, =S, -C(0)0CH2C6145, -NHC(0)0CH2C6Hs, C1-6 alkyl, -C1-6 haloalkyl, -0-CE-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 15 3- to 12-membered heterocycle.
102561 In certain embodiments, for a compound or salt of any one of Formulas (IA), (LB), or (IC), It.6 is C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -0R20 , -SR", -C(0)N(R20)2, _N(R20) _ S(0)R2 , 20 -S(0)2R20, _corm, _ K C(0)0R20, -0C(0)R20; and R2 is independently selected at each occurrence from hydrogen; C1-6 alkyl, C3-carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, -C(0)0CH2C6if5, -NHC(0)0CH2C6H5, C1-6 alkyl, -Ci-6haloalkyl, 25 -0-C14 alkyl, C24 alkenyl, C24 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.
102571 In certain embodiments, for a compound or salt of any one of Formulas (IA), (1B), or (IC), R6 is Ci4 alkyl substituted with -0R20, and R20 is selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents 30 independently selected from halogen, -OH, and -N1-12.

[0258] In certain embodiments, for a compound or salt of any one of Formulas (IA), (JIB), or (IC), R71, R7", Rw, R8", R91, R9", Rlil, and Rlip" are independently selected at each occurrence from hydrogen and halogen; and C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen.
5 [0259] In certain embodiments, for a compound or salt of any one of Formulas (LB) or (IC), wherein R7' and Rs' are each hydrogen. In certain embodiments, for a compound or salt of any one of Formulas (JIB) or (IC), wherein R7" and Rs" are each C1-6 alkyl. In certain embodiments, for a compound or salt of any one of Formulas (LB) or (IC), RT" and Rs" are each methyl.
10 102601 In certain embodiments, for a compound or salt of any one of Formulas (JIB) or (IC), R9P, R9", Riot, and Rm.' are independently selected at each occurrence from hydrogen and C1-6 alkyl.
[0261] In certain embodiments, for a compound or salt of any one of Formulas ([13) or (IC), R9', R9, Rill, and R1 " are each hydrogen.
15 [0262] In certain embodiments, for a compound or salt of any one of Formulas (IA), (113), or (IC), R11 and R12 are independently selected from hydrogen, halogen, -OR', _sR20, _C(0)N(R20)2, _TAR2o)2, _C(0)R20, -C(0)0R20, -0C(0)R20;
and Cbealkyl, optionally substituted with one or more substituents independently selected from halogen, -0R20, _sR20, -C(0)N(R20)2, N(R20)2, -C(0)R20, -C(0)0R20, _OC(0)R20 , 20 C3-12 carbocycle, and 3- to 12-membered heterocycle.
[0263] In certain embodiments, for a compound or salt of any one of Formulas (IA) or (IC), Rn and R" are independently selected from hydrogen, halogen, -, -SR20, -C(0)N(R20)z, 2 _ Nat2o),, _ C(0)R2 , -C(0)0R20, -0C(0)R20.; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from 25 halogen, -0R20, -5R20, -C(0)N(R20)2, 2 ick ())2, -C(0)R20, -C(C)0R20, -0C(0)R20, C3-12 carbocycle, and 3- to 12-membered heterocycle.
[0264] In certain embodiments, for a compound or salt of any one of Formulas (IA), (1B), or (IC), le and R" taken together form an optionally substituted 5-to 6-membered heterocycle.

102651 In certain embodiments, for a compound or salt of any one of Formulas (IA), (B3), or (IC), R" and R12 taken together form an optionally substituted carbocycle.
102661 In certain embodiments, for a compound or salt of any one of Formulas 5 (IA), (lE), or (IC), X2 is C(0).
102671 In certain embodiments, the compound is represented by:
4.1 R., NH2 ../
H N

H2N....õ...----irN-...,.................-----........0 O /
õI N..... NH2 ---."
N
jr,-N-,..õ...........õ--...,,,0 O /
0, N..... NH2 ...,"
H N
Isy_yert¨c_ C Xr-N-....õ.............--...õ, O /
0 Ns, N H2 I _..,.
H - N
X.....y_N-.......õ.õ,..-.....Th N,... NH2 H
oxyl*N
I
CN....,.............,..--õ,õ

/
HO op I
H
. "--- N
I)4,7N-4 0ir N...,..õ..,.....--õ..õ

, or HN *

H
N
I

-..,...........-----...õõ0 \-0 or a pharmaceutically acceptable salt of any one thereof 102681 In certain aspects, the disclosure provides a pharmaceutical composition of a compound or pharmaceutically acceptable salt of any one of Formulas (IA), (B3), or (IC), and a pharmaceutically acceptable excipient.
5 102691 In certain embodiments, for a compound or salt of any one of Formulas (IA), (B3), or (IC), the compound or salt is further covalently bound to a linker, 102701 In certain aspects the disclosure provides a compound represented by Formula (HA):
(R15),õ

N NõR-N_1( R26e#N--)c;Xlyi R6 R13 Ria Rs Rlo R7 Rs (HA), 10 or a pharmaceutically acceptable salt thereof, wherein:
R2 and le are independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R20, -SR20, -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20, -C(0)0R20, -0C(0)R20, -NO2, =0, =S, 15 =N(R20), and -CN;
R21, .k. n23, and R25 are independently selected from hydrogen; C1-6 alkyl, C2-6 alkenyl, and C24 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R20, -SR20, -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20, -C(0)0R20, -0C(0)R20, -NO2, =0, =S, 20 =N(Rm), and -CN; and or R23 and R11 taken together form a 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -0R20, _sR20, -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20 , -C(0)0R20, -0C(0)R20, -NO2, =0, =S, =N(R20), and -CN; and wherein one of R21, R23, and R25 is L3;
25 R6 is selected from halogen, -0R20, _N(R20)2, (0 )N(R2 )2, C A2 , ill -C(0)0R20, -S(0)R20, and -S(0)2R20; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R20, -SR20, -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)21k20, -C(0)R20 , -C(0)0R20, -0C(0)R20, -NO2, =0, =S, =N(R20), and -CN;
5 le, le, R9, and It1 are independently selected at each occurrence from hydrogen and halogen; and CI-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen;
R1". and R12 are independently selected from hydrogen, halogen, -OR', -SR20 , -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R2 , -C(0)R20, -C(0)0R20, -0C(0)R20, -NO2, 10 and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, , -SR20, -C(0)N(R20)2, -N(R20)2, -S(0)R20, eS(0)2R20, -C(0)R20, -C(0)0R20, -0C(0)R20 , -NO2, =0, =S, =N(R20), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; or It" and R12 taken together form a C3-6 carbocycle optionally substituted with one or 15 more substituents independently selected from halogen, -0R20, -SR20, -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20, -C(0)0R20, -0C(0)R20, -NO2, =0, =S, =N(R20), and -CN;
R" and RH are independently selected at each occurrence from hydrogen, halogen, -0R20, -SR20, -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20 , 20 -C(0)0R20, -0C(0)R20, -NO2, -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR', -SR20, -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20 , -C(0)0R20, -0C(0)R20, -NO2, =0, =S, =N(R20), -CN, C3-12 carbocycle, and 3- to membered heterocycle; and C3-12 carbocycle and 3- to 12-membered heterocycle, each 25 of which is optionally substituted with one or more substituents independently selected from halogen, -0R20, -SR20, -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20 , -C(0)0R20, -0C(0)R20, -NO2, =0, =S, =N(R20), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R15 is independently selected at each occurrence from halogen, -0R20, -SR20 , 30 -C(0)N(R20)2, -N(R20)2, -S(0)R20, -S(0)2R20, -C(0)R20, -C(0)0R20, -0C(0)R20, -NO2, =S, =N(R20), -CN, CI-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, C3-12 carbocycle, and 3-to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NI-b, =0, =S, -C1-6 alkyl, -C1-6haloalkyl, -0-Ct-6alkyl, C2-6 alkenyl, C2-6a1kynyl, C3-12 carbocycle, and 3-to 12-membered heterocycle;
5 It' is selected from hydrogen; and CI-fl alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, C1-6 alkyl, -Cl-flhaloalkyl, -0-C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle;
10 R2 is independently selected at each occurrence from hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NW, =0, =S, -C(0)0CH2C6145, -NHC(0)0CH2C6Hs, CI-6 alkyl, -C1-6 haloalkyl, -0-C t-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 15 3- to 12-membered heterocycle;
L3 is a linker;
X' is 0, S, or NR16;
X2 is C(0) or S(0)2;
n is 1, 2, or 3;
20 x is 1, 2, or 3;
w is 0, 1, 2, 3, or 4; and z is 0, 1, or 2.
[0271] In certain embodiments, for a compound or salt of Formula (IIA), X' is 0. In certain embodiments, for a compound or salt of Formula (BA), n is 2. In certain 25 embodiments, for a compound or salt of Formula (11A), x is 2. In certain embodiments, for a compound or salt of Formula (HA), z is 0. In certain embodiments, for a compound or salt of Formula (HA), z is 1.
[0272] In certain embodiments, the compound of Formula (IA) is represented by (BB) or (IC):

(R15)w N N, Rii R12 R23 049 010 , R25 \
R1SzN _2( R4 Ro" Ri 0"
R7. R8 MBA
(R16)w N
N,R 2 23 R11 R R9' R10' I

RT. R8õ

R4¨ N
X1 \R6 R13 R14 R9" Rio"

(IIC), or a pharmaceutically acceptable salt thereof, wherein R7', R7n, Rw, R8, R9t, R9, and RI' are independently selected at each occurrence from hydrogen and halogen; and 5 Ct-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen.
102731 In certain embodiments, for a compound or salt of any one of Formulas (HA), (IIB), or (IIC), R2 and le are independently selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents independently selected from 10 halogen, -0R20, _sR20, _c(o)N(R20)2, _mR2o)2., _ S(0)R2 , -S(0)2R20, -C(0)R20 , -C(0)0R20, -0C(0)R20, -NO2, =0, =S, =N(R20), and ¨CN.
102741 In certain embodiments, for a compound or salt of any one of Formulas (HA), (IIB), or (IIC), R2 and R4 are independently selected from hydrogen and alk-yl. In certain embodiments, for a compound or salt of any one of Formulas (IA), 15 (IIB), or (11C), R2 and R4 are each hydrogen.
102751 In certain embodiments, for a compound or salt of any one of Formulas (HA), (IIB), or (IIC), R23 is selected from hydrogen and C1-6 alkyl optionally substituted with one or more halogens. In certain embodiments, for a compound or salt of any one of Formulas (IA), (IfB), or (IIC), R23 is hydrogen.

[0276] In certain embodiments, for a compound or salt of any one of Formulas (HA), (IM), or (HC), R2' is selected from hydrogen and C1-6 alkyl optionally substituted with one or more halogens. In certain embodiments, for a compound or salt of any one of Formulas (HA), (I1B), or (IIC), R2' is hydrogen.
5 [0277] In certain embodiments, for a compound or salt of any one of Formulas (HA), (ID3), or (IIC), R2' is L3.
102781 In certain embodiments, for a compound or salt of any one of Formulas (HA), (ID!), or (IIC), R25 is selected from hydrogen and C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, , 10 _sR20, _qcomR20)2, _NR-R20µft2, _ S(0)R2 , -S(0)2R20, -C(0).K.n20, _C(0)0R20, -0C(0)R20 , -NO2, =0, =S, =N(R20), and -CN. In certain embodiments, for a compound or salt of any one of Formulas (HA), (BB), or (IIC), R25 is hydrogen.
[0279] In certain embodiments, for a compound or salt of any one of Formulas (HA), (ID3), or (IIC), R25 is L3.
15 [0280] In certain embodiments, for a compound or salt of any one of Formulas (HA), (IH3), or (HC), 1(6 is selected from halogen, -OR', and eN(R20)2; and C1-6 alkyl, C24 alkenyl, C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R20, _sR20, _0(Q)N(R20)2, _N(R20)2, _ S(0)R2 , 20 -S(0)2R20, _cor2o, _ .K. C(0)0R20, -0C(0)R20, -NO2, =0, =S, =N(R20), and -CN; and 1(20 is independently selected at each occurrence from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, -C(0)0CH2C6H5, -NHC(0)0CH2C6Hs, 25 C14 alkyl, -C14 haloalkyl, -0-CI-6 alkyl, C24 alkenyl, C24 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.
[0281] In certain embodiments, for a compound or salt of any one of Formulas (HA), (ID3), or (IIC), 1t6 is C1-6 alkyl optionally substituted with one or more substituents 30 independently selected from halogen, -OR', -SR20, -C(0)N(R20)2, _TAR20)2, _so0ooR20 , -S(0)2R20, _cor20, _ C(0)0R2 , -0C(0)R20; and 1t20 is independently selected at each occurrence from hydrogen, -NH2, -C(0)0CH2C6H5; CI-6 alkyl, C3-12 carbocycle, and 3-to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, -C(0)0CH2C6H5, -NHC(0)0CH2C6Hs, 5 CI-6 alkyl, -C1-6 haloalkyl, -0-C r-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.
102821 In certain embodiments, for a compound or salt of any one of Formulas (HA), (ID3), or (HC), R6 is C1-6 alkyl substituted with -0R20, and 10 R2 is selected from hydrogen and CI-6 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OH, and -NH2.
102831 In certain embodiments, for a compound or salt of any one of Formulas (ITB) or (IIC), Rr, R7", IV', le", R91., R911, ler, and Rw" are independently selected at each occurrence from hydrogen and halogen; and CI-6 alkyl optionally substituted with 15 one or more substituents independently selected from halogen.
102841 In certain embodiments, for a compound or salt of any one of Formulas (Ill) or (IIC), R7' and BY are hydrogen.
102851 In certain embodiments, for a compound or salt of any one of Formulas (Ill) or (IIC), R7" and RP are CI-6 alkyl.
20 102861 In certain embodiments, for a compound or salt of any one of Formulas (DB) or (LIC), R7" and R8" are methyl.
102871 In certain embodiments, for a compound or salt of any one of Formulas (nil) or (HC), R9r, Rw, and Rw" are independently selected at each occurrence from hydrogen and CI-6 alkyl.
25 102881 In certain embodiments, for a compound or salt of any one of Formulas (DB) or (HC), R9', R9", 10 , and Rw" are each hydrogen.
102891 In certain embodiments, for a compound or salt of any one of Formulas (HA), (ID3), or (HC), R" and 1:0-2 are independently selected from hydrogen, halogen, -0R20, -SR20, -C(0)N(R20)2, -N(R20)2, -C(0)R20, -C(0)0R20, and -0C(0)R20;
30 and C14alkyl optionally substituted with one or more substituents independently selected from halogen, -0R20, -SR20, -C(0)N(R20)2, -N(R20)2, -C(0)R20, -C(0)0R20 , -0C(0)R20, C3-12 carbocycle, and 3- to 12-membered heterocycle.
[0290] In certain embodiments, for a compound or salt of any one of Formulas (HA) or (HC), R13 and R14 are independently selected from hydrogen, halogen, -OR', -SR20, -C(0)N(R20)2, -N(R20)2, -C(0)1120, -C(0)0R20, and -0C(0)R20;
5 and CL-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -0R20, -SR20, -C(0)N(R20)2, -N(R20)2, -C(0)R20, -C(0)0R20 , -0C(0)R20, C3-12 carbocycle, and 3- to 12-membered heterocycle.
[0291] In certain embodiments, for a compound or salt of any one of Formulas (HA), (IIB), or (HC), R23 and R" taken together form an optionally substituted 10 5- to 6-membered heterocycle.
[0292] In certain embodiments, for a compound or salt of any one of Formulas (HA), (IIB), or (HC), R" and R12 taken together form an optionally substituted carbocycle.
[0293] In certain embodiments, for a compound or salt of any one of Formulas 15 (HA), (IIB), or (IIC), X2 is C(0).
[0294] In certain embodiments, for a compound or salt of any one of Formulas (HA), (IIB), or (IIC), L3 is a cleavable linker. In certain embodiments, for a compound or salt of any one of Formulas (IA), (BB), or (IIC), L3 is cleavable by a lysosomal enzyme.
20 [0295] In certain embodiments, for a compound or salt of any one of Formulas (HA), (BB), or (LIC), L3 is represented by the formula:

1 itepeptide,, L5 rRX

-H
wherein:
L4 represents the C-terminus of the peptide and L5 is selected from a bond, 25 alkylene and heteroalkylene, wherein 12 is optionally substituted with one or more groups independently selected from RTh, and RX is a reactive moiety; and 1(30 is independently selected at each occurrence from halogen, -OH, -CN, -0-alkyl, -SH, =0, =S, -NH2, -NO2; and Ci-Cio alkyl, C2-Cio alkenyl, and C2-Cio alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -OH, -CN, -0-alkyl, -SH, =0, =S, -NI-12, and -NO2.
[0295] In certain embodiments, for a compound or salt of any one of Formulas 5 (HA), (BB), or (HC), RX comprises a leaving group. In certain embodiments, for a compound or salt of any one of Formulas WAX (I113), or (IIC), RX is a maleimide or an alpha-halo carbonyl. In certain embodiments, for a compound or salt of any one of Formulas (HA), (LIE), or (HC), the peptide of L3 comprises Val-Cit or Val-Ala.
[0297] In certain embodiments, for a compound or salt of any one of Formulas 10 (HA), (ID3), or (LIC), L3 is represented by the formula:
iss(litc eticc -9 n RX
wherein:
RX comprises a reactive moiety; and n is 0-9.
15 [0298] In certain embodiments, for a compound or salt of any one of Formulas (HA), (I1.13), or (HC), RX comprises a leaving group. In certain embodiments, for a compound or salt of any one of Formulas (hA), (DB), or (IIC), RX is a maleimide or an alpha-halo carbonyl. In certain embodiments, for a compound or salt of any one of Formulas (HA), (1113), or (HC), L3 is further covalently bound to an antibody to form a 20 conjugate.
[0299] In certain embodiments, the disclosure provides a conjugate represented by the formula:
(D L3_) wherein:
25 n is 1 to 20;
D is a compound or salt of any one of a Category B compound of Formulas (IA), (I13), or (IC); and L3 is a linker moiety; or D-L3 is a compound or salt of any one of a Category B compound of Formulas (HA), (DB), or (IIC).
[0300] In certain embodiments, for a conjugate of a compound or salt of any one of Formulas (IA), (D3), (IC), (HA), (JIB), and (IIC), n is selected from 1 to 8.
In certain 5 embodiments, for a conjugate of a compound or salt of any one of Formulas (IA), (1113), (IC), (IA), (DB), and (IIC), n is selected from 2 to 5. In certain embodiments, for a conjugate of a compound or salt of any one of Formulas (IA), (1B), (IC), (IA), (DB), and (IIC), n is 2.
103011 In certain embodiments, for a compound or salt of any one of Formulas 10 (HA), (ID3), and (IIC), -L3 is represented by the formula:

VILO
4,peptide,, 5-RX,/
wherein:
L4 represents the C-terminus of the peptide and L5 is selected from a bond, alkylene and heteroalkylene, wherein L5 is optionally substituted with one or more 15 groups independently selected from R30;
RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein 7 on RX* represents the point of attachment to the residue of the antibody; and R3 is independently selected at each occurrence from halogen, -OH, -CN, -0-20 alkyl, -SH, =0, =S, -NH2, -NO2; and CE-Ctoalkyl, C2-Cmalkenyl, and C2-Cioalkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -OH, -CN, -0-alkyl, -SH, =0, =S, -NH2, and -NO2.
[0302] In certain embodiments, for a compound or salt of any one of Formulas 25 (HA), (ID3), or (IIC), RX* is a succinamide moiety, hydrolyzed succinamide moiety or a mixture thereof and is bound to a cysteine residue of an antibody.
[0303] In certain embodiments for a compound of Formulas (ILA), (JIB) and (DC), -L3 is represented by the formula:

wherein:
Rris a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein 7 on RX* represents the point of attachment to 5 the residue of the antibody; and n is 0-9.
103041 In some aspects, the present disclosure provides a conjugate represented by the following structure:
a G;
-=Vt"*.Te.%%4%.-AN
a 10 or a pharmaceutically acceptable salt thereof, wherein Ab comprises an antibody, D is a compound or salt of a Category B compound of Formula (HD):
'NH
1>-\
(I1D) wherein R4 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group comprising from 1 to 8 carbons, each J is hydrogen, 15 each U is N, each t is 2, Q is not present, the dashed line represents a point of attachment of the adjuvant to G1 , and G1 is a bond; subscript a is an integer from 1 to 40; and subscript r is an integer from 1 to 10. In certain embodiments, D has the following structure:

N 44,N>art traL.,õ
H
CN) -4- . In further embodiments, the conjugate has the following structure:

At N
k H2NAN irr Linkers 5 [0305] The conjugates include a linker(s) that attaches an antibody to at least one immune-stimulatory compound, such as a myeloid cell agonist. A linker can be, for example, a cleavable or a non-cleavable linker. A conjugate can comprise multiple linkers. The linkers in a conjugate can be the same linkers or different linkers.
[0306] As will be appreciated by skilled artisans, a linker connects an immune-10 stimulatory compound(s), such as a myeloid cell agonist, to the antibody by forming a covalent linkage to the compound at one location and a covalent linkage to the antibody at another location. The covalent linkages can be formed by reaction between functional groups on the linker and functional groups on the immune-stimulatory compound and on the antibody. As used herein, the expression "linker" can include (i) 15 unattached forms of the linker that can include a functional group capable of covalently attaching the linker to an immune-stimulatory compound and a functional group capable of covalently attached the linker to an antibody; (ii) partially attached forms of the linker that can include a functional group capable of covalently attaching the linker to an antibody and that can be covalently attached to an immune-stimulatory 20 compound, or vice versa; and (iii) fully attached forms of the linker that can be covalently attached to both an immune stimulatory compound and to an antibody.
In some specific embodiments, the functional groups on a linker and covalent linkages formed between the linker and an antibody can be specifically illustrated as Rx and Rx', respectively.
[0307] A linker can be short or long, and cleavable or non-cleavable. A linker can contain segments that have different characteristics, such as segments of flexibility 5 or segments of rigidity, segments of hydrophilicity, and/or segments of hydrophobicity.
A linker can be chemically stable to extracellular environments, for example, chemically stable in the blood stream, and/or may include linkages that are not stable.
A linker can include linkages that are designed to cleave and/or immolate or otherwise breakdown specifically or non-specifically inside cells. A cleavable linker can be 10 sensitive to enzymes at a specific site, such as the lysosome or the extracellar space adjacent cancer cells.
[0308] A cleavable linker can include a valine-citrulline peptide, a valine-alanine peptide, a phenylalanine-lysine or other peptide, such as a peptide that forms a protease recognition and cleavage site. Such a peptide-containing linker can contain a 15 pentafluorophenyl group. A peptide-containing linker can include a succimide or a maleimide group A peptide-containing linker can include a para aminobenzoic acid (PABA) group. A peptide-containing linker can include an aminobenzyloxycarbonyl (PABC) group. A peptide-containing linker can include a PABA or PABC group and a pentafluorophenyl group. A peptide-containing linker can include a PABA or PABC
20 group and a succinimide group. A peptide-containing linker can include a PABA or PABC group and a maleimide group.
[0309] A non-cleavable linker is generally protease-insensitive and insensitive to intracellular processes. A non-cleavable linker can include a maleimide group. A
non-cleavable linker can include a succinimide group. A non-cleavable linker can be 25 maleimido-alkyl-C(0)- linker. A non-cleavable linker can be maleimidocaproyl linker.
A maleimidocaproyl linker can be N-maleimidomethylcyclohexane-1-carboxylate. A

maleimidocaproyl linker can include a succinimide group. A maleimidocaproyl linker can include pentafluorophenyl group.
[0310] A linker can be a combination of a maleimidocaproyl group and one or 30 more polyethylene glycol molecules. A linker can be a maleimide-PEG4 linker. A
linker can be a combination of a maleimidocaproyl linker containing a succinimide group and one or more polyethylene glycol molecule& A linker can be a combination of a maleimidocaproyl linker containing a pentafluorophenyl group and one or more polyethylene glycol molecules. A linker can contain a ma1eimide(s) linked to polyethylene glycol molecules in which the polyethylene glycol can allow for more 5 linker flexibility or can be used lengthen the linker.
03111 A linker can be a (maleimidocaproy1)-(valine-alanine)-(para-aminobenzyloxycarbonyl) linker. A linker can be a (maleimidocaproy1)-(valine-citrulline)-(para-aminobenzyloxycarbonyl) linker. A linker can be a (maleimidocaproyl)-(phenylalanine-lysine)-(para-aminobenzyloxycarbonyl) linker.
10 103121 A linker can also contain segments of alkylene, alkenylene, alkynylene, polyether, polyester, polyamide, polyamino acids, peptides, polypeptides, cleavable peptides, and/or aminobenzyl-carbamates. A linker can contain a maleimide at one end and an N-hydroxysuccinimidyl ester at the other end. A linker can contain a lysine with an N-terminal amine acetylated, and a valine-citrulline, valine-alanine or phenylalanine-15 lysine cleavage site. A linker can be a link created by a microbial transglutaminase, wherein the link can be created between an amine-containing moiety and a moiety engineered to contain glutamine as a result of the enzyme catalyzing a bond formation between the acyl group of a glutamine side chain and the primary amine of a lysine chain. A linker can contain a reactive primary amine. A linker can be a Sortase A
20 linker. A Sortase A linker can be created by a Sortase A enzyme fusing an LXPTG
recognition motif (SEQ 111) NO: 11) to an N-terminal GGG motif to regenerate a native amide bond. The linker created can therefore link to a moiety attached to the LXPTG
recognition motif (SEQ ID NO: 11) with a moiety attached to the N-terminal COG

motif. A linker can be a link created between an unnatural amino acid on one moiety 25 reacting with oxime bond that was formed by modifying a ketone group with an alkoxyamine on another moiety. A moiety can be part of a conjugate. A moiety can be part of an antibody, such as an antibody. A moiety can be part of an immune-stimulatory compound, such as a myeloid cell agonist. A moiety can be part of a binding domain. A linker can be unsubstituted or substituted, for example, with a 30 substituent. A substituent can include, for example, hydroxyl groups, amino groups, nitro groups, cyano groups, azido groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, acyl groups, acyloxy groups, amide groups, and ester groups.
[0313] A linker can be polyvalent such that it covalently links more than one immune-stimulatory compound to a single site on the antibody, or monovalent such that 5 it covalently links a single immune-stimulatory compound to a single site on the antibody.
103141 Exemplary polyvalent linkers that may be used to attach many immune-stimulatory compounds to an antibody of the conjugate are described. For example, Fleximer linker technology has the potential to enable high-DAR conjugate with good 10 physicochemical properties. As shown below, the Fleximer linker technology is based on incorporating molecules into a solubilizing poly-acetal backbone via a sequence of ester bonds. The methodology renders highly-loaded conjugates (DAR
up to 20) whilst maintaining good physicochemical properties. This methodology can be utilized with an immune-stimulatory compound as shown in the scheme below, where 15 Drug' refers to the immune-stimulatory compound.
irrHOy -,TrOH OH) to-oto mtroT 0 n add Fieximer loket o 0 HO
E
MN
1-ÃN FIN
0-Drug O¨Dfug` 0-Ortig' 103151 To utilize the Fleximer linker technology depicted in the scheme above, an aliphatic alcohol can be present or introduced into the immune-stimulatory compound. The alcohol moiety is then attached to an alanine moiety, which is then 20 synthetically incorporated into the Fleximer linker. Liposomal processing of the conjugate in vitro releases the parent alcohol-containing drug.
[0316] By way of example and not limitation, some cleavable and noncleavable linkers that may be included in the conjugates described herein are described below.

[0317] Cleavable linkers can be cleavable in vitro and in vivo. Cleavable linkers can include chemically or enzymatically unstable or degradable linkages.
Cleavable linkers can rely on processes inside the cell to liberate an immune-stimulatory compound, such as reduction in the cytoplasm, exposure to acidic 5 conditions in the lysosome, or cleavage by specific proteases or other enzymes within the cell. Cleavable linkers can incorporate one or more chemical bonds that are chemically or enzymatically cleavable while the remainder of the linker can be non-cleavable.
[0318] A linker can contain a chemically labile group such as hydrazone and/or 10 disulfide group. Linkers comprising chemically labile groups can exploit differential properties between the plasma and some cytoplasmic compartments. The intracellular conditions that can facilitate immune-stimulatory compound release for hydrazine-containing linkers can be the acidic environment of endosomes and lysosomes, while disulfide-containing linkers can be reduced in the cytosol, which can contain high thiol 15 concentrations, e.g., glutathione. The plasma stability of a linker containing a chemically labile group can be increased by introducing steric hindrance using substituents near the chemically labile group.
[0319] Acid-labile groups, such as hydrazones, can remain intact during systemic circulation in the blood's neutral pH environment (pH 7.3-7.5) and can 20 undergo hydrolysis and can release an immune-stimulatory compound once the conjugate is internalized into mildly acidic endosomal (pH 5.0-6.5) and lysosomal (pH
4.5-5.0) compartments of the cell. This pH dependent release mechanism can be associated with nonspecific release of the immune-stimulatory compound. To increase the stability of the hydrazone group of the linker, the linker can be varied by chemical 25 modification, e.g., substitution, allowing tuning to achieve more efficient release in the lysosome with a minimized loss in circulation.
[0320] Hydrazone-containing linkers can contain additional cleavage sites, such as additional acid-labile cleavage sites and/or enzymatically labile cleavage sites.
Conjugates including exemplary hydrazone-containing linkers can include, for example, 30 the following structures:

(Ia) N "N
)1 0 (Ib) N.. =õfirw.).5_st )1 0 Ab (1."--)11.-NtAb N
(Ic) wherein D is an immune-stimulatory compound and Ab is an antibody, respectively, 5 and n represents the number of compound-bound linkers (LP) bound to the antibody. In certain linkers, such as linker (Ia), the linker can comprise two cleavable groups, a disulfide and a hydrazone moiety. For such linkers, effective release of the unmodified free immune-stimulatory compound can require acidic pH or disulfide reduction and acidic pH. Linkers such as (Ib) and (Ic) can be effective with a single hydrazone 10 cleavage site.
[0321] Other acid-labile groups that can be included in linkers include cis-aconityl-containing linkers. cis-Aconityl chemistry can use a carboxylic acid juxtaposed to an amide bond to accelerate amide hydrolysis under acidic conditions.
103221 Cleavable linkers can also include a disulfide group. Disulfides can be 15 thermodynamically stable at physiological pH and can be designed to release an immune-stimulatory compound upon internalization inside cells, wherein the cytosol can provide a significantly more reducing environment compared to the extracellular environment. Scission of disulfide bonds can require the presence of a cytoplasmic thiol cofactor, such as (reduced) glutathione (GSH), such that disulfide-containing 20 linkers can be reasonably stable in circulation, selectively releasing the immune-stimulatory compound in the cytosol. The intracellular enzyme protein disulfide isomerase, or similar enzymes capable of cleaving disulfide bonds, can also contribute to the preferential cleavage of disulfide bonds inside cells. GSH can be present in cells in the concentration range of 0.5-10 inM compared with a significantly lower 25 concentration of GSH or cysteine, the most abundant low-molecular weight thiol, in circulation at approximately 5 M. Tumor cells, where irregular blood flow can lead to a hypoxic state, can result in enhanced activity of reductive enzymes and therefore even higher glutathione concentrations. The in vivo stability of a disulfide-containing linker can be enhanced by chemical modification of the linker, e.g., use of steric hindrance 5 adjacent to the disulfide bond.
[0323] Immune-stimulatory conjugates including disulfide-containing linkers can include the following structures:

ci))(S--S-..2r}LNI-Ab (Ha) H
R R
n (lib) D----------"S'S Ab n (tft) R R
10 n wherein D is an immune-stimulatory compound and Ab is an antibody, respectively, n represents the number of compounds bound to linkers bound to the antibody and R is independently selected at each occurrence from hydrogen or alkyl, for example.

Increasing steric hindrance adjacent to the disulfide bond can increase the stability of 15 the linker. Structures such as (ha) and (IIc) can show increased in vivo stability when one or more R groups is selected from a lower alkyl such as methyl.
[0324] Another type of linker that can be used is a linker that is specifically cleaved by an enzyme. For example, the linker can be cleaved by a lysosomal enzyme.
Such linkers can be peptide-based or can include peptidic regions that can act as 20 substrates for enzymes. Peptide based linkers can be more stable in plasma and extracellular milieu than chemically labile linkers.
[0325] Peptide bonds can have good serum stability, as lysosomal proteolytic enzymes can have very low activity in blood due to endogenous inhibitors and the unfavorable pH value of blood compared to lysosomes. Release of an immune-25 stimulatory compound from an antibody can occur due to the action of lysosomal proteases, e.g., cathepsin and plasmin. These proteases can be present at elevated levels in certain tumor tissues. A linker can be cleavable by a lysosomal enzyme. The lysosomal enzyme can be, for example, cathepsin B, cathepsin S, P-glucuronidase, orp-galactosidase.
103261 The cleavable peptide can be selected from tetrapeptides such as Gly-5 Phe-Leu-Gly, Ala-Leu-Ala-Leu, dipeptides such as Val-Cit, Val-Ala, and Phe-Lys, or other peptides. Dipeptides can have lower hydrophobicity compared to longer peptides, depending on the composition of the peptide.
[0327] A variety of dipeptide-based cleavable linkers can be used in the immune-stimulatory conjugates described herein.
10 [0328] Enzymatically cleavable linkers can include a self-immolative spacer to spatially separate the immune-stimulatory compound from the site of enzymatic cleavage. The direct attachment of an immune-stimulatory compound to a peptide linker can result in proteolytic release of the immune-stimulatory compound or of an amino acid adduct of the immune-stimulatory compound, thereby impairing its activity.
15 The use of a self-immolative spacer can allow for the elimination of the fully active, chemically unmodified immune-stimulatory compound upon amide bond hydrolysis [0329] One self-immolative spacer can be a bifunctional para-aminobenzyl alcohol group (PABA), which can link to the peptide through the amino group, forming an amide bond, while amine containing immune-stimulatory compounds can be 20 attached through carbamate functionalities to the benzylic hydroxyl group of the linker (to give ap-amidobenzylcarbaniate, PA13C). The resulting pro-immune-stimulatory compound can be activated upon protease-mediated cleavage, leading to a 1,6-elimination reaction releasing the unmodified immune-stimulatory compound, carbon dioxide, and remnants of the linker. The following scheme depicts the fragmentation of 25 p- amidobenzyl carbamate and release of the immune-stimulatory compound:
0 so 0 X¨D protease Op 0 \,t(-13 1,6-eliminatior!

HN
+
peptide N H2 X-D
wherein X-D represents the unmodified immune-stimulatory compound and the carbonyl group adjacent "peptide" is part of the peptide. Heterocyclic variants of this self-immolative group have also been described.

[0330] An enzymatically cleavable linker can be a f3-g,lucuronic acid-based linker. Facile release of an immune-stimulatory compound can be realized through cleavage of the 13-glucuronide glycosidic bond by the lysosomal enzyme 13-glucuronidase. This enzyme can be abundantly present within lysosomes and can be 5 overexpressed in some tumor types, while the enzyme activity outside cells can be low.
13-glucuronic acid-based linkers can be used to circumvent the tendency of an immune-stimulatory conjugate to undergo aggregation due to the hydrophilic nature of B-glucuronides. In certain embodiments, 13-glucuronic acid-based linkers can link an antibody to a hydrophobic immune-stimulatory compound. The following scheme 10 depicts the release of an immune-stimulatory compound (D) from an immune-stimulatory conjugate containing a 13-glucuronic acid-based linker:
HO
HO
HO oCi .1D voucuronidase HO sap At).
1,6-elimination HO
Op 1 CO2 FiNyMkb HNyAb OH OH
wherein Ab indicates the antibody.
[0331] A variety of cleavablef3-glucuronic acid-based linkers useful for linking 15 drugs such as auristatins, camptothecin and doxorubicin analogues, CBI
minor-groove binders, and psymberin to antibodies have been described. These it-glucuronic acid-based linkers may be used in the conjugates described herein. In certain embodiments, the enzymatically cleavable linker is a13-galactoside-based linker. I3-Galactoside is present abundantly within lysosomes, while the enzyme activity outside cells is low.
20 [0332] Additionally, immune-stimulatory compounds containing a phenol group can be covalendy bonded to a linker through the phenolic oxygen. One such linker relies on a methodology in which a diamino-ethane "Space Link" is used in conjunction with traditional "PABO"-based self-immolative groups to deliver phenols.
[0333] Cleavable linkers can include non-cleavable portions or segments, and/or 25 cleavable segments or portions can be included in an otherwise non-cleavable linker to render it cleavable. By way of example only, polyethylene glycol (PEG) and related polymers can include cleavable groups in the polymer backbone. For example, a polyethylene glycol or polymer linker can include one or more cleavable groups such as a disulfide, a hydrazone or a dipeptide.
[0334] Other degradable linkages that can be included in linkers can include ester linkages formed by the reaction of PEG carboxylic acids or activated PEG
5 carboxylic acids with alcohol groups on an immune-stimulatory compound, wherein such ester groups can hydrolyze under physiological conditions to release the immune-stimulatory compound. Hydrolytically degradable linkages can include, but are not limited to, carbonate linkages; imine linkages resulting from reaction of an amine and an aldehyde; phosphate ester linkages formed by reacting an alcohol with a phosphate 10 group; acetal linkages that are the reaction product of an aldehyde and an alcohol;
orthoester linkages that are the reaction product of a formate and an alcohol;
and oligonucleotide linkages formed by a phosphoramidite group, including but not limited to, at the end of a polymer, and a 5' hydroxyl group of an oligonucleotide.
[0335] A linker can contain an enzymatically cleavable peptide moiety, for 15 example, a linker comprising structural formula (Ma), (Mb), (Inc), or (Md):
RY
is q 0 011a) N T
peptide..õN
y _ X

OAA
Lpeptide-õN 101 Fe RY

ii-TiLpeptide"...N
RY

Rz 0 (Ind) It q Or s'1/4-TeAThepticle....N
20 or a pharmaceutically acceptable salt thereof, wherein: "peptide"
represents a peptide (illustrated in N¨>C orientation, wherein peptide includes the amino and carboxy "termini") that is cleavable by a lysosoma1 enzyme; T represents a polymer comprising one or more ethylene glycol units or an alkylene chain, or combinations thereof; Ra is selected from hydrogen, alkyl, sulfonate and methyl sulfonate; KY is hydrogen or C1-4 alkyl-(0)14C14 alkylene)s-GI or C14 alkyl-(N)-[(C14 alkylene)-G12; Rz is C14 alkyl-(0)r-(Cr-4 allcylene)s-G2; GI is SO3H, CO2H, PEG 4-32, or a sugar moiety; G2 is SO3H, CO2H, or a PEG 4-32 moiety; r is 0 or I; s is 0 or 1; p is an integer ranging from 0 to 5;
5 q is 0 or 1; xis 0 or 1; y is 0 or 1; 1 represents the point of attachment of the linker to an immune-stimulatory compound; and * represents the point of attachment to the remainder of the linker.
103361 In certain embodiments, the peptide can be selected from natural amino acids, unnatural amino acids or combinations thereof In certain embodiments, the 10 peptide can be selected from a tripeptide or a dipeptide. In particular embodiments, the dipeptide can comprise L-amino acids and be selected from Val-Cit; Cit-Val;
Ala-Ala;
Ma-Cit; Cit-Ma; Asn-Cit; Cit-Asn; Cit-Cit; Val-Glu; Glu-Val; Ser-Cit; Cit-Ser;
Lys-Cit; Cit-Lys; Asp-Cit; Cit-Asp; Ma-Val; Val-Ala; Phe-Lys; Lys-Phe; Val-Lys;
Lys-Val;
Ma-Lys; Lys-Ala; Phe-Cit; Cit-Phe; Leu- Cit; Cit-Leu; Ile-Cit, Cit-Ile; Phe-Arg; Mg-15 Phe; Cit-Trp; and Trp-Cit, or salts thereof.
103371 Exemplary embodiments of linkers according to structural formula (IIIa) are illustrated below (as illustrated, the linkers include a reactive group suitable for covalently linking the linker to an antibody):

0 H 111) 01 CAA
(IIIa.1) trk N 0 0 -N-jcieN'''!"."14 H
H
HN

N

-XicatNH
H (f? S0--11A
N
(IIIa.3) etWir ---fe-11/4%N
- H
H
0 0 :-....803H 0 -(IIIa.4) CKA
H
H

0 0'1/4 (IIIa.5) õõ)OcNir:uL 101 -N

( NH2 N

NH
(IIIa.6) _ H

0 cNH2 0 0A1( * (IIIa.7) _ N
H 0 _ H

L.NA0 H o011 _ H

( ONE
N
wherein -04" indicates an attachment site of a linker to an immune-stimulatory compound.
103381 Exemplary embodiments of linkers according to structural formula (11%), (Mc), or (1114) that can be included in the conjugates described herein can include the linkers illustrated below (as illustrated, the linkers can include a reactive group suitable for covalendy linking the linker to an antibody):

H
(Mb. 1) t_LNAHNorNYLIFµil 0 a ( NH2 NAO
H

(IIIb.2) crc.........õ.õ,,,,A0 N
- isir.. 1/4õ,N 0 ....) O
H i H
0( x2 H

(IIIb.3) cr.õ.........---...õ...--j--, Xr. N
.,....õ1,_ N 0 O H 0 = H

1.4 0 ON
iq......A 41110 (IIIb.4) seCAN
E N
" "
o o c NH2 NO
H

H
(IIIb.5) \ H 0 H

( NH2 H

0'11A
(IIIb.6) " 0 =

H
H2N .....e.. N
I I

H.......A
N
(IIIb.7) tze---"---AN H 0 _ N
\ z H
0 ( H

(IIIb.8) cirl)LicrilljL SI
-N
H _ H

ON
(IIIb.9) ..,..KN
- cr .........õ----...õ Sy N jib..

H
H .7.
0 0 c x2 H

OejV 0 (IIIb.10) cr..........--..õ...-..........X N N '....A-N le C.- X2 H

cr............õ........A0 )criii.......AN 0 (IIIb.11) = H 0 H
SO3H ' n C NH2 N AO
H

criniA0 i)icriiN

(IIIb.12) H i H

803H 0 c NH2 N AO
H

(IIIb.13) N
O

(Illb.14) N)cr'r;LAN
0' o H vj 4110 (IIIb.15) -N
o = H
E H

N

O
I I
(IIIb.16) NILO 0 H

N N
H

OH

Hot.
(IIIb.17) NLH
NrNAJ
HI
H

HO3S.L.,....0 (HIM 8) 1/2110 IS 0 H -%--'', Nili.N.,..õ---...N.A.õ---...õ.."........)?
H
II H

OH
HO,,..

t (IIIb.19) itirµk-Ari-1-11-N
\ 0 ......z..., 0 41111 0.1,µ

H
(IIk. 1 ) cri....õ......Ø--..õ..Ø...}...X.rN.."...
.
N
H 0 _ H
(--IA AO
H

el?
H
H2N N.,.
0 ....) ......1/4 0 (IIIc.2) N 3/4"ICH N
H
yff,0 H
H2N,..e..N
Oil ) 0 (IIIc.3) is fr.0 0 OMe H

(IIIc.4) N j, lir N
NH

ish HO
HO2C t = .
0 e NH z.--,,7\70 e-c 0 NH N

o 0 o sen 0)IA
N
N

_ H
o r NH2 N
-fro ono (IIId. I) 401 17 - CI).-Oy.1 )-11 -fro 0 H2N..f0 NH n (IIId.2) 0 I
_ 0 O

yi H

0) Nn 0.1) H

()y) 0110 IIId.3) 0 o .0H
-%
Ho2c : OH
OH
H2N---fo (NH
ono N

H H
(IIId.4) 00 H
frO 0 wherein sr"' indicates an attachment site to an immune-stimulatory compound.
103391 The linker can contain an enzymatically cleavable sugar moiety, for example, a linker comprising structural formula (WO, (IVb), (IVO, (IVA or (IVe):
0 i --- xi o (IVa) N 0i H AOH

H02C z OH

OH
HO2Cõ, µõ riOHi%

(IVb) - OH
0 b q *X1 4- *
(IVC) 0 AOH
HO2C : OH
OH
OH
H02Cõ,(3 õ,OH

(IVd) _ OH

AL-0 -re-' q 410 )0 -...*
*

40 xi0 (IVe) Wit H r OH
0 "µ
OH
OH OH
5 or a pharmaceutically acceptable salt thereof, wherein: q is 0 or 1; r is 0 or 1; X' is CH2, 0 or NH; 'represents the point of attachment of the linker to an immune-stimulatory compound; and * represents the point of attachment to the remainder of the linker 103401 Exemplary embodiments of linkers according to structural formula (IVa) that may be included in the immune-stimulatory conjugates described herein can 10 include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody):

-frO

--..., (IVa.1) 0 Nyt...,..õ..,__.
yLe.õ.õ,..õ,õ j?
H N
Ho2c,(07 0 HO'. 41`0H
OH
-le -.....

(IVa.2) . NA-#"--"N'IL)13 H
H /

HON 0H V.1i 0 OH
Ot (IVa.3) * ,--,..,-0-...õ-----.N..A._õ---...õ...---,,,,h11?

H
HO2C4670yNH 0 HO . ..10H
OH
frO

(IVa.4) N'jl-'-'--MI)L''e--"---rl?\
HO2CtrOTO H H

HO'. -e'OH
OH

0 al N
------%"N"A 7-----0N Nr.,,,.1.-?
(IVa.5) H H k -H

OH
fro (IVa.6) 0 0 N
NA__t ____.N ?
H H

HO'lty .110H
OH
lir.0 (IVa.7) is 74?
NA--------N-JO
H H N

H:gitH
OH
fr0 (IVa.8) 0 m 0 ..s.--t.t.k., H H

HOVOH
OH

R j sµ
NA------%NA------------N
(IVa.9) H H 0 HOVOH
OH

Sir-0 0 ...., (IVa.10) H H

HO''' t H
V'e OH
Sr0 0 -....õ

I.
N
(IVa.11) 101 ins NA"-----44%N"--%0 0 HO"( '"OH
OH
frO

--õ, H037 H
iy3R\
(IVa.12) 0 Ciii N --i4Nr 0 HO2C(02#0 H
H
HO'µ. d"OH
OH
, wherein sir' represents the point of attachment of a linker to an immune-stimulatory.
103411 Exemplary embodiments of linkers according to structural formula (IVb) that may be included in the conjugates described herein include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody).
Sr0 (IVb.1) Ho2ci070 0 HO"( "OH

H
OH 0..õ..----Ø-----,..N.N).5 /

--sro o (IVb.2) HOVOHe H
OH 0=01µ1)(j1?

1f0 (IVb.3) HO:VOHS

OH 0,...--,.,_,NH
H

-frO

HO2CiOt 0 (IVb.4) HO'''ritH
Hyt ,õ)?
OH
N
0-,----...o,.....õ..N
H

-frO

HO2C 4,70 0 (IVb.5) HO'. .#'0H

OH
NA--------)5 H
/

yt0 (IVb.6) HO2C 000 is HOC(../H
H
OH0,.--,,aõ--,,a,,-,,,N
oil?

(IVb.7) HO2CiOrTO

HO . .40H SLII?
OH

(IVb.8) HO2CirOt *

'''OH
OH

Aro HO2C.õ1/4(01Dro0 (IVb.9) HO"0101 4"/OH

OH

to (IVb.10) 2C=CLI.- µµµ
HO _ OH

OH

5 wherein isid represents the point of attachment of a linker to an immune-stimulatory compound.
103421 Exemplary embodiments of linkers according to structural formula (IVc) that may be included in the conjugates described herein include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the 10 linker to an antibody).

OH
,,,A
HOD

H

(IVc.1) 1.1 ir`-e '''IrrIL--,'"%'-'11?
H

Co OH
HO,n ,. .00H

(IVc.2) H
i )<LO
OH
..
Ho, ,,,On H

(IVc.3) II ON)7%1-?
H

ICLO
OH
oria .,,OH
---4.,, (IVc.4) 0 H

0 cf-s- II ii P=Lire j o H 0 3 S 0 OH
HO.õ OH n.,µ
0 0 .02H

(Ivc.,) loi 0,0 )5, H -1---11? --'-'.-.-N 1 1 H

OH
H0H0.8..,µOH

(IVc.6) 0 H

le Or."---AX---------- vi ill N1/21C-r------Thsfj, )<L0 OH
HO,,. OH
n,,, (IVc.7) 0 H

I. (:)......õ..-0...,..---...eN
x.iremji "CLO
OH
A
0 0 .02H

(ive.8) is H

NLO

OH
HO,õ .,NOH
n0 0 CO2H
(IVc.9) --a%µ""--.%-t0 H 0 . 0iliLiN,y-wiji OH
HOF,. 0H
A.0 (IVc.10) le )(LO
OH
HO,,. OH
A,,,, 0 0 c02H
(Iwen) * 0 H
N NyWNJ5 0 H ) 0 i wherein sir' represents the point of attachment of a linker to an immune-stimulatory compound.
[0343] Exemplary embodiments of linkers according to structural formula (IVd) that may be included in the conjugates described herein include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody):
cr0 Li OH
si HO,,.
.00H
------Thr (IVd.1) ell 0 0 OH
c--CmiH
N õ,%se.---....0 0 HOAOH
(IVd.2) 0 0 OH
H
(IVd.3) cr..õ..õ..---T.N..õ..--,0,--..õ..0õ-----....0 0 HOAOH

OH
n Ha,.
.,\OH rE11 -----------0"--------a"-------0 SO (IVd.4) NH 0 0 CO2H
OA-a-el 0 Co HOAOH
ttr-""--AN----1- -------0 . .
(IVd.5) \ H

H
or N...........--.0,----....õ,0,...e.----t ati HO,,,. .t.OHO2 (IVd.6) \ 0 , wherein siss' represents the point of attachment of a linker to an immune-stimulatory compound.
103441 Exemplary embodiments of linkers according to structural formula (lye) 10 that may be included in the conjugates described herein include the linkers illustrated below (as illustrated, the linkers include a group suitable for coyalently linking the linker to an antibody):

frO

(IVe.1) 0 OH
lix070 (1101 0 0 HO etIOH
OH

(IVe.2) OH 101 N N

H

HOLipx '2.''OH
OH
wherein stra represents the point of attachment of a linker to an immune-stimulatory compound.
[0345] Although cleavable linkers can provide certain advantages, the linkers comprising the conjugate described herein need not be cleavable. For non-cleavable linkers, the immune-stimulatory compound release may not depend on the differential properties between the plasma and some cytoplasmic compartments. The release of the immune-stimulatory compound can occur after internalization of the immune-stimulatory conjugate via antigen-mediated endocytosis and delivery to lysosomal compartment, where the antibody can be degraded to the level of amino acids through intracellular proteolytic degradation. This process can release an immune-stimulatory compound derivative, which is formed by the immune-stimulatory compound, the linker, and the amino acid residue or residues to which the linker was covalently attached. The immune-stimulatory compound derivative from immune-stimulatory conjugates with non-cleavable linkers can be more hydrophilic and less membrane permeable, which can lead to less bystander effects and less nonspecific toxicities compared to immune-stimulatory conjugates with a cleavable linker. Immune-stimulatory conjugates with non-cleavable linkers can have greater stability in circulation than immune-stimulatory conjugates with cleavable linkers. Non-cleavable linkers can include alkylene chains, or can be polymeric, such as, for example, based upon polyalkylene glycol polymers, amide polymers, or can include segments of alkylene chains, polyalkylene glycols and/or amide polymers. The linker can contain a 5 polyethylene glycol segment having from 1 to 6 ethylene glycol units.
[0346] The linker can be non-cleavable in vivo, for example, a linker according to the formulations below:

(Va) 1/21LHOto>""a"--- N Rx (Vb) (W) NAILrN A(4 Rx (Vd) Rx (Ye) -9 N
A H Rx )0Laer, frekilett: N
(Vf) RX
or salts thereof, wherein: Ra is selected from hydrogen, alkyl, sulfonate and methyl 15 sulfonate; it' is a reactive moiety including a functional group capable of covalently linking the linker to an antibody; and ,041# represents the point of attachment of the linker to an immune-stimulatory compound.
[0347] Exemplary embodiments of linkers according to structural formula (Va)-(Vf) that may be included in the conjugates described herein include the linkers 20 illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody, and =Pri" represents the point of attachment of the linker to an immune-stimulatory compound:

(Va.1) (Vc.1) =1/2-1Le (Vc.2) (Vd.1) (Vd.2) 0 O., (Vd.3) j,Lr01,1?

(Vd.4) H TOTAN
We.!) 103481 Attachment groups that are used to attach the linkers to an antibody can 10 be electrophilic in nature and include, for example, maleimide groups, alkynes, alkynoates, allenes and allenoates, activated disulfides, active esters such as NHS esters and HOBt esters, haloformates, acid halides, alkyl, and benzyl halides such as haloacetamides. There are also emerging technologies related to "self-stabilizing"
maleimides and "bridging disulfides" that can be used in accordance with the 15 disclosure.
103491 Maleimide groups are frequently used in the preparation of conjugates because of their specificity for reacting with thiol groups of, for example, cysteine groups of the antibody of a conjugate. The reaction between a thiol group of an antibody and a drug with a linker including a maleimide group proceeds according to the following scheme:

( e..
Antibod ..-S
SH Antibodyy-- 1-NTh ¨I.-%.....4NTh Linking Group Linking Group O

Drug Drug [0350] The reverse reaction leading to maleimide elimination from a thio-substituted succinimide may also take place. This reverse reaction is undesirable as the 5 maleimide group may subsequently react with another available thiol group such as other proteins in the body having available cysteines. Accordingly, the reverse reaction can undermine the specificity of a conjugate. One method of preventing the reverse reaction is to incorporate a basic group into the linking group shown in the scheme above. Without wishing to be bound by theory, the presence of the basic group may 10 increase the nucleophilicity of nearby water molecules to promote ring-opening hydrolysis of the succinimide group. The hydrolyzed form of the attachment group is resistant to deconjugation in the presence of plasma proteins. So-called "self-stabilizing" linkers provide conjugates with improved stability. A
representative schematic is shown below:
Drug S
AntibodyeSH +
Antibody--¨N.- %.1N¨KDrug : Base !Base ¨( Ant body--S Drug ¨
_Sl Drug ...- Antibodyy(--HN¨<
-Base : Base+

H
:0-H
.
[0351] The hydrolysis reaction schematically represented above may occur at either carbonyl group of the succinimide group. Accordingly, two possible isomers may result, as shown below:

o HO
Antibody"-4Drug Antibody-3"r Drug HN¨K
HN¨( Base Base Base+
OH

103521 The identity of the base as well as the distance between the base and the maleimide group can be modified to tune the rate of hydrolysis of the thio-substituted succinimide group and optimize the delivery of a conjugate to a target by, for example, 5 improving the specificity and stability of the conjugate.
103531 Bases suitable for inclusion in a linker described herein, e.g., any linker described herein with a maleimide group prior to conjugating to an antibody, may facilitate hydrolysis of a nearby succinimide group formed after conjugation of the antibody to the linker. Bases may include, for example, amines (e.g., -N(R26)(R27), 10 where R26 and R27 are independently selected from H and C1-6 alkyl), nitrogen-containing heterocycles (e.g., a 3- to 12-membered heterocycle including one or more nitrogen atoms and optionally one or more double bonds), amidines, guanidines, and carbocycles or heterocycles substituted with one or more amine groups (e.g., a 3- to 12-membered aromatic or non-aromatic cycle optionally including a heteroatom such as a 15 nitrogen atom and substituted with one or more amines of the type -N(R26)(R27), where R26 and n27 are independently selected from H or C1-6 alkyl). A basic unit may be separated from a maleimide group by, for example, an alkylene chain of the form ¨(CH2)0r, where m is an integer from 0 to 10. An alkylene chain may be optionally substituted with other functional groups as described herein.
20 103541 A linker described herein with a maleimide group may include an electron withdrawing group such as, but not limited to, -C(0)R, =0, -CN, -NO2, -CX3, -X, -COOR, -CONR2, -COR, -COX, -SO2R, -S020R, -SO2NFIR, -SO2NR2, P03R2, -P(0)(CH3)NITR, -NO, -NR.3 , -CR=CR2, and -CCR, where each R is independently selected from H and C I-6 alkyl and each X is independently selected from F, Br, Cl, and 25 I. Self-stabilizing linkers may also include aryl, e.g., phenyl, or heteroaryl, e.g., pyridine, groups optionally substituted with electron withdrawing groups such as those described herein.

[0355] Examples of self-stabilizing linkers are provided in, e.g., U.S. Patent Publication Number 2013/0309256, the linkers of which are incorporated by reference herein. It will be understood that a self-stabilizing linker useful in conjunction with immune-stimulatory compounds may be equivalently described as unsubstituted 5 maleimide-including linkers, thio-substituted succinimide-including linkers, or hydrolyzed, ring-opened thio-substituted succinimide-including linkers.
[0356] In certain embodiments, a linker comprises a stabilizing linker moiety selected from.

"bbct NLOHN*1%0H

¨rC) oiyN 0 c tie NH

N H2 =
10 [0357] In the scheme provided above, the bottom structure may be referred to as (maleimido)-DPR-Val-Cit-PAB, where DPR refers to diaminopropinoic acid, Val refers to valine, Cit refers to citrulline, and PAB refers to para-aminobenzylcarbonyl. 4-re"
represents the point of attachment to an immune-stimulatory compound.
103581 A method for bridging a pair of sulfhydryl groups derived from 15 reduction of a native hinge disulfide bond has been disclosed and is depicted in the schematic below. An advantage of this methodology is the ability to synthesize homogenous DAR4 conjugates by full reduction of IgGs (to give 4 pairs of sulfhydryls from interchain disulfides) followed by reaction with 4 equivalents of the alkylating agent. Conjugates containing "bridged disulfides" are also claimed to have increased 20 stability.

reduoe disulfide 1 -4"
T
it \ - 6¨SH HS¨.0 .
= SH

C1/4 \--ii.
S NA
________________________________________________________________ A1025 op ors HA
H in situ elimination ' [
4k 11µ __________________ , * 11 soSO2 0 o o _____________________________________ . : s att NA
W "
de 0 "bridged disulfide"
[0359] Similarly, as depicted below, a maleimide derivative that is capable of bridging a pair of sulthydryl groups has been developed.
S
:

_______________________________________________________________________________ _ .

NO

[0360] A linker can contain the following structural formulas (Via), (VIb), or (Vic):

VI
(VIa) 0 la Rq crirr*
(VIb) 0 ( )y 0 tj \
N, "

cfrNO 0, *
(Vic) 0 Rw or salts thereof, wherein: Rq is H or-0-(CH2CH20)ii-CH3; x is 0 or 1; y is 0 or 1; G2 is -CH2CH2CH2S03H or¨CH2CH20-(CH2CH20)11-CH3; Rw is¨O-CH2CH2S03H or ¨NH(C0)-CH2CH20-(CH2CH20)12-CH3; and * represents the point of attachment to the remainder of the linker.
103611 Exemplary embodiments of linkers according to structural formula (VIa) and (V1b) that can be included in the conjugates described herein can include the linkers illustrated below (as illustrated, the linkers can include a group suitable for covalently linking the linker to an antibody):
OH
HO2C11, att0H
a%
_ (VIa.1) 0 op 1:1 H III- 0 'cc H i H
OH
HO. .00H
,,n (VIa.2) 2 0 ? 0 0 )4.?
X% N
H

ii \-o) N
(VIa.3) 1 H H

N yezizrity:
yre0 0 40 A-0 0 _de H.7- 0 N
(VIa.4) frO Ili 0 H

0 =
HO2C , OH
OH
0/0)¨

r N N
( Vth .1 ) N:14 1 11?

H
rsil 0 Sr0= 0 0 01(¨P t (VIb.2) Netk...1?

F H

Ny, fro 0 _______________________________________________________________________________ _______ /803H
C
N
Kisi I si,si?
= 0 (VIb.3) is Ni---..N
H

0 ,,,OH
HO2C : OH
OH

/
( N
Niõ IN)?
N
N
H H

yr 401 Nyc....HN Ny-(VIb.4) 0=0 µ,0H
0 .
HO2C , OH
OH
act /0 i CO
N
N:.
i.."?.

N
r 0 (VIb.6) H
lir-0 101 0 0 NOH
0 ' HO2C : OH
OH

pot r0 N
N
z 0 H
(VIIb.7) "T.0 IP 0 0 skOH
HO2C , OH
OH
,N, N N ri - --N,....---L--"--4-¨/
\ ii = 0 H

H
(VIIb.8) --l.r.0 IP

.0H
HO2C , OH
OH
, wherein sirs' represents the point of attachment of the linker to an immune-stimulatory compound.
103621 Exemplary embodiments of linkers according to structural formula (VIc) that can be included in the immune-stimulatory conjugates described herein can include the linkers illustrated below (as illustrated, the linkers can include a group suitable for covalently linking the linker to an antibody).
z 0 =.12>
-Ari3O IP 0 (Vic.1) (0 0 0 .00H
H038) HO2C : OH
OH

= 0 II ! y. $ c 3) ICN
'"ye'N
H
N I
(VIc.2) frO al 0 0 I I (:)4 (0 0 HO3S) -( = 0 H i (VIc.3) frO IP

(0 0 /
H 03S) H
H2N ,,..e.. N .1 I I

(VIc.4) ).(ii.0 µtir---N
H
=NH 0 7 _______________________________________________________________________________ _____ rlircro N) (õ0 0 H 03S) H

(VIc.5) lii0 so a 0 Nr(7.5oN
( HO

ale-g "OH
) ..-: HO3S
OH
H ! iL H

(VIc.6) yro SI

%OH
0 ', 0---.

I-102C : OH
0-cr" or OH
wherein ire' represents the point of attachment of the linker to an immune-stimulatory compound.

103631 A linker can be attached to an antibody at any suitable position.
Factors to be considered in selecting an attachment site include whether the linker is cleavable or non-cleavable, the reactive group of the linker for attachment to the antibody, the chemical nature of the immune-stimulatory compound and compatabiltity with reactive 5 sites on the linker and the antibody, and the effect of the attachment site on functional activities of the Fc domain. A linker may be attached to a terminus of an amino acid sequence of an antibody or can be attached to a side chain of an amino acid of an antibody, such as the side chain of a lysine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamine, a non-natural amino acid residue, or glutarnic acid residue. A
10 linker may be bound to a terminus of an amino acid sequence of an Fc domain or Fc region of an antibody, or may be bound to a side chain of an amino acid of an Fc domain of an antibody, such as the side chain of a lysine, setine, threonine, cysteine, tyrosine, aspartic acid, glutamine, a non-natural amino acid residue, or glutamic acid residue.
15 103641 In some embodiments, a linker is attached to a hinge cysteine of an antibody Fc domain. A linker can be attached to an antibody at a light chain constant domain lysine. A linker can be attached to an antibody at an engineered cysteine in the light chain. A linker can be attached to an antibody at an engineered light chain glutamine. A linker can be attached to an antibody at an unnatural amino acid 20 engineered into the light chain. A linker can be attached to an antibody at a heavy chain constant domain lysine A linker can be attached to an antibody at an engineered cysteine in the heavy chain. A linker can be attached to an antibody at an engineered heavy chain glutamine. A linker can be attached to an antibody at an unnatural amino acid engineered into the heavy chain. Amino acids can be engineered into an amino 25 acid sequence of an antibody as described herein or as known to the skilled artisan and can be connected to a linker of a conjugate. Engineered amino acids can be added to a sequence of existing amino acids. Engineered amino acids can be substituted for one or more existing amino acids of a sequence of amino acids.
103651 A linker can be attached to an antibody via a sulfhydryl group. A
linker 30 can be attached to an antibody via a primary amine. A linker can be a link created between an unnatural amino acid on an antibody by reacting with oxime bond that was formed by modifying a ketone group with an alkoxyamine on an immune stimulatory compound.
103661 As is known by skilled artisans, the linker selected for a particular conjugate may be influenced by a variety of factors, including but not limited to, the 5 site of attachment to the antibody (e.g., lys, cys or other amino acid residues), structural constraints of the drug pharmacophore and the lipophilicity of the drug. The specific linker selected for a conjugate should seek to balance these different factors for the specific antibody/drug combination.
103671 For example, conjugates have been observed to effect killing of 10 bystander antigen-negative cells present in the vicinity of the antigen-positive tumor cells. The mechanism of bystander cell killing by conjugates has indicated that metabolic products formed during intracellular processing of the conjugates may play a role. Neutral cytotoxic metabolites generated by metabolism of the conjugates in antigen-positive cells appear to play a role in bystander cell killing while charged 15 metabolites may be prevented from diffusing across the membrane into the medium, or from the medium across the membrane, and therefore cannot affect bystander killing In certain embodiments, the linker is selected to attenuate the bystander effect caused by cellular metabolites of the conjugate. In certain embodiments, the linker is selected to increase the bystander effect.
20 103681 The properties of the linker, or linker-compound, may also impact aggregation of the conjugate under conditions of use and/or storage.
Typically, conjugates reported in the literature contain no more than 3-4 drug molecules per antibody molecule. Attempts to obtain higher drug-to-antibody ratios ("DAR") often failed, particularly if both the drug and the linker were hydrophobic, due to aggregation 25 of the conjugate. In many instances, DARs higher than 3-4 could be beneficial as a means of increasing potency. In instances where an immune-stimulatory compound is more hydrophobic in nature, it may be desirable to select linkers that are relatively hydrophilic as a means of reducing conjugate aggregation, especially in instances where DARs greater than 3-4 are desired. Thus, in certain embodiments, a linker incorporates 30 chemical moieties that reduce aggregation of the conjugates during storage and/or use.
A linker may incorporate polar or hydrophilic groups such as charged groups or groups that become charged under physiological pH to reduce the aggregation of the conjugates. For example, a linker may incorporate charged groups such as salts or groups that deprotonate, e.g., carboxylates, or protonate, e.g., amines, at physiological pH.
5 [0369] In particular embodiments, the aggregation of the conjugates during storage or use is less than about 40% as determined by size-exclusion chromatography (SEC). In particular embodiments, the aggregation of the conjugates during storage or use is less than 35%, such as less than about 30%, such as less than about 25%, such as less than about 20%, such as less than about 15%, such as less than about 10%, such as 10 less than about 5%, such as less than about 4%, or even less, as determined by size-exclusion chromatography (SEC).
Conjugates [0370] A conjugate as described herein comprises an antibody and at least one linker attached to at least one immune-stimulatory compound, such as a myeloid cell 15 agonist or other agonist TLR8 agonist, TLR7 agonist, other TLR
agonist, STING
agonist, RIG-I-Like receptor agonist, C-type lectin receptors agonist, or cytosolic DNA
Sensors agonist). In some aspects, the present disclosure provides a conjugate represented by Formula I:
= = Dx I
(D;
20 wherein:
A is an antibody, L is the linker;
Dx is the immune-stimulatory compound;
n is selected from 1 to about 20 or 2 to about 10 or 3 to about 8; and 25 z is selected from 1 to 20.
[0371] In further aspects, the present disclosure provides an antibody conjugate represented by the formula:
(D L3_) wherein:
n is selected from 1 to about 20 or 2 to about 10 or 3 to about 8;
L3 is a linker; and D is selected from a compound or salt of a compound of any one of Category A
5 Formulas (IA), (B3), (HA), (DB), (IIC), (IBA), (IBB), (IVA), (IVB), and (IVC), or any one of Category B Formulas (IA), (JIB), (IC), (IA), (BB), and (RC).
103721 In some embodiments, the immune-stimulatory compound is a myeloid cell agonist. In some embodiments, the immune-stimulatory compound is a TLR8 agonist. In some embodiments, the immune-stimulatory compound is a TLR7 agonist.
10 In some embodiments, the immune-stimulatory compound is a TLR3 agonist.
In some embodiments, the immune-stimulatory compound is a TLR4 agonist. In some embodiments, the immune-stimulatory compound is a TLR5 agonist. In some embodiments, the immune-stimulatory compound is a TLR9 agonist. In some embodiments, the immune-stimulatory compound is a STING agonist. In some 15 embodiments, the immune-stimulatory compound is a RIG-I-Like receptor agonist. In some embodiments, the immune-stimulatory compound is a C-type lectin receptors agonist. In some embodiments, the immune-stimulatory compound is a cytosolic DNA
Sensors agonist.
103731 In some embodiments, the TLR8 agonist compound is a compound 20 selected from any one of Category A Formulas (IA), (113), (HA), (IB3), (IIC), (IIIA), (HID), (IVA), (IVB), and (IVC). In some embodiments, TLR7 agonist is a compound selected from any one of Category B Formulas (IA), (IB), (IC), (IA), (IB3), and (IIC).
103741 In some aspects, the present disclosure provides a conjugate comprising at least one immune-stimulatory compound (e.g., a compound or salt thereof), an 25 antibody, and at least one linker, wherein each immune-stimulatory compound is linked, i.e., covalently bound, to the antibody through a linker. The linker can be selected from a cleavable or non-cleavable linker. In some embodiments, the linker is cleavable. In other embodiments, the linker is non-cleavable. Linkers are further described in the present application in the preceeding section, any one of which can be 30 used to connect an antibody to an immune-stimulatory compound.

[0375] In a conjugate, the drug loading is represented by z, the number of immune-stimulatory compound-linker molecules per antibody, or the number of immune-stimulatory compounds per antibody, depending on the particular conjugate.
Depending on the context, z can represent the average number of immune-stimulatory 5 compound(-linker) molecules per antibody, also referred to the average drug loading. z can range from 1 to 20, from 1-50 or from 1-100. In some conjugates, z is preferably from 1 to 8. In some preferred embodiments, when z represents the average drug loading, z ranges from about 2 to about 5. In some embodiments, z is about 2, about 3, about 4, or about 5. The average number of immune-stimulatory compounds per 10 antibody in a preparation of conjugate may be characterized by conventional means such as mass spectroscopy, liquid chromatography/mass spectrometry (LC/MS), UHC, ELISA assay, and HPLC.
103761 A number of conjugates are consistent with the disclosure herein. The conjugates generally comprise an immune-stimulatory compound covalently bound to 15 an antibody that localizes the conjugate to a target tissue, cell population or cell. The antibody is covalently attached to each immune-stimulatory compound, either directly or through a linker that tethers the immune-stimulatory compound to the antibody.
Antibodies listed herein as well as antibodies to antigens or epitiopes thereof listed herein or otherwise known to one of skill in the art are consistent with the conjugates as 20 disclosed herein.
[0377] Some exemplary conjugates are as follows. A conjugate can comprise an antibody, at least one immune-stimulatory compound, and optionally at least one linker. A conjugate can comprise an antibody, at least one TLR7 agonist, and at least one linker. A conjugate can comprise an antibody, at least one TLR8 agonist, and at 25 least one linker. A conjugate can comprise an antibody, at least one Compound A
TLR8 agonist, and at least one linker. A conjugate can comprise an antibody, at least one Compound B TLR7 agonist, and at least one linker. A conjugate can comprise an antibody, at least one TLR3 agonist, and at least one linker. A conjugate can comprise an antibody, at least one TLR4 agonist, and at least one linker. A conjugate can 30 comprise an antibody, at least one TLR5 agonist, and at least one linker. A conjugate can comprise an antibody, at least one TLR9 agonist, and at least one linker.
A

conjugate can comprise an antibody, at least one STING agonist, and at least one linker.
A conjugate can comprise an antibody, at least one RIG-I agonist, and at least one linker. A conjugate can comprise an antibody, at least one C-type lectin receptor agonist, and at least one linker. A conjugate can comprise an antibody, at least one 5 cytosolic DNA Sensors agonist, and at least one linker.
03781 In some embodiments, the immune stimulatory compound is a myeloid cell agonist. A number of myeloid cell agonists are consistent with the disclosure herein such as a TLR8 agonist. Exemplary TLR8 agonists are provided herein. In some embodiments, a myeloid cell agonist-linker compound (Linker-Payload) is 10 selected from any of Linker-Payloads provided herein.
Category A and Category B Conjugates 103791 In certain embodiments, the disclosure provides an immune-stimulatory conjugate (or conjugate) of a or an antibody and at least one compound of any one of 15 Category A Formulas (IA), (D3), (IA), (DB), (DC), (DA), (IDB), (WA), (IVB), and (IVC), each compound optionally attached to the antibody via a linker. In certain embodiments, the disclosure provides an immune-stimulatory conjugate of an antibody and at least one compound of any one of Category B Formulas (IA), (113), (IC), (HA), (DB), and (IIC), each compound optionally attached to the antibody via a linker. In 20 certain embodiments, the average Drug-to-Antibody Ratio (DAR) of the pharmaceutical composition is selected from 1 to about 8, 2 to about 6, about 3 to about 5, or about 4.
103801 In certain embodiments, the disclosure provides a pharmaceutical composition suitable for intravenous or subcutaneous administration, comprising an immune stimulatory conjugate of a compound of any one of Category A Formulas (IA), 25 (D3), (ILA), (DB), (IIC), (DIA), (MB), (WA), (IVB), and (IVC) and a pharmaceutically acceptable excipient. In certain embodiments, the disclosure provides a pharmaceutical composition suitable for intravenous or subcutaneous administration, comprising an immune stimulatory conjugate of a compound of any one of Category B Formulas (IA), (D)), (IC), (IIA), (DB), and (IIC), and a pharmaceutically acceptable excipient. In 30 certain embodiments, the average Drug-to-Antibody Ratio (DAR) of the pharmaceutical composition is selected from 1 to about 8, 2 to about 6, about 3 to about 5, or about 4.

103811 In certain embodiments, the disclosure provides a method for the treatment of a disease treatable by a TLR agonist (e.g., cancer, viral disease) comprising subcutaneously administering an effective amount of a conjugate of a compound of any one of Category A Formulas (IA), (JIB), (IA), (JIB), (BC), (IIIA), (IIIB), (IVA), (IVB), 5 and (IVC), or a pharmaceutical composition thereof suitable for intravenous or subcutaneous administration to a subject in need thereof. In certain embodiments, the disclosure provides a method for the treatment of cancer (e.g., breast, lung, stomach/gastric, colorectal) or viral infection (e.g., HBV, HCV), comprising intravenously or subcutaneously administering an effective amount of the conjugate of 10 a compound of any one of Category B Formulas (IA), (B3), (IC), (IIA), (IIB), and (IW), or a pharmaceutical composition thereof suitable for subcutaneous administration to a subject in need thereof. In any of the embodiments herein, the conjugate may be administered by slow infusion.
103821 The disclosure provides a method of preparing an antibody conjugate of 15 the formula:
( D¨L3+Antibody n wherein:
n is selected from 1 to 20;
L3 is a linker; and 20 D is selected from a compound or salt of a compound of any one of Category A
Formulas (IA), (M), (HA), (IIB), (IIC), (IIIA), (IBB), (IVA), (IVB), and (IVC), and Category B Formulas (IA), (IB), (IC), (IIA), (IIB), and (11C), comprising contacting D-L3 with an antibody.
[0383] The disclosure provides a method of preparing an antibody conjugate of 25 the formula:
( D¨L3+Antibody n wherein:
n is selected from 1 to 20;
1,3 is a linker; and D is selected from a compound of any one of Category A Formulas (IA), (1B), (HA), (BB), (IIC), (IIIA), (IBB), (WA), (IVB), and (IVC), and Category B
Formulas (IA), ([13), (IC), (HA), (JIB), and (IIC), comprising contacting L3 with the antibody to form L3-antibody and contacting 5 L3 antibody with D to form the conjugate.
103841 In some embodiments, L3 and D together have a structure selected from:

yO
HN

IN.YLHN

N, H2Nyo HN

isss,Rxr. NH
H
N

H2 0 Oa N, 0 \ea\

\RXZACcrH 4, 0 [µiimi H
N

HN

AO

N, NH2 %tRXJ0 ---fr H 0 Sp 0 N'Thr - H
o HN
H2NAo , ,A.NH2 0 --tn.:, 0 H
0 0 [zi N

H
N
--- r--\
H N

0 \----\
NH
0.)---NH2 , o o hi õ......¶ N, NH2 0 XrieH 0 * 0-AN N
,1/4.-RXI..:õ....-õ.õ...........,...õA

N N ..":-AN
--- Nr---\
H ! H
o A, o \---- \
NH
0.).--NH2 , FI2N y0 HN

0 o oy rtN *

H
---- Nr--\
0 \----\
, Hp tip HN
H
,killirE4 .itcRx,-,r-N:II H
0 ..õ,..-7.õ..
Oy N ....,....--,N * r... Iczb 0 o 11..õ.AN
H
--- /Th N

HN
H
N N
0 40) 0 oTNNAc _in_ 0 N, \
0 \
H2N tO
HN
H
N 1.41 kRn - N 0 4,1 0y 14 0 H

`NI 0 NH2 N, Nr-\

H2NyO
Amic-ro 1111ri -r le N

H2N y0 HN

H
N
0 0 1. OyN

LL

N, H2Ny0 HN

yiLIlir A MC-WY

=

NrTh 0 \--\
H2N,f0 HN

j=L\ r IM)C11111 N
õI 0 H

11 N, 0 \--\
coLN 0 r _ H
FF H N N, N H2 /Th HN 0 \
H2NAo RXzJ%is/ 40 crAN.---y-, is ratii 0 NH2 F F
rt, H H
HN

and a salt of any one thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein 5 on RX* represents the point of attachment to the residue of the antibody.
103851 In some embodiments, RX* comprises a succinamide moiety and is bound to a cysteine residue of an antibody. In some embodiments, RX* comprises a hydrolyzed succinamide moiety and is bound to a cysteine residue of an antibody.
[0386] The compounds disclosed herein, in some embodiments, are used in 10 different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C.
In one particular embodiment, the compound is deuterated in at least one position.
Such deuterated forms can be made by the procedure described in U.S Patent Nos.
5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the 15 duration of action of drugs.
[0387] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 20 13C- or 14C-enriched carbon are within the scope of the present disclosure.
[0388] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
For example, the compounds may be labeled with isotopes, such as for example, deuterium (214), tritium (3H), iodine-125 (1251) or carbon-14 (4C). Isotopic substitution 25 with 2H, 13c, 14c, 15c, 12N, l3N, 15N, 16N, 160, 170, 14F, 15F, 16F, 17F, 18F, 33s, 34s, "S, 36S, "Cl, "Cl, "Br, 'Br, 125I are all contemplated. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
[0389] In certain embodiments, the compounds disclosed herein have some or all of the III atoms replaced with 21-I atoms. The methods of synthesis for deuterium-5 containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic method&
103901 Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and 10 Development. [In: Curr., Phann. Des., 2000; 6(10)] 2000, 110 pp; George W.; Vanma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony.
Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
[0391] Deuterated starting materials are readily available and are subjected to 15 the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
[0392] Compounds of the present disclosure also include crystalline and 20 amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
25 103931 Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present disclosure that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as 30 those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride.

[0394] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by 5 chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof (Jean Jacques, Andre Collet, Samuel H.
Wilen, "Enantiomers, Racemates and Resolutions," John Wiley and Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.
10 [0395] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts.
As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described 15 herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
[0396] In certain embodiments, compounds or salts of the compounds described herein may be prodrugs attached to antibodies to form conjugates. The term "prodrug"
20 is intended to encompass compounds which, under physiologic conditions, are converted into active compounds, e.g., TLR8 agonists, TLR7 agonists, other TLR

agonists, STING agonist, RIG-I-Like receptor agonists, C-type lectin receptors agonists, or cytosolic DNA Sensors agonists. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed or otherwise cleaved under 25 physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal.
[0397] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein are included within the 30 scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound 103981 In certain embodiments, an immune-stimulatory compound, such as a TLR8 agonist or TLR7 agonist, is modified as a prodrug with a masking group, such that the TLR8 agonist, TLR7 agonist or other agonist, has limited activity or is inactive until it reaches an environment where the masking group is removed to reveal the active 5 compound. For example, a TLR8 agonist or TLR7 agonist can be covalently modified at an amine involved in binding to the active site of a TLR8 receptor such that the compound is unable to bind the active site of the receptor in its modified (prodrug) form. In such an example, the masking group is removed under physiological conditions, e.g., enzymatic or acidic conditions, specific to the site of delivery, e.g., 10 intracellular or extracellular adjacent to target cells. Masking groups may be removed from the amine of the compound or salt described herein due to the action of lysosomal proteases, e.g., cathepsin and plasmin. These proteases can be present at elevated levels in certain tumor tissues. The masking group may be removed by a lysosomal enzyme.
The lysosomal enzyme can be, for example, cathepsin B, cathepsin S,13-glucuronidase, 15 or13-galactosidase.
103991 In certain embodiments, an amine masking group inhibits binding of the amine group of the compound with residues of a TLR8 receptor. The amine masking group may be removable under physiological conditions within a cell but remains covalently bound to the amine outside of a cell. Masking groups that may be used to 20 inhibit or attenuate binding of an amine group of a compound with residues of a TLR8 receptor include, for example, peptides and carbamates.
104001 Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic 25 Transformations (1989); T. W. Greene and P. G. M Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser 's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).
104011 The activation, stimulation or augmentation of an immune response by 30 an immune-stimulatory conjugate, such as a myeloid cell agonist, can be measured in vitro by co-culturing immune cells (e.g., myeloid cells) with cells targeted by the conjugate and measuring cytokine release, chemokine release, proliferation of immune cells, upregulation of immune cell activation markers, ADCC, or any combination thereof. ADCC can be measured by determining the percentage of remaining target cells in the co-culture after administration of the conjugate with the target cells, myeloid 5 cells, and other immune cells. In some embodiments, an immune-stimulatory conjugate can activate or stimulate immune cell activity, as determined by in vitro assay, such as a cytokine release assay, by detection of activation markers (e.g., MEC class II
markers) or other assays known in the art. In some embodiments, an immune-stimulatory conjugate has an EC50 of 100 n1V1 or less, as determine by cytokine release assay. In 10 some embodiments, an immune-stimulatory conjugate has an EC50 of 50 nlv1 or less, as determine by cytokine release assay. In some embodiments, an immune-stimulatory conjugate has an EC50 of 10 nlY1 or less, as determine by cytokine release assay. In some embodiments, an immune-stimulatory conjugate has an EC50 of 1mM or less.
Exemplary Combination Therapy 15 104021 Conjugates described herein can be administered in combination with one or more other modes of treatment in a combination therapy. The other mode or modes of treatment can be provided before, substantially contemporaneous with, and/or after the immune-stimulatory conjugate. Exemplary combination therapies comprise an immune-stimulatory conjugate described herein and a second anti-cancer agent.
In 20 some embodiments, the second anti-cancer agent is a small molecule chemotherapy and/or a biologic therapy, such as a therapeutic antibody. In some embodiments, the second anti-cancer agent is or comprises an immune checkpoint inhibitor, a therapeutic comprising a HER2-targeting agent, a kinase inhibitor, or a molecularly targeted therapy. In some embodiments, a combination therapy comprises surgery and/or 25 radiation therapy in addition to an immune-stimulatory conjugate described herein, with or without a second anti-cancer agent.
[0403] Second anti-cancer agents useful in the methods provided herein include, for example, chemotherapy agents, ionizing radiation, chemotherapy protective agents, molecularly targeted therapy, anti-cancer biologic therapy, immune checkpoint 30 inhibitor, therapeutic agents targeting HERZ kinase inhibitors, and other anti-cancer drugs. Examples of chemotherapy agents contemplated as further therapeutic agents include alkylating agents, such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide (IFEX0), melphalan (Alkeran ), and chlorambucil);

bifunctional chemotherapeutics (e.g., bendamustine); nitrosoureas (e.g., carmustine 5 (BCNU, BiCNUO; polifeprosan 20 implant (Gliadel )), lomustine (CCNU), and semustine (methyl-CCNU)); ethyleneimines and methyl-melamines (e.g., triethylenemelamine (TEM), triethylene thiophosphoramide (thiotepa), and hexamethylmelamine (HMM, altretamine)); alkyl sulfonates (e.g., busulfan (Mylerane), busulfan injection (Busulfexe)); and triazines (e.g., dacabazine (DTIC));
10 antimetabolites, such as folic acid analogues (e.g., methotrexate (Folexe), trimetrexate, and pemetrexed (multi-targeted antifolate)); pyrimidine analogues (such as 5-fluorouracil (5-FU, Adrucil , Efudex0), capecitabine (Xeloda0), fluorodeoxyuridine, tezacitabine, gemcitabine, cytosine arabinoside (AraC, cytarabine (Cytosar-U
);
cytarabine Liposome injection (DepoCyte)), 5-azacytidine, and 2,2'-15 difluorodeoxycytidine); purine analogues (e.g., 6-mercaptopurine (Purinethol0), 6-thioguanine, azathioprine, 2'-deoxycoformycin (pentostatin), erythrohydroxynonyladenine (EHNA), fludarabine phosphate (Fludara0), 2 chlorodeoxyadenosine (cladribine, 2-CdA)); Type I topoisomerase inhibitors such as camptothecin (CPT), topotecan (Hycamptine), and irinotecan (Camptosar0);
natural 20 products, such as epipodophylotoxins (e.g., etoposide (Vepeside) and teniposide (Vumon )); vinca alkaloids (e.g., vinblastine (Velban ), vincristine (Oncovin0), and vinorelbine (Navelbine0)); anti-tumor antibiotics such as actinomycin D
(dactinomycin, Cosmegan0), doxorubicin hydrochloride (Adriamycin , Rubex0), mitoxantrone (Novantronee), and bleomycin sulfate (Blenoxane0), radiosensitizers 25 such as 5-bromodeozyuridine, 5-iododeoxyuridine, and bromodeoxycytidine;
platinum coordination complexes such as cisplatin (Platinol*), carboplatin (Paraplatin0), and oxaliplatin (Eloxatin0); substituted ureas, such as hydroxyurea (Hydrea0);
microtubule inhibitors such as paclitaxel (Taxo10), docetaxel (Taxotere0), and eribulin (Halavene);
FOLFOX (a chemotherapy regimen comprising Folinic acid (leucovorin) "FOL", 30 Fluorouracil (5-F1.1) "F", and Oxaliplatin (E(oxatin) "OX"), immunosuppressive agents such as cyclophosphamide (Cytoxan or Neosar0); hormone-based compound such as anastrozole (Arimidexe), exemestane (Aromasin*), letrozole (Femara*), fulvestrant (Faslodexe), bicalutamide (Casodexe), Flutamide (Eulexine), Nilutamide (Nilandrone), Enzalutamide (Xtandi0), apalutamide (Erleada0), darolutamide (Nubega.0), Degarelix (Firmagone), Toremifene (Farestone), goserelin (Zoladexe), 5 Triptorelin (Trelstar0), Histrelin (Vantase), leuprolide (Luprone) and tamoxifen citrate (Nolvadexe); an anti-inflammatory agent such as dexamethasone; an anti-androgen compound such as flutamide (Eulexine); an anthracycline compound such as idarubicin (Idamycin , Zavedosit) and epirubicin (Ellence8); bioreductive anti-cancer agent such as tirapazamine (Tirazonee); serine/threonine kinase inhibitors such as 10 CDK4/6 inhibitors abemaciclib (Verzenio0), palbociclib (Ibrance0), and ribociclib (Kisciali0); tyrosine kinase inhibitors such as tucatinib, cabozantinib, afatinib, erlotinib, pyrotinib, neratinib, poziotinib, dacomitinib, gefitinib, lapatinib, osimertinib, larotrectinib, axitinib, lenvatinib, pazopanib, regorafenib, and sunitinib;
and methylhydrazine derivatives such as N methylhydrazine (WEI) and procarbazine.
15 104041 Anticancer molecularly targeted therapy target specific molecules involved in the development, growth and spread of cancer cells. In some embodiments, a molecularly targeted therapy is a small molecule or comprises an antibody or antigen binding fragment. Examples of molecularly targeted include ALK inhibitors such as crizotinib, ceritinib, and alectinib; BCL2 inhibitors such as venetoclax, obatoclax, 20 navitoclax, and gossypol; PARP inhibitors such as iniparib and olaparib;
BRAF
inhibitors such as vernurafenib and dabrafenib; and angiogenesis inhibitors such as VEGF and/or VEGFR inhibitors, including axitinib, sunitinib, pazopanib, cabozantinib, vandetanib, motesanib, regorafenib, cediranib, lenvatinib, sorafenib, ziv-aflibercept, aflibercept, ranibizumab, ramucirumab, and bevacizumab.
25 104051 Examples of anti-cancer biologic therapy include biologic therapy comprising antibodies (e.g., therapeutic antibodies or antigen binding fragments thereof, antibody conjugates, cellular immunotherapy (e.g., chimeric antigen receptor (CAR) T cells, T cell receptor (TCR) immunotherapy, dendritic cell therapy), and Fc-fusion proteins. In some embodiments, an anti-cancer biologic therapy targets a tumor 30 antigen, or a molecule in involved in development, growth, and/or spread of cancer cells (molecularly targeted immunotherapy). Examples of antibody conjugate therapy contemplated for use as therapeutic agents include, for example, sacituzumab govitecan and enfortumab vedotin.
[0406] In some embodiments, additional anti-cancer agents useful in the methods provided herein include chemotherapy protective agents that prevent or 5 descrease toxic side effects of chemotherapy agents. Examples of chemotherapy protect agents contemplated for use as further therapeutic agents include, for example, leucovorin (folinic acid), allpuronol (Zyloprim0), rasburicase (Fasturtece), amifostine (Ethyo10), dexrazoxane (Zinecard0), and mesna (Mesnexa).
[0407] In certain embodiments, the combination therapy comprises a conjugate 10 described herein and palbociclib. In further embodiments, the combination therapy comprises a conjugate described herein and abemaciclib. In still further embodiments, the combination therapy comprises a conjugate described herein and ribociclib.
Immune Checkpoint Inhibitors [0408] In some embodiments, combination therapies comprise a conjugate 15 described herein and a second anti-cancer agent, wherein the second anti-cancer agent is or comprises an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is an antagonist of PD-1, PD-L1, and/or PD-L2. In some embodiments, the antagonist of PD-1, PD-L1, and/or PD-L2 is a small molecule, such as INCB 86550, 1,3,4- and 1,2,4-oxadiazole and 1,3,4- and 1,2,4-thiadiazole 20 compounds (see WO 2015/033301 WO 2016/142894; WO 2016/142833, WO 2018/051255; WO 2018/07375, and Guzik etal., Molecules 24:2071, 2019, the compounds from which are incorporated herein by reference), and GS-4224;
peptides and peptidomimetics such as AUNP-12 and heptapeptide SNTSEFS-NH2 (SEQ ID NO:
12)), macrocyclic peptides such as BMS-57, BMS-71, and BMS99; ansamycin class of 25 antibiotics such as geldanamycin and rifabutin; Fc-fusion proteins, such as AMP-224;
and antibodies, such as pembrolizumab (CEYTRUDA ); pembrolizumab biosimilar;
nivolumab (OPDIVO ); nivolumab biosimilar; pidilizumab; pidilizumab biosimilar;
cemiplimab; AMP-514 (MEDI0608, see U.S. Patent No. 8,609,089,B2); MDX-1105;
dostarlimab; tislelizumab; ICD-033, AGEN2034; STI-A1010; STI-A1110;
durvalumab;
30 atezolizumab; avelumab; BMS-936559; or a PD-1 antibody disclosed in U.S.
Patent No. 8,008,449; 6,808,710; 7,488,802; 8,168,75; or 8,354,509; or PCT
Publication No.
WO 2012/145493. In some embodiments, the immune checkpoint inhibitor is an anti-PD1 antibody selected from pembrolizumab (KEYTRUDA0); pembrolizumab biosimilar; nivolumab (OPDIV00); nivolumab biosimilar; pidilizumab;
pidilizumab 5 biosimilar; toripalimab; cemiplimab; cemiplimab biosimilar, dostarlimab;
tislelizumab;
BMS-936559; AMP-514 (MEDI0608, see U.S. Patent No. 8,609,089,B2); AGEN2034;
and STI-A1110. In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody selected from atezolizumab; atezolizumab biosimilar; durvalumab;
durvalumab biosimilar; avelumab; avelumab biosimilar; MDX-1105; BMS-936559;
KD-033; and STI-A1010.
[0409] In certain embodiments, the immune checkpoint inhibitor is an inhibitor of TIGIT, e.g., an anti-TIGIT antibody such as tiragolumab.
[0410] In some embodiments, the combination therapy comprises a conjugate described herein and an additional therapeutic agent comprising pembrolizumab, 15 nivolumab, pidilizumab, or a biosimilar thereof. In certain embodiments, the combination therapy comprises a conjugate described herein and pembrolizumab or a biosimilar thereof. In certain further embodiments, the combination therapy comprises a conjugate described herein and nivolumab or a biosimilar thereof Therapeutic Agents Targeting HER2 20 [0411] In some embodiments, combination therapies comprise a conjugate described herein and an additional therapeutic agent targeting HER2, such as kinase inhibitors and/or therapeutic agents comprising an anti-HER2 antibody. In some embodiments, a kinase inhibitor is a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, including a CDK4/6 inhibitor. In some embodiments, a CDK4/6 25 inhibitor is selected from abemaciclib (Verzenio0), palbociclib (Ibrance0), and ribociclib (Kisqa1i0). Nonlimiting exemplary tyrosine kinase inhibitors include tucatinib, cabozantinib, afatinib, erlotinib, pyrotinib, neratinib, poziotinib, dacomitinib, gefitinib, lapatinib, osimertinib, larotrectinib, axitinib, lenvatinib, pazopanib, regorafenib, and sunitinib. In some embodiments, the tyrosine kinase inhibitor is 30 selected from tucatinib, cabozantinib, pyrotinib, neratinib, and poziotinib. In some embodiments, an additional therapeutic is an adenosine receptor antagonist, such as AB928. Therapeutic agents comprising an anti-HER2 antibody include anti-HER2 antibodies or antigen binding fragments thereof and anti-HER2 antibody conjugates. In some embodiments, the therapeutic agent comprising an anti-HER2 antibody is selected 5 from trastuzumab, a trastuzumab biosimilar (such as trastuzumab-qyyp (TRAZIMERATm), trastuzumab-plcrb (HERZUMA0), trastuzumab-dttb (ONTRUZANTO), trastuzumab-anns (KANJINTITm), trastuzumab-dkst (OgivriTm), fam-trastuzumab deruxtecan-nxki (ENHERTUO, DS-8201), ado-trastuzumab emtansine (KADCYLA0), trastuzumab duocarmazine (SYD985), PF-06804103, 10 trastuzumab auristatin-0101, margetuximab, zenocutuzumab (MCLA-128), (Zymeworks); ZW49 (Zymeworks); RC48-ADC (RemeGen); RG6148 (DHES0815A);
or RG6194 (BTRC4017A).
[0412] In some embodiments, the combination therapy comprises a conjugate described herein and an additional therapeutic agent selected from any one of 15 trastuzumab, trastuzumab-qyyp, trastuzumab-pkrb, trastuzumab-dttb, trastuzumab-anns, trastuzumab-dkst, and margetuximab. In certain embodiments, the combination therapy comprises a conjugate described herein and trastuzumab. In certain further embodiments, the combination therapy comprises a conjugate described herein and trastuzumab-qyyp.
20 [0413] In further embodiments, the combination therapy comprises a conjugate described herein and an additional therapeutic agent selected from any one of fam-trastuzumab deruxtecan-nxki, ado-trastuzumab emtansine, and trastuzumab duocarmazine. In certain embodiments, the combination therapy comprises a conjugate described herein and fam-trastuzumab deruxtecan-nxki. In certain embodiments, the 25 combination therapy comprises a conjugate described herein and ado-trastuzumab emtansine.
[0414] In some embodiments, the combination therapy comprises a conjugate described herein and an additional therapeutic agent selected from any one of tucatinib, pyrotinib, neratinib, and poziotinib. In certain embodiments, the combination therapy 30 comprises a conjugate described herein and tucatinib.

Pharmaceutical Formulations [0415] The conjugates described herein are useful as pharmaceutical compositions for administration to a subject in need thereof Pharmaceutical compositions can comprise the conjugates described herein and one or more 5 pharmaceutically acceptable excipients, suitable for administration by a selected route.
A pharmaceutical composition can comprise any conjugate described herein. A
pharmaceutical composition can further comprise buffers, carbohydrates, and/or preservatives, as appropriate. Pharmaceutical compositions comprising a conjugate can be manufactured, for example, by lyophilizing the conjugate, mixing, dissolving, 10 emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions can also include the conjugates described herein in a free-base form or pharmaceutically-acceptable salt form.
[0416] Methods for formulation of the pharmaceutical compositions can include formulating any of the conjugates described herein with one or more inert, 15 pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition for intravenous or subcutaneous administration. Solid compositions can include, for example, powders, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH
buffering agents, and other pharmaceutically-acceptable additives.
Alternatively, the 20 compositions described herein can be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use [0417] The pharmaceutical compositions and formulations can be sterilized.
Sterilization can be accomplished by filtration through sterile filtration.
[0418] The pharmaceutical compositions described herein can be formulated for 25 administration as an injection, e.g., an intravenous or subcutaneous injection Non-limiting examples of formulations for injection can include a sterile suspension, solution or emulsion in oily or aqueous vehicles. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances which 30 increase the viscosity of the suspension. The suspension can also contain suitable stabilizers. Alternatively, the pharmaceutical compositions described herein can be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0419] The conjugates can be formulated for administration in a unit dosage form in association with a pharmaceutically acceptable vehicle. Such vehicles can be 5 inherently nontoxic, and non-therapeutic. A vehicle can be water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Nonaqueous vehicles such as fixed oils and ethyl oleate can also be used. The vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).
10 [0420] In some embodiments, an aqueous formulation of a conjugate provided herein, such as for subcutaneous administration, has a pH from 4-5.2. The aqueous formulation may comprise one or more excipients, such as, for example, one or more buffering agents, one or more lyoprotectants, and the like. In some embodiments, the pH of the formulation is from 4-5.1, 4.1-5.1, 4.2-5.1, 4.3-5.1, 4.4-5.1, 4.5-5.1, 4-5, 4.1-15 5, 4.2-5, 4.3-5, 4.4-5, or 4.5-5. In some embodiments, the formulation comprises at least one buffer. In various embodiments, the buffer may be selected from histidine, citrate, aspartate, acetate, phosphate, lactate, tromethamine, gluconate, glutamate, tartrate, succinate, malic acid, fumarate, a-ketoglutarate, and combinations thereof In some embodiments, the buffer is at least one buffer selected from histidine, citrate, 20 aspartate, acetate, and combinations thereof In some embodiments, the buffer is a combination of histidine and aspartate. In some embodiments, the total concentration of the buffer in the aqueous formulation is 10mM to 40mIv1, such as 15mM-30mM, 15mM-25mM, or 20 mM.
[0421] In some embodiments, the aqueous formulation comprises at least one 25 lyoprotectant. In some such embodiments, the at least one lyoprotectant is selected from sucrose, arginine, glycine, sorbitol, glycerol, trehalose, dextrose, alpha-cyclodextrin, hydroxypropyl beta-cyclodextrin, hydroxypropyl gamma-cyclodextrin, proline, methionine, albumin, mannitol, maltose, dextran, and combinations thereof In some embodiments, the lyoprotectant is sucrose. In some embodiments, the total 30 concentration of lyoprotectant in the aqueous formulation is 3-12%, such as 5-12%, 6-10%, 5-9%, 7-9%, or 8%.

[0422] In some embodiments, the aqueous formulation comprises at least one surfactant. Exemplary surfactants include polysorbate 80, polysorbate 20, poloxamer 88, and combinations thereof In some embodiments, the aqueous formulation comprises polysorbate 80. In some embodiments, the total concentration of the at least 5 one surfactant is 0.01%-0.1%, such as 0.01%43.05%, 0.01%4).08%, or 0.01%-0.06%, 0.01%-0.04%, 0.01%-0.03%, or 0.02%.
[0423] In some embodiments, the concentration of the conjugate in the aqueous formulation is 1 mg/mL-200 mg/mL, such as 10 mg/mL-160 mg/mL, 10 mg/mL-140 mg/mL, 10 mg/mL-120 mg/mL, 20 mg/mL-120 mg/mL, or 30 mg/mL-120 mg/mL, or 10 40 mg/mL-120 mg/mL, or 40 mg/mL-100 mg/mL. In some embodiments, the concentration of the conjugate in the aqueous formulation is 10 mg/mL-I40 mg/mL or 40 mg/mL-140 mg/mL.
Therapeutic Applications [0424] The combination therapies provided herein are useful for treating 15 plurality of different subjects including, but not limited to, a mammal, human, non-human mammal, a domesticated animal (e.g., laboratory animals, household pets, or livestock), non-domesticated animal (e.g., wildlife), clog, cat, rodent, mouse, hamster, cow, bird, chicken, fish, pig, horse, goat, sheep, rabbit, and any combination thereof. In various embodiments, the subject is a human.

[0425] In various embodiments, methods of treating cancer (e.g., breast, lung, stomach/gastric, colorectal) or viral infection (e.g., HBV, HCV) are provided, comprising administering to a subject with cancer or viral infection an immune checkpoint inhibitor and a conjugate provided herein, wherein the conjugate comprises an antibody that binds a tumor associated antigen for cancer, or a liver cell antigen for 25 viral infection. In some such embodiments, the immune checkpoint inhibitor is an antibody. In some such embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1 and/or PD-L1, e.g., an anti-PD-1 and/or anti-PD-Li antibody. In certain embodiments, the immune checkpoint inhibitor is an inhibitor of TIGIT, e.g., an anti-TIGIT antibody such as tiragolumab.

[0426] Nonlimiting exemplary inhibitors of PD-1 and/or PD-Li include pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab, or a biosimilar thereof. In some embodiments, the immune checkpoint inhibitor is an anti-PD1 antibody selected from pembrolizumab, nivolumab, zimberelimab, and 5 cemiplimab, or a biosimilar thereof In some embodiments, the immune checkpoint inhibitor is an anti.-PD-L1 antibody selected from atezolizumab, avelumab, and durvalumab, or a biosimilar thereof.
[0427] In some embodiments, the conjugate comprises an antibody that binds HERI In some embodiments, the anti-HER2 antibody of the conjugate comprises the 10 CDRs of pertuzumab, antigen binding fragment (e.g., variable regions) of pertuzumab, light and heavy chains of pertuzumab. In some embodiments, the anti-HER2 antibody of the conjugate comprises the CDRs of trastuzumab, antigen binding fragment (e.g., variable regions) of trastuzumab, light and heavy chains of trastuzumab.
[0428] In some such embodiments, the anti-HER2 antibody of the conjugate 15 comprises heavy chain (HC)-CDR1, HC-CDR2, HC-CDR3, light chain (LC)-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 1-6, respectively. In further embodiments, the anti-HER2 antibody of the conjugate comprises a heavy chain and light chain, wherein: (a) the heavy chain comprises HC-CDR1, HC-CDR2, and HC-CDR3 of SEQ
ID NOs: 1-3, respectively, and comprises a heavy chain variable region (YR) having an 20 amino acid sequence that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100% identity to the Vii amino acid sequence of SEQ ID NO: 7; and (b) the light chain comprises LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 4-6, respectively, and a light chain variable region (VL) having an amino acid sequence that 25 has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100%
identity to the Vt, amino acid sequence of SEQ ID NO: 8. In still further embodiments, the anti-HER2 antibody of the conjugate comprises a NTH comprising or consisting of the amino acid sequence of SEQ ID NO: 7 and a Vt, comprising or consisting of the amino acid 30 sequence of SEQ ID NO: 8. In yet further embodiments, the anti-HER2 antibody of the conjugate comprises a heavy chain and light chain, wherein: (a) the heavy chain comprises HC-CDR1, HC-CDR2, and HC-CDR3 of SEQ ID NOs: 1-3, respectively, and comprises an amino acid sequence that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100% identity to the heavy chain amino acid sequence of SEQ
5 ID NO: 9; and (b) the light chain comprises LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 4-6, respectively, and an amino acid sequence that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100% identity to the light chain amino acid sequence of SEQ ID NO: 10. In yet further embodiments, the anti-10 antibody of the conjugate comprises a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 9 and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 10.
[0429] In some such embodiments, the method comprises administering an additional therapeutic agent. In some such embodiments, the additional therapeutic 15 agent comprises a chemotherapy agent, a kinase inhibitor, a therapeutic agent targeting HER2, a biologic therapy such as a therapeutic antibody, a molecularly targeted therapy, a chemotherapy protective agent, or any combination thereof.
[0430] In some such embodiments, the therapeutic agent is a therapeutic agent targeting HER-2, such as kinase inhibitors and/or therapeutic agents comprising an anti-20 HER2 antibody. In some such embodiments, the therapeutic agent targeting HER2 is selected from trastuzumab, trastuzumab-qyyp, trastuzumab-pkrb, trastuzumab-dttb, trastuzumab-anns, trastuzumab-dkst, trastuzumab deruxtecan-nxki, ado-trastuzumab emtansine, trastuzumab, duocarmazine, margetuximab, zenocutuzumab (MCLA-128), tucatinib, cabozantinib, pyrotinib, neratinib, and poziotinib. In some such 25 embodiments, the therapeutic agent targeting HER2 comprises an anti-HER2 antibody, e.g., an anti-HER2 antibody or antigen binding fragment thereof, or anti-HER2 antibody conjugate. In some such embodiments, the therapeutic agent comprising an anti-HER2 antibody is selected from trastuzumab, trastuzumab-qyyp, trastuzumab-pkrb, trastuzumab-dttb, trastuzumab-anns, trastuzumab-dkst, trastuzumab deruxtecan-nxki, 30 ado-trastuzumab emtansine, trastuzumab, duocarmazine, margetuximab, zenocutuzumab (MCLA-128).

[0431] In some such embodiments, the kinase inhibitor is a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, such as a CDK4/6 inhibitor.
In some embodiments, a tyrosine kinase inhibitor is tucatinib, cabozantinib, afatinib, erlotinib, pyrotinib, neratinib, poziotinib, dacomitinib, gefitinib, lapatinib, osimertinib, 5 larotrectinib, axitinib, lenvatinib, pazopanib, regorafenib, or sunitinib. In some embodiments, the tyrosine kinase inhibitor is tucatinib, cabozantinib, pyrotinib, neratinib, or poziotinib. In some embodiments the CDK4/6 inhibitor is abemaciclib, palbociclib, or ribociclib.
[0432] In some such embodiments, the chemotherapy agent comprises a 10 hormone-based compound, optionally wherein the hormone based compound comprises anastrozole, exemestane, letrozole, fulvestrant, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, darolutamide, degarelix, torernifene, goserelin, triptorelin, histrelin, leuprolide, or tamoxifen citrate.
[0433] In some such embodiments, the chemotherapy agent comprises a 15 platinum coordination complex, optionally wherein the platinum coordination complex comprises cisplatin, oxaliplatin, or carboplatin.
[0434] In some such embodiments, the chemotherapy agent comprises a folic acid analog, optionally wherein the folic acid analog comprises pemetrexed, methotrexate, or trimetrexate.
20 [0435] In some such embodiments, the chemotherapy agent comprises a pyrimidine analog, optionally wherein the pyrimidine analog comprises fluorouracil, capecitabine, fluorodeoxyufidine, tezacitabine, gemcitabine, cytosine arabinoside, cytarabine, 5-azacytidine, or 2,2'-difluorodeoxycytidine.
[0436] In some such embodiments, the chemotherapy agent comprises a 25 microtubule inhibitor, optionally wherein the microtubule inhibitor comprises paclitaxel, docetaxel, and eribulin.
[0437] In some such embodiments, the chemotherapy protective agent comprises leucovorin (folinic acid), allpuronol, rasburicase, amifostine, dexrazoxane, or mesna.
30 104381 In any of the aforementioned embodiments, the linker-payload compound of the conjugate has a structure selected from:

HN

myliplyi N
405---Rwre N
H
0 0 0.,...õNi -a31.,,N
N

, I I
H
, FI2N tO
HN

RXt ts "rqlYL\11 rµl H

H
N

N
A0 N__ . H
N ,....-o -õ--01 -..,1 Xff.,H o . n o rt-Thr ri tztrRX:I.,...,.........,......%__A_ N NIAN
H H
N

0 \---"\
HN

/
OSr ..iN1 o 0 JI,N..., NH2 0 Xiiii 0 is 0 [1 H
N ---- i----\
H H
N

NH
Cd%.--NH2 H2 N yel HN
H H
FRx,wyNxiltily N4 H H

a a Oy N......õ..---N * 0 NH2 H

N, N
H

¨ r---...

H2Nto HN

0 rIXII\H" 0 11 Oy ii N, -H2Ny0 HN
H
0 0 * 031 YTh reN., 0 0 Wer5CN
N-% 0 N H F F
11101 rajN N, NH2 H H
reN, HN
0 \--Th H2NAb and a salt of any one thereof, wherein the RX* is a bond, a succinimide moiety, or a 5 hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX*
represents the point of attachment to the residue of the antibody. In some embodiments, RX* comprises a succinamide moiety and is bound to a cysteine residue of an antibody.
In some embodiments, RX* comprises a hydrolyzed succinamide moiety and is bound to a cysteine residue of an antibody.
10 [0439] In certain embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4:0 Dx 1 z 0);

wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
5 L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2N tO
HN
H
(LyN

N N, NH2 rTh or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed 10 succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen; and (b) pembrolizumab.
[0440] In certain embodiments, a method of treating cancer comprises 15 administering:
(a) an antibody conjugate represented by Formula (I):
= = DX)]
z (J);
wherein:
A is an antibody;
20 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:

L and Dx have a structure of:
H2N y0 HN
H H
H
0 . Ckõ_õNrDcj,N

C) N.__ H
N
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein ) on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen;
(b) pembrolizumab; and (c) fam-trastuzumab deruxtecan-nx1d.
[04411 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4, 4, Dx i 1 z 0);
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Ny0 HN

\111 0 H 0 I.
N, /Th or a salt thereof, wherein the RX+ is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(13) pembrolizumab; and (c) ado-trastuzumab emtansine.
[0442] In further embodiments, a method of treating cancer comprises administering:
10 (a) an antibody conjugate represented by Formula (I):
4) = DX)]
z (i);
wherein:
A is an antibody;
n is one;
15 z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2NtO
HN
oL

0 N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein )4 on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) pembrolizumab; and (c) a chemotherapy agent comprising pemetrexed; and (d) a chemotherapy agent comprising carboplatin; and optionally wherein the cancer is a non-small cell lung cancer (NSCLC).
10 104431 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = x 1 z 0);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2NtO
HN
oL

0 N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein )4 on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) pembrolizumab; and (c) a chemotherapy agent comprising pemetrexed; and (d) a chemotherapy agent comprising cisplatin; and optionally wherein the cancer is a NSCLC.
10 104441 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = x 1 z 0);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

1-12Ny0 HN
H
ARc irwNiNli.N

or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RIC* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) atezolizumab;
(c) bevacizumab;
(d) a chemotherapy agent comprising carboplatin; and (e) a chemotherapy agent comprising paclitaxel; and 10 optionally wherein the cancer is a NSCLC.
[0445] In certain embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
z (J);
15 wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 20 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Ny0 HN

0 H 0 le 01/2.,õ,NalN
N, 0 \--I\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein "1- on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen; and (b) nivolumab.
[04461 In certain embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
= =
x 10 z (I);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
15 L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
N2Ny0 HN

y-3.1( oaN 0 ISC

0 H 0 *
N, o or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a HER2 antigen; and 5 (13) trastuzumab.
[04471 In certain embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = Dx 1 z (J);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 15 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure Of:
H2 Ny0 HN
ARx<yHNA H

0 le 0.õ,e,Nraj 0 N, 1,4 or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein -44 on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a HER2 antigen; and (b) fam-trastuzumab deruxtecan-nxki.

[0448] In certain embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = x 1 z (J);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2N tO
HN
H

r.....31.õ1 N, N H2 \---\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein t on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a HER2 antigen; and (b) ado-trastuzumab emtansine.
104491 In certain embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
x 1 1 z (J);

wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
5 L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2Ny.0 HN

1111;\,11 or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed 10 succinimide moiety bound to a residue of an antibody, wherein .-st on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a HER2 antigen; and (b) tucatinib.
104501 In certain embodiments, a method of treating a HER2-expressing cancer 15 comprises administering:
(a) an antibody conjugate represented by Formula (I):
= Dx 1 z (J);
wherein:
A is an antibody;
20 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:

L and Dx have a structure of:
FuNto HN
H

or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a HER2 antigen; and (b) palbociclib.
104511 In certain embodiments, a method of treating a HER2-expressing cancer comprises administering:
10 (a) an antibody conjugate represented by Formula (I):

z 0);
wherein:
A is an antibody;
n is one;
15 z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2N tO
HN

0 10 OGL1 N N, NH2 0 \---\
or a salt thereof, wherein the RX+ is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 HER2 antigen; and (b) abemaciclib.
[04521 In certain embodiments, a method of treating HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = 1 10 z (J);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
15 L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2Ny0 HN
H
Nts%11 N
raj N
ON
, NH2 or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein --A on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a HER2 antigen; and 5 (b) ribociclib.
[04531 In further embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = Dx 1 z (J);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 15 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2NtO
HN
H
NH

N, 2 0 \Th or a salt thereof, wherein the RS is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein --A on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a HER2antigen;
(b) trastuzurnab; and (c) a chemotherapy regimen comprising leucovorin, fluorouracil, and oxaliplatin (FOLFOX); and optionally wherein the cancer is a gastric cancer.
[0454] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):

z 0);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2Nyo HN
ARx<
H
0 41) NH2 N, o r¨\\

or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab; and (d) a chemotherapy regimen comprising leucovorin, fluorouracil, and oxaliplatin (FOLFOX); and optionally wherein the cancer is a gastric cancer.
[0455] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
= =

wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2N tO
HN
H
0 411ONOLA N, NH2 or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen;
(b) trastuzumab;
(c) nivolumab; and (d) a chemotherapy regimen comprising leucovorin, fluorouracil, and oxaliplatin (FOLFOX); and optionally wherein the cancer is a gastric cancer.

[04561 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = Dx 1 z (J);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2Ny0 HN
H

N, /Th 0 \---\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein )4 on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen;
(b) trastuzumab;
(c) atezolizumab; and (d) a chemotherapy regimen comprising leucovorin, fluorouracil, and oxaliplatin (FOLFOX); and optionally wherein the cancer is a gastric cancer.

In further embodiments, a method of treating HER2-expressing cancer comprises administering:

(a) an antibody conjugate represented by Formula (I):
= 1 Z (J):
wherein:
A is an antibody;
5 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

yO
HN

(111-n-0, NaIN

N, o or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a FIER2 antigen;
15 (b) trastuzumab; and (c) a chemotherapy regimen comprising leucovorin, fluorouracil, and cisplatin; and optionally wherein the cancer is a gastric cancer.
[0458] In further embodiments, a method of treating cancer comprises 20 administering:
(a) an antibody conjugate represented by Formula (I):

z (J);
wherein:
A is an antibody;
n is one;
5 z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2N y0 HN

ARC IN,,A111 N, 10 or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen;
(b) trastuzumab;
15 (c) pembrolizumab; and (d) a chemotherapy regimen comprising leucovorin, fluorouracil, and cisplatin; and optionally wherein the cancer is a gastric cancer.
[04591 In further embodiments, a method of treating cancer comprises 20 administering:
(a) an antibody conjugate represented by Formula (I):

z (J);
wherein:
A is an antibody;
n is one;
5 z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

HN
Ha\ H
NH

N, 2 10 or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein -S. on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen;
(b) trastuzumab;
15 (c) nivolumab; and (d) a chemotherapy regimen comprising leucovorin, fluorouracil, and cisplatin; and optionally wherein the cancer is a gastric cancer.
[0460] In further embodiments, a method of treating cancer comprises 20 administering:
(a) an antibody conjugate represented by Formula (I):

z (J);
wherein:
A is an antibody;
n is one;
5 z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
1-0 y0 HN

ThCY11;11 0 _pt.-L.__ H 0 N, f-Th 10 or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen;
(b) trastuzumab;
15 (c) atezolizumab; and (d) a chemotherapy regimen comprising leucovorin, fluorouracil, and cisplatin; and optionally wherein the cancer is a gastric cancer.
1104611 In further embodiments, a method of treating a HER2-expressing cancer 20 comprises administering:
(a) an antibody conjugate represented by Formula (I):

z (J);
wherein:
A is an antibody;
n is one;
5 z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
ii2N y0 HN
H
Rn0 NH2 N, n 10 or a salt thereof, wherein the RX+ is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to ITER2 antigen;
(b) trastuzumab; and 15 (c) a chemotherapy comprising capecitabine; and optionally wherein the cancer is a gastric cancer.
104621 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
= =
DX

20 z (I):
wherein:

A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 5 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2N y0 HN

NHz N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab; and optionally wherein the cancer is a gastric cancer.
15 [0463] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
=
z 0);
wherein:
20 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2N y0 HN
N
i.HA,,,õ

H

0 1110 0.........NratC---.N N, ll H

N
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein Y on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen;
(b) trastuzumab;
(c) nivolumab; and 10 optionally wherein the cancer is a gastric cancer.
[04641 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = Dx 1 1 z (J);
15 wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 20 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Ny0 HN
H
ARdcwyNiNir.N
0 H 0 SI oyNiN

or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RIC* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) atezolumab; and optionally wherein the cancer is a gastric cancer.
1104651 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) =

z (J);
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure Of:

H2N yO
HN
Ha\rH

0 H 0 le NOLAN N, LkN0 \--- re\
\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab; and (d) a chemotherapy comprising capecitabine; and optionally wherein the cancer is a gastric cancer.
10 [0466] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = DX)]
Z (i);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2N tO
HN
ARIY

INI
mN 0 N, 0 \-\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein -)4 on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) nivolumab; and (d) a chemotherapy comprising capecitabine; and optionally wherein the cancer is a gastric cancer.
10 [0467] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = x 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2N tO
HN

IR lit\ 011 m INI N 0 .,N H2 N N

or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein -)4 on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) atezolizumab; and (d) a chemotherapy comprising capecitabine; and optionally wherein the cancer is a gastric cancer.
10 [0468] In further embodiments, a method of treating a FIER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = Dx 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2N tO
HN
ARIY

INI
mN 0 .N

0 \-\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein -)4 on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a HER2antigen;
(b) trastuzumab; and (c) a chemotherapy regimen comprising capecitabine and oxaliplatin; and optionally wherein the cancer is a gastric cancer.
[0469] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
= Dm /1 z (J);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2N y0 HN
ARC
H

0OyN1lLiflycyNNH2 , 0 \-- re\
\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein )4 on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(13) trastuzumab;
(c) pembrolizumab; and (d) a chemotherapy regimen comprising capecitabine and oxaliplatin; and optionally wherein the cancer is a gastric cancer.
10 1104701 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
=
x z 0);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2Ny0 HN
RAH
N N
N
1--n N

H

N
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein -$ on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) nivolumab; and (d) a chemotherapy regimen comprising capecitabine and oxaliplatin; and optionally wherein the cancer is a gastric cancer.
10 [0471] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = Dx / 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and D. have a structure of:

H2Ny.0 HN

rsly:1)Yri cuN 0 0 \---\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein --A on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) atezolizumab; and (d) a chemotherapy regimen comprising capecitabine and oxaliplatin; and optionally wherein the cancer is a gastric cancer.
10 [0472] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
Dx 1 1 Z (0;
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2N tO
HN
ARIY

INI
mN 0 N, 0 \-\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein -)4 on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab; and (d) a chemotherapy comprising docetaxel; and optionally wherein the cancer is a breast cancer.
10 [0473] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = x 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2N yO
HN
Ha\ H

0 H 0 le NOLAN N, LkN0 \--- re\
\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab; and (d) a chemotherapy comprising paclitaxel; and optionally wherein the cancer is a breast cancer 10 [0474] In further embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = DX)]
Z (i);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2Ny0 HN
RCY
RAH

N, r-\\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein -$ on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 BER2 antigen;
(b) trastuzumab;
(c) palbociclib; and (d) a hormone-based compound selected from any one or more of anastrozole, exemestane, letrozole, fulvestrant, bicalutamide, flutamide, nilutamide, 10 enzalutamide, apalutamide, darolutamide, degarelix, toremifene, goserelin, triptorelin, histrelin, leuprolide, and tamoxifen citrate; and optionally wherein the cancer is a breast cancer.
[0475] In further embodiments, a method of treating a HER2-expressing cancer comprises administering:
15 (a) an antibody conjugate represented by Formula (I):

z 0);
wherein:
A is an antibody;
n is one;
20 z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2N y0 HN
0 ky N, NH2 or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 HER2 antigen;
(b) trastuzumab;
(c) abemaciclib; and (d) a hormone-based compound selected from any one or more of anastrozole, exemestane, letrozole, fulvestrant, bicalutamide, flutamide, nilutamide, 10 enzalutamide, apalutamide, darolutamide, degarelix, toremifene, goserelin, triptorelin, histrelin, leuprolide, and tamoxifen citrate; and optionally wherein the cancer is a breast cancer.
[0476] In further embodiments, a method of treating cancer comprises administering:
15 (a) an antibody conjugate represented by Formula (I):
4) = DX)]
Z (0;
wherein:
A is an antibody;
n is one;
20 z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Ny0 HN

.,ilN

0 H 0 I.

or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein "1- on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab;
(d) atezolizumab; and (e) a chemotherapy agent comprising docetaxel; and 10 optionally wherein the cancer is a breast cancer.
[0477] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
=
z (J);
15 wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 20 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2N y0 HN
ARc H

or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein )4 on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(13) trastuzumab;
(c) pembrolizumab;
(d) atezolizumab; and (e) a chemotherapy comprising paclitaxel; and 10 optionally wherein the cancer is a breast cancer.
[0478] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
= Dx 1 z 0);
15 wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 20 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Ny0 HN
H
H

0 0 *
N, 0 \-\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein --1( on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) fam-trastuzumab deruxtecan-nxki; and (c) durvalumab; and optionally wherein the cancer is a breast cancer.
1104791 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = DX)]
z (J);
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2N y0 HN
=
n OyNXNN, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RIC* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) fam-trastuzumab deruxtecan-nxki; and (c) atezolizumab; and optionally wherein the cancer is a breast cancer 1104801 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) =

z (J);
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2N yO
HN
Ha\ H

0 H 0 le NOLAN N, LkN0 \--- re\
\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) ado-trastuzumab emtansine; and (c) durvalumab; and optionally wherein the cancer is a breast cancer [0481] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
= Dx 1 z 0);
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

HN

N , or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) ado-trastuzumab emtansine; and (c) atezolizumab; and optionally wherein the cancer is a breast cancer.
[0482] In any of the aforementioned embodiments having a linker-payload (L-10 Dx) structure of H2Ny0 HN
H

N, Nc the antibody comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain 15 variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, RX* comprises a succinamide moiety and is bound to a cysteine residue of an antibody construct. In some embodiments, RX* comprises a hydrolyzed 20 succinamide moiety and is bound to a cysteine residue of an antibody construct.

[0483] In certain embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = Dx 1 1 z (J);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2Ny0 HN
H
1-1RXCINAr"

o *

N, rTh or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein --44 on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen; and (b) pembrolizumab.
[0484] In certain embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = Dx 1 z 0);

wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
5 L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H,Nto HN-I
H
1%1RXIN)NTI
LIN

rxiN
0 OyNõ,...õ,--..N

N I N, 0 \
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed 10 succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen;
(b) pembrolizumab; and (c) fam-trastuzumab deruxtecan-nxId.
15 [04851 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):

z 0);
wherein:
20 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:

L and Dx have a structure of:
H,Nto HN
ERXIEllYLYN

0 H le 0y rl 0 N\----\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents 5 the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen;
(b) pembrolizumab; and (c) ado-trastuzumab emtansine.
[04861 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
= Dx 1 z imp;
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2N to HN

511 ::11:11rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) pembrolizumab; and (c) a chemotherapy agent comprising pemetrexed; and (d) a chemotherapy agent comprising carboplatin; and optionally wherein the cancer is a NSCLC.
10 [0487] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2N to HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) pembrolizumab; and (c) a chemotherapy agent comprising pemetrexed; and (d) a chemotherapy agent comprising cisplatin; and optionally wherein the cancer is a NSCLC.
10 [0488] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2Nto HN

511 ::11:11rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) atezolizumab;
(c) bevacizumab;
(d) a chemotherapy agent comprising carboplatin; and (e) a chemotherapy agent comprising paclitaxel; and 10 optionally wherein the cancer is a NSCLC.
[04891 In certain embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
DX)]
Z 0);
15 wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 20 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Ny0 HN

::11:11HN1re1ll OP
0 0 OyN..N

NH

=N N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen; and (b) nivolumab.
104901 In certain embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
= Dx 1 1 10 z (J);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
15 L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H,Nto HN
O H
-.ru 1.. tri 40 ===,..,.AN N, ra\

or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a HER2 antigen; and 5 (13) trastuzumab.
[0491] In certain embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = Dx 1 z (J);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 15 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2Ny0 HN

FRXIN

0 0 Oy so a t iN

N, rTh I\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein -$ on RX*
represents 20 the point of attachment to the residue of the antibody, wherein the antibody binds to a ITER2 antigen; and (b) fam-trastuzumab deruxtecan-nxki.
[0492] In certain embodiments, a method of treating a HER2-expressing cancer comprises administering:

(a) an antibody conjugate represented by Formula (I):
=
Z (J):
wherein:
A is an antibody;
5 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2Ny0 HNI
H
"--RXWYNXLINIIIrN

8=N, o or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a HER2 antigen; and 15 (b) ado-trastuzumab emtansine.
[0493] In certain embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
= Dx 1 1 z imp;
20 wherein:
A is an antibody;

n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
5 L and Dx have a structure of:
H2NtO
HN
oL
H

N
rThs%
0 \
or a salt thereof, wherein the RX+ is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein --A on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 10 HER2 antigen; and (b) tucatinib.
[0494] In certain embodiments, a method of treating a BER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
= DX)]
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
20 L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and D. have a structure of:

H2Ny0 HN

::11:11HN1re1ll OP
0 0 OyN..N

NH

=N N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 HER2 antigen; and (b) palbociclib.
104951 In certain embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
= Dx 1 1 10 z (J);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
15 L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H,Nto HN
O H
-.ru 1.. tri 40 ===,..,.AN N, ra\

or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a HER2 antigen; and 5 (b) abemaciclib.
[0496] In certain embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) = Dx 1 z (J);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4; and L and Dx have a structure of:
H2Ny0 HN
H
1RX(14)\'N

NH

rTh or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein --A on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to HER2 antigen; and 20 (b) ribociclib.
[0497] In further embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):

z (J);
wherein:
A is an antibody;
n is one;
5 z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2N tO
HN

Oy N
nN.z.1 0 NH
N

N, r---10 or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a HER2 antigen;
(b) trastuzumab; and 15 (c) a chemotherapy regimen comprising leucovorin, fluorouracil, and oxaliplatin (FOLFOX); and optionally wherein the cancer is a gastric cancer.
[0498] In further embodiments, a method of treating cancer comprises administering:
20 (a) an antibody conjugate represented by Formula (I):

x 1 z (J);
wherein:

A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 5 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H,Nto HN
H
O H
Oy N
so ijazsa.
I

- r-\
or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein )4 on RX*
represents 10 the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab; and (d) a chemotherapy regimen comprising leucovorin, fluorouracil, and 15 oxaliplatin (FOLFOX); and optionally wherein the cancer is a gastric cancer.
[0499] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
=

20 z (I);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;

L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:
H2N tO
HN
H
N:S
FRXC iryW Ny 0 40 0 \
5 or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein -$ on RX*
represents the point of attachment to the residue of the antibody, wherein the antibody binds to a tumor associated antigen;
(b) trastuzumab;
10 (c) nivolumab; and (d) a chemotherapy regimen comprising leucovorin, fluorouracil, and oxaliplatin (FOLFOX); and optionally wherein the cancer is a gastric cancer.
105001 In further embodiments, a method of treating cancer comprises 15 administering:
(a) an antibody conjugate represented by Formula (I):
= 40 Dx 1 z 0);
wherein:
A is an antibody;
20 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Nto HN

511 ::11:11rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) atezolizumab; and (d) a chemotherapy regimen comprising leucovorin, fluorouracil, and oxaliplatin (FOLFOX); and 10 optionally wherein the cancer is a gastric cancer.
[05011 In further embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
DX)]
Z 0);
15 wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 20 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2N to HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 HER2 antigen;
(b) trastuzumab; and (c) a chemotherapy regimen comprising leucovorin, fluorouracil, and cisplatin; and optionally wherein the cancer is a gastric cancer.
10 [0502] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2Nto HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab; and (d) a chemotherapy regimen comprising leucovorin, fluorouracil, and cisplatin; and 10 optionally wherein the cancer is a gastric cancer.
[0503] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
DX)]
Z 0);
15 wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 20 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Nto HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) nivolumab; and (d) a chemotherapy regimen comprising leucovorin, fluorouracil, and cisplatin; and 10 optionally wherein the cancer is a gastric cancer.
[0504] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
DX)]
Z 0);
15 wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 20 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Nto HN

511 ::11:11rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) atezolizumab; and (d) a chemotherapy regimen comprising leucovorin, fluorouracil, and cisplatin; and 10 optionally wherein the cancer is a gastric cancer.
[0505] In further embodiments, a method of treating a FIER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
DX)]
Z 0);
15 wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 20 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Nto HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed suecinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 HER2 antigen;
(b) trastuzumab; and (c) a chemotherapy comprising capecitabine; and optionally wherein the cancer is a gastric cancer.
[0506] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 4> DX)]
Z 0);
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Nto HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab; and optionally wherein the cancer is a gastric cancer.
[0507] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 4> DX)]
Z 0);
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Nto HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) nivolumab; and optionally wherein the cancer is a gastric cancer.
[0508] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 4> DX)]
Z 0);
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 17),, is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Nto HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) atezolumab; and optionally wherein the cancer is a gastric cancer.
[0509] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 4> DX)]
Z 0);
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2N to HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab; and (d) a chemotherapy comprising capecitabine; and optionally wherein the cancer is a gastric cancer.
10 [0510] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2N to HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) nivolumab; and (d) a chemotherapy comprising capecitabine; and optionally wherein the cancer is a gastric cancer.
10 [0511] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2N to HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) atezolizumab; and (d) a chemotherapy comprising capecitabine; and optionally wherein the cancer is a gastric cancer.
10 [0512] In further embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2Nto HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 HER2 antigen;
(b) trastuzumab; and (c) a chemotherapy regimen comprising capecitabine and oxaliplatin; and optionally wherein the cancer is a gastric cancer.
[0513] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 4> DX)]
Z 0);
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2N to HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab; and (d) a chemotherapy regimen comprising capecitabine and oxaliplatin; and optionally wherein the cancer is a gastric cancer.
10 [0514] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2N to HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) nivolumab; and (d) a chemotherapy regimen comprising capecitabine and oxaliplatin; and optionally wherein the cancer is a gastric cancer.
10 [0515] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2N to HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) atezolizumab; and (d) a chemotherapy regimen comprising capecitabine and oxaliplatin; and optionally wherein the cancer is a gastric cancer.
10 [0516] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2N to HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab; and (d) a chemotherapy comprising docetaxel; and optionally wherein the cancer is a breast cancer.
10 [0517] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2N to HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab; and (d) a chemotherapy comprising paclitaxel; and optionally wherein the cancer is a breast cancer.
10 [0518] In further embodiments, a method of treating a HER2-expressing cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 1 z (J);
wherein:
15 A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
20 L and Dx have a structure of:

H2Ny0 HN

::11:11HN1re1ll OP
0 0 OyN..N

NH

=N N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a HER2 antigen;
(b) trastuzumab;
(c) palbociclib; and (d) a hormone-based compound selected from any one or more of anastrozole, exemestane, letrozole, fulvestrant, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, darolutamide, degarelix, toremifene, goserelin, niptorelin, histrelin, leuprolide, and tamoxifen citrate; and optionally wherein the cancer is a breast cancer.
[05191 In further embodiments, a method of treating a HER2-expressing cancer comprises administering (a) an antibody conjugate represented by Formula (I):
4) = Dx 1 z 0);
wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Ny0 HN

::11:11HN1re1ll OP
0 0 OyN..N

NH

=N N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 HER2 antigen;
(b) trastuzumab;
(c) abemaciclib; and (d) a hormone-based compound selected from any one or more of anastrozole, exemestane, letrozole, fulvestrant, bicalutamide, flutamide, nilutamide, 10 enzalutamide, apalutamide, darolutamide, degarelix, toremifene, goserelin, triptorelin, histrelin, leuprolide, and tamoxifen citrate; and optionally wherein the cancer is a breast cancer.
1105201 In further embodiments, a method of treating cancer comprises administering:
15 (a) an antibody conjugate represented by Formula (I):
4) = Dx 1 z 0);
wherein:
A is an antibody;
n is one;
20 z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound, wherein:
L and Dx have a structure of:

H2Nto HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab;
(d) atezolizumab; and (e) a chemotherapy agent comprising docetaxel; and 10 optionally wherein the cancer is a breast cancer.
[05211 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
DX)]
Z 0);
15 wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 20 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Nto HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) trastuzumab;
(c) pembrolizumab;
(d) atezolizumab; and (e) a chemotherapy comprising paclitaxel; and 10 optionally wherein the cancer is a breast cancer.
[05221 In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
DX)]
Z 0);
15 wherein:
A is an antibody;
n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and 20 Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Nto HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) fam-trastuzumab deruxtecan-nxki; and (c) durvalumab; and optionally wherein the cancer is a breast cancer.
[0523] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 4> DX)]
Z 0);
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Nto HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) fam-trastuzumab deruxtecan-nxki; and (c) atezolizumab; and optionally wherein the cancer is a breast cancer.
[0524] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 4> DX)]
Z 0);
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Nto HN

5::11:1111rell NH

N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) ado-trastuzumab emtansine; and (c) durvalumab; and optionally wherein the cancer is a breast cancer.
[0525] In further embodiments, a method of treating cancer comprises administering:
(a) an antibody conjugate represented by Formula (I):
4) 4> DX)]
Z 0);
wherein:
A is an antibody;
15 n is one;
z is selected from 2 to about 8 or from 2 to about 4;
L is the linker; and Dx is the immune-stimulatory compound; wherein:
L and Dx have a structure of:

H2Ny0 HN

PlyLiJy.

OyN.N is N, or a salt thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody, wherein the antibody binds to a 5 tumor associated antigen;
(b) ado-trastuzumab emtansine; and (c) atezolizumab; and optionally wherein the cancer is a breast cancer.
[0526] In any of the aforementioned embodiments having a linker-payload 10 structure of H2N y0 HN

irly HN L1)1( -s ERX.1 0 so Oy the antibody comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain 15 variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, RX* comprises a succinamide moiety and is bound to a cysteine residue of an antibody construct. In some embodiments, RX* comprises a hydrolyzed 20 succinamide moiety and is bound to a cysteine residue of an antibody construct.

105271 In any of the aforementioned embodiments, the cancer may be a HER2-expressing cancer, such as breast cancer, stomach/gastric cancer, colorectal cancer, non-small cell lung cancer (NSCLC), urothelial cancer, endometrial cancer, or ovarian cancer.
5 105281 In various embodiments, methods of treating HER2-expressing cancer are provided, comprising administering a conjugate provided herein, wherein the conjugate comprises an antibody that binds HER2, and an additional therapeutic agent comprising a kinase inhibitor, a therapeutic agent comprising an anti-HER2 antibody, or both the tyrosine kinase inhibitor and therapeutic agent comprising an anti-10 antibody. In some embodiments, the anti-HER2 antibody of the conjugate comprises the CDRs of pertuzumab, antigen binding fragment (e.g., variable regions) of pertuzumab, light and heavy chains of pertuzumab. In some embodiments, the anti-HER2 antibody of the conjugate comprises the CDRs of trastuzumab, antigen binding fragment (e.g., variable regions) of trastuzumab, light and heavy chains of trastuzumab.
15 105291 In some such embodiments, the anti-HER2 antibody of the conjugate comprises heavy chain (HC)-CDR1, HC-CDR2, HC-CDR3, light chain (LC)-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 1-6, respectively. In further embodiments, the anti-HER2 antibody of the conjugate comprises a heavy chain and light chain, wherein: (a) the heavy chain comprises HC-CDR1, HC-CDR2, and HC-CDR3 of SEQ
20 ID NOs: 1-3, respectively, and comprises a heavy chain variable region (VH) having an amino acid sequence that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100% identity to the VH amino acid sequence of SEQ ID NO: 7; and (b) the light chain comprises LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 4-6, 25 respectively, and a light chain variable region (VI.) having an amino acid sequence that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100%
identity to the VL amino acid sequence of SEQ ID NO: 8. In still further embodiments, the anti-HER2 antibody of the conjugate comprises a VH comprising or consisting of the amino 30 acid sequence of SEQ ID NO: 7 and a NIL comprising or consisting of the amino acid sequence of SEQ ID NO: 8. In yet further embodiments, the anti-HER2 antibody of the conjugate comprises a heavy chain and light chain, wherein: (a) the heavy chain comprises HC-CDR1, HC-CDR2, and HC-CDR3 of SEQ ID NOs: 1-3, respectively, and comprises an amino acid sequence that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 5 99%, at least 99.5%, or 100% identity to the heavy chain amino acid sequence of SEQ
ID NO: 9; and (b) the light chain comprises LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 4-6, respectively, and an amino acid sequence that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100% identity to the light chain 10 amino acid sequence of SEQ ID NO: 10. In yet further embodiments, the anti-HER2 antibody of the conjugate comprises a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 9 and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 10.
[0530] In some such embodiments, the method comprises administering a 15 conjugate comprising an antibody that binds HER2 and an additional therapeutic agent comprising an anti-HER2 antibody, wherein the anti-HER2 antibody of the conjugate and the anti-HER2 antibody of the additional therapeutic agent bind different epitopes of HER2. For example, the anti-HER2 antibody of the conjugate may comprise pertuzumab or the CDRs or antigen binding fragment (e.g., variable regions of 20 pertuzumab), while the anti-HER2 antibody of the additional therapeutic agent comprises trastuzumab or a biosimilar thereof, or the CDRs or antigen binding fragment (e.g., variable regions of trastuzumab).
[0531] In any of the aforementioned embodiments, the additional therapeutic agent is selected from trastuzumab, trastuzumab-qyyp, trastuzumab-pkrb, trastuzumab-25 dub, trastuzumab-anns, trastuzumab-dkst, trastuzumab deruxtecan-nxki, ado-trastuzumab emtansine, trastuzumab duocarmazine, margetuximab, and zenocutuzumab (MCLA-128 (Merus)).
[0532] In some embodiments, the additional therapeutic agent is a kinase inhibitor selected from a tyrosine kinase inhibitor and a serinSthreonine kinase 30 inhibitor. In some embodiments, the tyrosine kinase inhibitor is tucatinib, cabozantinib, afatinib, erlotinib, pyrotinib, neratinib, poziotinib, dacomitinib, gefitinib, lapatinib, osimertinib, larotrectinib, axitinib, lenvatinib, pazopanib, regorafenib, or sunitinib. In some embodiments, the serine/threonine kinase inhibitor is a CDK4/6 inhibitor, such as abemaciclib (Verzenio0), palbociclib (Ibrance0), or ribociclib (Kisqali0).
105331 In some embodiments, the additional therapeutic agent is a small 5 molecule tyrosine kinase inhibitor that inhibits HER2. In some embodiments, the additional therapeutic agent is selected from tucatinib, cabozantinib, pyrotinib, neratinib, and poziotinib.
[0534] In some embodiments, the additional therapeutic agents further comprises a chemotherapy agent, an immune checkpoint inhibitor, a biologic therapy 10 such as a therapeutic antibody, a molecularly targeted therapy, chemotherapy protective agent, or any combination thereof.
[0535] In some such embodiments, the immune checkpoint inhibitor is an antibody. In some such embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1 and/or PD-L1, e.g., an anti-PD-1 and/or anti-PD-Li antibody. Examples of 15 anti-PD-1 and/or anti-PD-Li antibodies include pembrolizumab, nivolumab, cerniplimab, avelumab, durvalumab, and atezolizumab, or a biosimilar thereof.
In some embodiments, the immune checkpoint inhibitor is an anti-PD1 antibody selected from pembrolizumab, nivolumab, and cemiplimab, or a biosimilar thereof In some embodiments, the immune checkpoint inhibitor is an anti-PD-Ll antibody selected from 20 avelumab, durvalumab, and atezolizumab, or a biosimilar thereof.
[0536] In some such embodiments, the chemotherapy agent comprises a hormone-based compound, optionally wherein the hormone based compound comprises anastrozole, exemestane, letrozole, fulvestrant, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, darolutamide, degarelix, toremifene, goserelin, triptorelin, 25 histrelin, leuprolide, or tamoxifen citrate.
[0537] In some such embodiments, the chemotherapy agent comprises a platinum coordination complex, optionally wherein the platinum coordination complex comprises cisplatin, oxaliplatin, or carboplatin.
[0538] In some such embodiments, the chemotherapy agent comprises a folic 30 acid analog, optionally wherein the folic acid analog comprises pemetrexed, methotrexate, or trimetrexate.

[0539] In some such embodiments, the chemotherapy agent comprises a pyrimidine analog, optionally wherein the pyrimidine analog comprises fluorouracil, capecitabine, fluorodeoxyuridine, tezacitabine, gemcitabine, cytosine arabinoside, cytarabine, 5-azacytidine, or 2,2'-difluorodeoxycytidine.
5 [0540] In some such embodiments, the chemotherapy agent comprises a microtubule inhibitor, optionally wherein the microtubule inhibitor comprises paclitaxel, docetaxel, and eribulin.
[0541] In some such embodiments, the chemotherapy protective agent comprises leucovorin (folinic acid), allpuronol, rasburicase, amifostine, dexrazoxane, or mesna.
[0542] In any of the aforementioned embodiments, the linker-payload compound of the conjugate has a structure selected from:
H2Ny.0 HN
H
N__ NH2 0 401 0.1/4__CUN

\
0 \
H2N tO
HN
ti 0 N

N

N, H2 o /Th ti4 I N, NH2 0 NxIA
'X/ 0 OANThr n 0 N
r--H H

=
15 H2No A %Li, 0 yr. H 0 0 0 N
N
H
lar RXIAN H
0 H r N N ' N¨ \

0 \ ---- \
N H
A

H2Ny0 ' HN

INIAIRII

t'RXii N
o 0 H H

Na.õN
a..
Oy N.....õ,...Th 0 I 1/2% 0 NH2 H N, N
H
---- Nr-\\
0 \Thl H2N y0 HN

Mt\ II
is---Rx.--:--------------y N
o 0 o H H
0 OyN.,...-...N

I), Nõ
N
H
çJ
- r-=
IN

0 \--"N
H2N 1/4,r0 HN

kilx13y M
e(RX'<WY N
H
0 0 0 0 rl N
tli U
N, N
HLJ-- r-\\
N

4 4AnCri 0 OC., 0 .. NH2 VR).(1.'NAN reN N F F
N ,-- IC

-- Nr---\
HN
0 \Th H2NAo , and a salt of any one thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein "A on RX*
represents the point of attachment to the residue of the antibody. In some embodiments, RX* comprises a succinamide moiety and is bound to a cysteine residue of an antibody.
5 In some embodiments, RX* comprises a hydrolyzed succinamide moiety and is bound to a cysteine residue of an antibody.
105431 In some embodiments, RX* comprises a succinamide moiety and is bound to a cysteine residue of an antibody construct.
105441 In some embodiments RX* comprises a hydrolyzed succinamide moiety 10 and is bound to a cysteine residue of an antibody construct.
105451 In certain aspects, the instant disclosure provides a method of treating HER2-expressing cancer comprising administering:
(a) a conjugate having the following structure:

r Orsji.1/244. N
I-IN
15 or a pharmaceutically acceptable salt thereof, wherein:
Ab is an antibody, D is a TLR7 agonist of formula:

N
or%-If wherein le is an alkyl, heteroallcyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group comprising from 1 to 8 carbons, each J is hydrogen, each U is N, each t is 2, Q is not present, the dashed line represents a point of attachment of D to GI, and GI is a bond;
subscript a is an integer from 1 to 40; and subscript r is an integer from 1 to 10; and 5 (b) a therapeutic antibody, a kinase inhibitor, a chemotherapy agent, or any N g Nt)__rj N
(N) combination thereof. In certain embodiments, D is -4-.
105461 In certain embodiments, the instant disclosure provides a method of treating HER2-expressing cancer comprising administering:
(a) a conjugate having the following structure:
r Q

Tht--N mt.t ..\\, tirren-----o-iaNNArialeNe-AN
H Ab 112N N.-.Nte I
i 4 r , wherein Ab is trastuzumab; and (b) a PD-1 and/or PD-L1 inhibitor, optionally wherein the PD-1 and/or PD-Li inhibitor comprises one or more of pembrolizumab, atezolizumab, and durvalumab.
105471 The combination therapies provided herein can be used in the methods 15 described herein as a therapeutic, for example, as a treatment that can be administered in an effective regimen to a subject in need thereof to achieve a therapeutic effect. A
therapeutic effect can be obtained in a subject by reduction, suppression, remission, alleviation or eradication of a disease state, including, but not limited to, one or more symptoms thereof A therapeutic effect in a subject having a disease or condition, or 20 exhibiting an early symptom thereof or exhibiting or otherwise suspected of being in or approaching an early stage of a disease or condition, can be obtained by a reduction, a suppression, a prevention, a delay, a remission, an alleviation or an eradication of the condition or disease, or pre-condition or pre-disease state. In various embodiments, the method comprises administering an effective regimen that results in a Tmax of the conjugate of greater than 4 hours following each administration of the conjugate. In some embodiments, the effective regimen results in a Tmax greater than 6 hours, greater than 8 hours, greater than 10 hours, greater than 12 hours, or greater than 15 5 hours following each administration of the conjugate.
[0548] In certain embodiments, the methods include administration of an immune-stimulatory conjugate, or a pharmaceutical composition thereof, to a subject in need thereof in an effective regimen to activate, stimulate or augment an immune response against a disease treatable with a TLR agonist (e.g., cancer or a viral disease).
10 The polypeptide of the conjugate recognizes an antigen associated with the disease or disease state, such as a tumor-associated antigen or liver cell antigen.
[0549] In certain embodiments, the cancer to be treated with the therapeutic combinations provided herein is a solid tumor, such as a sarcoma, a carcinoma or lymphoma. In some such embodiments, the antibody of the conjugate recognizes an 15 antigen on the target cells, such as a tumor-associated antigen. In some embodiments, the cancer is a HER2-expressing cancer and the antibody of the conjugate binds HER2.
In some embodiments, the HER2-expressing cancer is selected from breast cancer, stomach/gastric cancer, colorectal cancer, non-small cell lung cancer (NSCLC), urothelial cancer, endometrial cancer, and ovarian cancer. In some aspects, the HER2 20 expressing cancer expresses HER2 at a level of 2+ or 3+ as determined by immunohistochemistry 105501 In certain embodiments, the methods include administration of a combination therapy comprising a conjugate provided herein to a subject in need thereof to activate, stimulate or augment an immune response against tumor cells of a 25 solid tumor, such as brain, breast, lung, liver, kidney, pancreatic, colorectal, ovarian, head and neck, bone, skin, mesothelioma, bladder, stomach/gastric, prostate, thyroid, uterine or cervical/endometrial cells. In some such embodiments, the polypeptide of the conjugate recognizes an antigen on the tumor cells.
105511 In some cases, treatment comprises reduced tumor growth. In some 30 cases, treatment comprises tumor arrest. In some cases, combination therapy comprising a conjugate provided herein allows for dose reduction of an accompanying chemotherapy agent.
[0552] In certain embodiments, the methods include administration of a combination therapy comprising a conjugate provided herein (e.g., including a 5 agonist antibody conjugate specific for a liver cell antigen, such as a liver cell antigen expressed on a liver cell infected with a virus) to a subject in need thereof to activate, stimulate or augment an immune response against viral infection, such as a chronic viral infection (e.g., HBV, HCV). In some embodiments, the liver cell antigen is a hepatocyte antigen. In further embodiments, the liver cell antigen is ASGR1 10 (asialoglycoprotein receptor 1), ASGR2 (asialoglycoprotein receptor 2), TRF2, UGT1A1, SLC22A7, SLC13A5, SLC22A1, or C9. In particular embodiments, the liver cell antigen is ASGR1, ASGR2, or TRF2.
[0553] One of ordinary skill in the art would understand that the amount, duration and frequency of administration of a combination therapy described herein to a 15 subject in need thereof depends on several factors including, for example but not limited to, the health of the subject, the specific disease or condition of the subject, the grade or level of a specific disease or condition of the subject, the additional therapeutics the subject is being or has been administered, and the like.
[0554] In some aspects of practicing the methods described herein, the 20 conjugates are administered in an effective regimen of at least two or at least three cycles. Each cycle can optionally include a resting stage between cycles.
Cycles of administration can be of any suitable length. In some embodiments, each cycle is a week (7 days), 10 days, every two weeks (14 days or biweekly), every three week (21 days) or every four weeks (28 days). In some embodiments, each cycle is a month. In 25 some embodiments, at least two doses of the immune-stimulatory conjugate are administered more than 7 days apart, or more than 10 days apart. In some embodiments, at least one dose of the conjugate is administered more than 7 days, or more than 10 days, after the initial dose of the conjugate.
[0555] In certain embodiments, the total dose of the conjugate within a cycle is 30 from about 0.1 to about 10 mg/kg. In some embodiments, the total dose is from about 0.5 to about 7.5 mg/kg. In some embodiments, the total dose is from about 0.5 to about mg/kg. In some embodiments, the total dose is from about 0.5 to about 4 mg/kg.
In some embodiments, the total dose is from about 0.5 to about 3.5 mg/kg. In some embodiments, the total dose is from about 0.5 to about 2 mg/kg.
105551 In some embodiments, an effective regimen comprises at least two 5 cycles of administration of the conjugate to the subject and a total dose of greater than 0.4 mg/kg of the conjugate per cycle.
05571 Application of immune-stimulatory conjugates described herein shows substantial benefit in directing a subject's own immune response to cells of a particular site of disease or disorder, such as cells associated with the disease or disorder.
10 Activating or stimulating an immune response directed to targeted cells facilitates the reduction, inhibition of proliferation, inhibition of growth, inhibition of progression, inhibition of metastasis or otherwise inhibition up to and including in some cases clearance of the targeted cells. Thus, in some cases a targeted immune response activation or stimulation leads to inhibition of disease progression, or alleviation of at 15 least one symptom of a manifest disease in a patient, up to and in some cases including complete elimination of from one symptom to an entire disease state in a subject.
05581 In particular, the methods disclosed herein are well suited for use with immune stimulatory conjugates, such as immune stimulatory conjugates that direct an immune response in a subject to a particular disorder or disease location, cell type or 20 cell, Accordingly, practice of some methods herein comprises selection of a suitable subject such as a subject to be subjected to or undergoing a treatment with a conjugate that directs a ben7a7epine or benzazepine-like compound of the conjugate to a particular disorder or disease site, cell type or cell. Often, the subject is selected for practice of the method due to having at least one symptom of a disease or disorder, or 25 projected to develop at least one symptom of a disease or disorder (such as a subject in remission and at risk for relapse), suitable for treatment by a conjugate as disclosed herein. Some diseases are selected not based upon or not based solely on disease type, but upon detection or presence of a suitable epitope on a tumor, cell type or particular cell that facilitates localization of an immune-stimulatory conjugate to the epitope.

EXAMPLES
105591 The following examples are included to further describe some embodiments of the present disclosure and should not be used to limit the scope of the disclosure. The examples are not intended to represent that the experiments below are 5 all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (for example, amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
10 105601 While aspects of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such aspects are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the aspects of the disclosure described herein may be 15 employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

105611 The expression of activation markers, including CD86, CD40, CD80 and PD-L1, on human dendritic cells (DCs) following contact with a HER2-TLR8 conjugate in the presence of HER2-expressing tumor cells was determined. HER2-TLR8 comprises an anti-HER2 antibody comprising the heavy and light chains of SEQ
25 ID NOs: 9 and 10, respectively, conjugated to a TLR8-linker having the structure H2Ny0 HN

0.,w,NOUNN

NiTh \--\
Briefly, myeloid DCs were isolated from human blood using the EasySepTh Human Myeloid DC Enrichment Kit (StemCell Technologies, Catalog #19061). Isolated dendritic cells were plated with HER2-expressing BT474 tumor cells (ATCC) at a 2:1 5 ratio in the presence of titrating concentrations of HER2-TLR8 conjugate or HER2 mAb. After 24 hours, the cells were collected, washed and stained on ice with a collection of commercially available antibodies conjugated to fluorophores directed against PD-L1, CD86, CD80, CD40, CD45, and HLA-DR per the manufacturer's recommended protocol. After washing to remove unbound antibody-fluorophore 10 molecules, the stained cells are subjected to FACS analysis using a Celesta flow cytometer (BD Biosciences) with gating on live cells. The output was analyzed by FlowJo v10.2 software (FlowJo LLC).
[0562] The addition of HER2-TLR8 conjugate to the co-culture assays containing BT474 cells resulted in the upregulation of all activation markers, including 15 PD-L1, on the DC (see Figures 1A and 1B). Activation marker expression, including PD-L1, was not increased above baseline in co-cultures with the unconjugated mAb. These data demonstrate that agonism of TLR8 by the HER2-TLR8 composition result in the activation of DCs, including the upregulation of PD-Li. PD-Li is the ligand for the inhibitory receptor PD-1, a receptor expressed on T cells and other 20 immune cells.

HER2-TLR8 INDUCES THE PRODUCTION OF IFN-y A POTENT INDUCER OF PD-Li UPREGULATION
[0563] Numerous studies have shown the upregulation of PD-L1, a T cell 25 checkpoint molecule, by on tumor cells in the tumor microenvironment. (Abiko, Br J Cancer. 2015 Apr 28;112(9):1501-9; Garcia-Diaz A, Cell Rep. 2017 May 9;19(6):1189-1201; Mimura, Cancer Sci. 2018 Jan;109(1):43-53). To determine whether a HER2-TLR8 conjugate can induce production of IFN-y by human PBMCs in the presence of HER2 expressing tumor cells, the following experiment was conducted.
5 Human whole blood was obtained from Bloodworks Northwest (Seattle, WA) and collected in 10mL EDTA tubes. Human PBMCs were then isolated from the whole blood by Ficoll gradient centrifugation and resuspended in assay media (RPMI-Medium supplemented with 10% Fetal Bovine Serum, 1mM Sodium Pyruvate, lx GlutaMAX-1, 1X Non-Essential Amino Acids, 10m/vI HEPES and 0.5%
10 Penicillin/Streptomycin; all from Gibco). Isolated PBMCs were resuspended in assay media and plated in 96-well flat bottom microtiter plates (125,000/well). HER2-expressing tumor cells were removed from tissue culture flasks with HyQTASE
(Hyclone), washed twice, resuspended in assay media and were added to the microtiter plates (25,000/well) along with titrating concentrations of HER2-TLR8 conjugate.
15 After overnight culture, supernatants were harvested, and [EN-y levels were determined by a Meso Scale Discovery) analyte detection kit.
105641 As shown in Figure 2, HER2-TLR8 conjugate stimulated IFN-y production from huPBMCs in the presence of HER2 3+ (SK-BR-3) and HER2 2+
(MDA-453) expressing cells. In contrast, there was no IF N-7 production from 20 huPBMCs in the presence of tumor cells lacking the expression of HER2 (MDA-468).
These data indicate that the combination of HER2-TLR8 with a T cell checkpoint inhibitor, such as an anti-PD-1 small molecule or antibody, should provide enhanced efficacy.
EXAMPLE 3.

105651 Rodents do not express a functional homolog of TLR8 and attempts by multiple groups to generate relevant human TLR8 transgenic mice have been unsuccessful (Wang, J Biol Chem. 2006 Dec 8;281(49):37427-34; Guiducci, J Exp Med. 2013 Dec 16;210(13):2903-19). Like TLR8 in human, and in contrast to TLR7 in 30 human, TLR7 in mouse is expressed in myeloid cells. Using RNA expression data from the publicly available database Haemopedia, Figure 3 demonstrates the similarity in expression between TLR7 in mouse and TLR8 in human in dendritic cells and macrophages. Further, and as anticipated by similarity in expression and structure between mouse TLR7 and human TLR8, stimulation of TLR7 in murine myeloid cells 5 results in activation that mirrors that observed with TLR8 stimulation in human myeloid cells (Clarke, J. Cytokine Interferon Res. 2009, Feb;29(2):113-26; Gordon, J.
Immunol.
2005 Feb 1;174(3):1259-68). A HER2-TLR7 mouse surrogate consisting of a TLR7 agonist conjugated to an anti-human HER2 antibody of the mouse IgG2a isotype (HER2-TLR7) was generated for use in in vivo pharmacology studies. In vitro studies 10 with mouse myeloid cells derived from bone marrow demonstrate that the mouse surrogate has an EC50 of 0.5nM, equivalent to the potency of HER2-TLR8 conjugates on human myeloid cells (data not shown). These studies and findings collectively support 1-IER2-TLR7 conjugate as a surrogate molecule for HER2-TLR8 in mouse. As such, HER2-TLR7 was evaluated for activity in syngeneic mouse models.

AGENT EFFICACY MI A XENOGRAFT MOUSE MODEL
105661 The single agent efficacy in mice bearing HER2-expressing tumors with the 1-IER2-TLR7 agonist conjugate (i.e., surrogate for human HER2-TLR8 conjugate) 20 was examined. Briefly, SC1D mice (Taconic Biosciences, Albany, NY) were inoculated subcutaneously with about 1 x 106 NCI-N87 cells (HER2+ tumorigenic human epithelial cells) to generate the NCI-N87 xenograft mouse model_ Once palpable, tumor dimensions were measured by calipers and volume was calculated using the equation: Volume = xWxHx 0.5). When tumors reached approximately 25 90 mm3 (Day 0), mice were administered 5 mg/kg, 2 mg/kg, or 1 mg/kg HER2-TLR7 or unconjugated HER2-IgG2a mAb every 7 days for 4 doses. The HER2-TLR7 comprises anti-HER2 antibody variable domains comprising the heavy chain CDRs of SEQ ID
NOs: 1-3 and light chain CDRs of SEQ ID NOs: 4-6, conjugated to a TLR7 agonist-linker having the structure:

FI2N yo HN

11:LA\ INI
0 r0Et ris N

* / Ni-I2 An isotype control mAb (BioXcell, West Lebanon, NH), matched to the unconjugated HER2-IgG2a mAb, was dosed at 5 mg/kg on the same schedule. Tumor volumes were recorded 3 times per week.
5 105671 Treatment with the HER2-TLR7 surrogate resulted in significant inhibition of tumor growth at all doses tested (see Figures 4E, 4F, and 4G) as compared to the isotype antibody or unconjugated HER2-IgG2a antibody controls (see Figures 4A, 4B, 4C, and 4D). Like unconjugated HER2-IgG2a antibody treated group, the mice treated with IgG2a-TLR7 showed no delay in tumor growth (see Figures 4H, 4J, and 10 4K). These results demonstrate that the HER2-TLR7 surrogate is efficacious across a range of dose levels with robust single agent efficacy at dose levels as low as 1-2 mg/kg in viva EXAMPLES:
IN VIVO TREATMENT WITH A HER2-TLR7 SURROGATE RESULTS IN PD-Li 105681 The effect of treatment of mice bearing HER2-expressing tumors with the IIER2-TLR7 conjugate surrogate, on PD-L1 expression on the surface of tumor cells was examined. Briefly, female BALB/c mice (Jackson Laboratory) were inoculated subcutaneously with 5x105 human HER2-expressing CT26 tumor cells.
20 Once palpable, tumor dimensions were measured by calipers and volume was calculated using the following equation: Volume = (L xWxHx 0.5). When tumors reached an average of approximately 200 mm3 (Day 0), mice were administered mg/kg HER2-TLR7 or HER2 mAb (matched, unconjugated antibody control) subcutaneously on days 0, 2, and it At 48 hours post-doses one and three, tumors were harvested and dissociated using the Miltenyi mouse tumor digest kit. Single cell suspensions were assayed for PD-Li expression using flow cytometry.
105691 As shown in Figures 5A and 5B, tumor cells (identified as CD45 negative, forward scatter high) showed a significant increase in PD-Li expression at 5 both time points evaluated. These findings provide evidence that combination with immune checkpoint inhibition could enhance efficacy.
EXAMPLE 6, LEADS TO INCREASED TH1 CYTOKINES AND CHEMOKINES.
10 105701 The effect of treating tumor bearing mice with a combination of HER2-TLR7 conjugate surrogate and anti PD-1 on IFN-y and IF-10 expression was determined. Briefly, female BALB/c mice (Jackson Laboratory) were inoculated subcutaneously in the mammary fat with lx 105 human HER2-expressing EMT6 tumor cells. Once palpable, tumor dimensions were measured by calipers and volume was 15 calculated using the equation: Volume = (L xWxHx 0.5). When tumors reached approximately 97mm3 (Day 0), mice were given one dose of 10 mg/kg HER2-TLR7, HER2 mAb (matched, unconjugated antibody control), rat anti-PD1 (clone RMP1-14) or isotype controls, alone or in combination. Two or seven days later, tumors were excised, weighed placed in 500mL RPMI (Gibco) and mechanically dissociated on ice.
20 The resulting supernatants were analyzed by Luminex (Millipore) for intratumoral cytokines and chemokines. Data is expressed as picogram of analyte per gram of starting tissue.
105711 Figure 6A shows that IP10 production was significantly increased in the combination treated group at Day 2 compared to HER2-TLR7 or anti PD-1 treated 25 groups. Similarly, IFN-y production was augmented at Day 2 in tumors of mice treated with combination of HER2-TLR7 with anti-PD-1 compared to HER2-TLR7 treated mice (Figure 6B). This amplification of IFN-y was sustained at Day 7 after treatment These data indicate that the combination of an immune checkpoint inhibitor with HER2-TLR8 is expected to lead to enhanced chemolcine and cytolcine production by 30 immune cells.

EXAMPLE 7.

105721 The anti-tumor efficacy induced by single agent HER2-TLR7 conjugate 5 mouse surrogate (HER2-TLR7) was examined in combination with anti-PD1 therapy.
Female BALB/c mice (Jackson Laboratory) were inoculated subcutaneously with lx human HER2-expressing EMT6 tumor cells. Once palpable, tumor dimensions were measured by calipers and volume was calculated using the following equation:
Volume = (L x Wx Hx 0.5). When tumors reached approximately 90 mm3 (Day 0), 10 mice were given 10 mg/kg HER2-TLR7, HER2 mAb (naked antibody control), rat anti-PD1 (clone RMP1-14) or isotype controls, alone or in combination, every 7 days for a total of 3 doses. Tumor volume was recorded 3 times per week and mice were euthanized when tumors reached 1,500 MM3.
105731 Figure 7D spider plots show that this model is refractory to single agent 15 anti-PD1 therapy with no survival benefit or growth inhibition over the isotype control group (see Figure 7A). In contrast, treatment with HER2-TLR7 surrogate inhibited tumor growth with 60% of mice surviving to day 42 (see Figure 7C). Moreover, the combination of HER2-TLR7 with anti-PD1 therapy greatly enhanced the effect of either agent alone with 90% of mice surviving to day 42 (see Figure 7F).
20 EXAMPLE 8.
HER2-TLR8 AND A TRASTUZUMAB-LTICE MONOCLONAL ANTIBODY, HUMANIZED 4D5, 105741 The trastuzumab-like monoclonal antibody, humanized 405 mAb (hz4D5), was produced using the ExpiCHO expression system as described in the 25 manufacturer's protocol (Thermo Fisher Scientific). Briefly, 6x106ExpiCHO-S cells per ml were cultured in ExpiCHO Expression Medium followed by addition of ExpiFectamine CHO/plasmid DNA complexes Ogg DNA/ml) directly to cells.
ExpiCHO Feed and Enhancer were added the day after transfection to support long-term, high-density transient transfections and to enhance protein production_ The cell 30 culture supemantants were harvested on Day 7 following transfection.
Hz4D5 from the ExpiCHO supernatants were purified to homogeneity over HiScreen MabSelect SuRe protein A column on GE AKTA Pure ml system. It was confirmed for purity on Size Exclusion Chromatography using Agilent 1260 Infinity machine.
105751 Analysis of simultaneous versus competitive binding of HER2-TLR8 5 and hz4D5 to human HER2 extra-cellular domain (ECD) was performed using an Octet Red 96TM instrument (ForteBio). The experiments were performed using the following steps: (1) Regeneration and neutralization of penta-his sensor in 10mM
glycine-HC1 (pH 1.5) and PBS/0.1%BSA/0.02%Tween20 (pH 7.4), respectively in triplicate; (2) baseline acquisition (30s); (3) immobilization of monomeric human 10 HER2 ECD with 10x histidine tag to penta-his sensor at a concentration of 5gg/mL in PBS/0.1%BSA/0.02%Tween20 (180s); (4) second baseline acquisition (60s);
(5) association of test article #1 (HER2-TLR8 or hz4D5) at 25 gg/mL until saturation (300s); (6) third baseline acquisition (15s); (7) association of test article #2 (HER2-TLR8 or hz4D5) at 25 gg/mL (300s); (8) dissociation in baseline buffer (60s).
The data 15 were analyzed using Octet Data Analysis Software HT 9.0TM (ForteBio).
105761 The interactions of HER2-TLItit and hz4D5 with monomeric human HER2 ECD were evaluated using Octet Red 96TM in 2 orientations. Figure 8A
shows Orientation #1 whereby HER2-TLR8 binds to HER2 ECD until saturation and then either HER2-TLR8 or hz4D5 is added. Figure 8B shows Orientation #2 whereby 20 hz4D5 binds to HER2 ECD until saturation and then either hz4D5 or HER2-TLR8 is added. Affinity of either test article to immobilized HER2 ECD is subject to 2:1 binding avidity and no dissociation of test article #1 is observed in the third baseline step.
105771 Figure 8A shows that additional mass is observed when hz4D5 is added 25 to a HER2-TLR8 saturated surface, indicating additional binding sites are available, whereas no additional mass is observed when HER2-TLR8 is added to an already HER2-TLR8 saturated surface, indicating all HER2-TLR8 binding sites are taken up.
Figure 8B shows that additional mass is observed when HER2-TLR8 is added to a hz4D5 saturated surface, indicating additional binding sites are available, whereas no 30 additional mass is observed when hz4D5 is added to an already hz4D5 saturated surface, indicating all hz4D5 binding sites are taken up. Together, these two orientations confirm that HER2-TLR8 and hz4D5 do not compete for binding space on HER2 ECD when either site is saturated with the other test article.
Furthermore, this data confirmed that HER2-TLR8 and hz4D5 are able to bind simultaneously to human HER2 ECD.
5 EXAMPLE 9.

LIKE ANTIBODY, HZ4D5, IN VITRO
[0578] The ability of trastuzumab to inhibit HER2-dependent tumor cell growth in vitro has been extensively described in the literature (see, e.g., Yamashita-Kashima et 10 al., Clin. Cancer Res. 17:5060, 2011; Ko et al., Mot Oncol. 9:398, 2015:
Nami et al , Cancers /0:342, 2018). SBT6050 and hz4D5 (trastuzumab binding domain) recognize distinct, non-overlapping epitopes on HER2. Briefly, BT-474 tumor cells were cultured in the presence of HER2-TLR8 conjugate, negative control mAb conjugated to agonist (IgG1-TLR8), or isotype control mAb alone or in combination with 1:1 ratio of 15 trastuzumab-like monoclonal antibody hz4D5. Cells were incubated for 3 days and tumor cell viability was measured using Cell Titer-Glo Luminescent Cell Viability Kit (Promega). Results are expressed as a percentage decrease in viability compared to BT-474 tumor cells grown in media alone.
[0579] Antibody hz4D5 showed significant anti-proliferative effects on the 20 growth of BT-474 tumor cells, whereas the combination of hz4D5 and HER2-agonist conjugate increased this effect (Figure 9), HER2-TLR8 agonist conjugate alone had no effect on the growth of BT474 tumor cells (Figure 9). In short, HER2-agonist conjugate does not affect the ability of hz4D5 to inhibit the growth of HER2 positive tumor cells in vitro. These results indicate that trastuzumab function will likely 25 be maintained, and even enhanced, when used in combination with HER2-agonist conjugate in vivo.

EXAMPLE 10.
ComBrtoNG HER2-TLR8 CONJUGATE WITH A TRASTUZUMAB-LIKE MONOCLONAL
ANTIBODY AUGMENTS RELEASE OF PBMC TNF-A AND IFN-r PRODUCTION IN THE

5 105801 Production of TNF-a and IFN-y from PBMC co-cultured with positive tumor cell lines contacted with a HE.R2-TLR8 conjugate and hz4D5, a trastuzumab-like monoclonal antibody, was examined. The HER2-TLR8 conjugate does not cross-block binding or the function of the trastuzumab-like monoclonal antibody (see Examples 8 and 9). Peripheral blood mononuclear cells (PBMC) were 10 isolated from normal human donor peripheral blood using SepMaten1-50 PBMC
Isolation Tubes (STEMCELL Technologies) according to manufacturers instructions.
Isolated PBMC were cultured with the HER2-expressing tumor cell lines NCI-N87, BT-474, HCC-1954 (ATCC) or the HER2-negative tumor cell line MDA-MB-468 (ATCC) at a 5:1 ratio in the presence of titrated concentrations of a HER2-15 conjugate, the matched unconjugated HER2 mAb control, a trastuzumab-like humanized monoclonal antibody (hz4D5) or an isotype control monoclonal antibody.
After 24 hours the cell-free supernatants were collected and stored at -80 C
prior to analysis. TNF-a levels in the cell-free supernatants were quantified using the TNF-a (human) AlphaLISA Detection Kit (Perkin Elmer) according to manufacturer's 20 instructions. IFN-y levels in the cell-free supernatants were quantified using the U-PLEX Biomarker Group 1 (Human) Multiplex Assay (Mesa Scale Diagnostics) according to manufacturer's instructions.
105811 Representative data is shown in Figure 10A for TNF-a and Figure 10B
for IFN-y. Figure 10A shows HER2-TLR8 induced TNF-a production is augmented in 25 PBMC cultured with the HER2-expressing tumor cell lines NCI-N87, BT-474 or HCC-1954 when combined with the trastuzumab-like monoclonal antibody hz4D5 compared to the combination of HER2-TLR8 and an isotype control. No TNT-a production was observed with the combination of hz4D5 and the matched unconjugated HER mAb indicating that TLR8 agonism is required for TNF-a release. TNF-a production was 30 observed with the HER2-negative tumor cell line MDA-M13-468 only in cultures containing HER2-TLR8 at the highest concentrations tested indicating that the activity is also dependent upon HER2. As observed for TNF-a, Figure 10B shows IFN-y production is augmented in PBMC cultured with the HER2-expressing tumor cell line NCI-N87 when HER2-TLR8 is combined with the trastuzumab-like monoclonal antibody hz4D5 compared to the combination of HER2-TLR8 and an isotype control monoclonal antibody.
105821 Taken together these data demonstrate augmented TNF-a and LFN-y production by the combination of HER2-TLR8 and the trastuzumab-like monoclonal antibody hz4D5 over the effects observed with HER2-TLR8 alone. These effects are mediated by the TLR8 agonist conjugate rather than by HER2-TLR8 binding to a different epitope than 4D5 and suggest combining HER2-TLR8 with a clinical targeting antibody, such as trastuzumab, may increase therapeutic efficacy in certain tumor settings.
EXAMPLE 11:

ANTIBODY, HUMANIZED 4D5 (HZ4D5), IS EFFICACIOUS IN A XENOGRAFT MOUSE MODEL
105831 This example shows that the robust single agent efficacy, including an 80% cure rate, achieved with the HER2-TLR7 mouse surrogate conjugate at 10 mg/kg is not impeded by combination with the trastuzumab-like monoclonal antibody, hz4D5.
The trastuzumab-like monoclonal antibody, humanized 4D5 mAb (hz4D5), does not cross-block HER2-TLR7 binding, suggestive of binding to different regions of HER2.
SCID mice (Charles River) were inoculated subcutaneously with 1 x 106 NCI-N87 (HER2+) tumor cells. Once palpable, tumor dimensions were measured by calipers and volume was calculated using the equation: Volume = (L xWxHx 0.5). When tumors reached approximately 90 mm3 (Day 0), mice were given 10 mg/kg 1-IER2-TLR7, HER2 mAb (matched, unconjugated antibody control), or isotype controls (BioXcell), alone or in combination with 10 mg/kg hz4D5, every 7 days for a total of 4 doses.
Tumor volume was recorded 3 times per week.
105841 As shown in Figures 11A-11F, mice treated with isotype controls, the unconjugated HER2 mAb, or hz4D5 showed no delay in tumor growth. Combination of HER2 mAb with hz4D5 initially showed tumor growth inhibition, but the tumors eventually grew out. However, HER2-TLR7 as a single agent resulted in profound efficacy with 8/10 mice completely clearing their tumors by Day 66 at this dose level.
Importantly, the combination of HER2-TLR7 with hz4D5 had no adverse effect on the single agent efficacy of HER2-TLR7 at this dose level.
5 EXAMPLE 12.
COMBINATION OF A TRASTUZUMAI3-LIKE MONOCLONAL ANTIBODY, HUMANIZED 4D5 mAs (Hz4D5), AND LOW DOSE HER2-TLR7 SURROGATE CONJUGATE DEMONSTRATES
ENHANCED EFFICACY OVER SINGLE AGENTS IN A XENOGRAFT MOUSE MODEL
[0585] To examine whether the efficacy of HER2-TLR7 mouse surrogate 10 conjugate combined with the trastuzumab-like monoclonal antibody, hz4D5, was increased as compared to either agent administered alone, a low dose of the TLR7 mouse surrogate conjugate was used. Briefly, SCID mice (Charles River) (n =
10) were inoculated subcutaneously with about lx106NCI-N87 (HER2+) tumor cells.
Once palpable, tumor dimensions were measured by calipers and volume and calculated 15 using the equation: Volume = (L xWxHx 0.5). When tumors reached approximately 100 mm3 (Day 0), mice were dosed with HER2-TLR7 mouse surrogate conjugate (1 mg/kg), matched unconjugated HER2-IgG2a mAb (1 mg/kg), or isotype mAb control matched to unconjugated HER2-IgG2a mAb (5 mg/kg) alone or in combination with the trastuzumab-like monoclonal antibody hz4D5 (5 mg/kg) every 7 days for a total of 3 20 doses. Tumor volume was recorded 3 times per week.
105861 HER2-TLR7 administered at the low dose in this example allowed for evaluation of efficacy in combination with the trastuzumab-like monoclonal antibody, hz4D5, as compared to the single agents alone. Mice treated with unconjugated IgGa mAb, hz4D5, or HER2-TLR7 surrogate showed some delay in tumor growth 25 compared to the isotype control group, but the tumors eventually grew.
However, mice treated with the HER2-TLR7 surrogate in combination with hz4D5 showed a significant reduction in tumor growth (Figure 12F) compared to all other treated groups (Figures 12A-E). These data show that the HER2-TLR7 surrogate in combination with trastuzumab-like monoclonal antibody, hz4D5 results in entranced efficacy over the 30 single agents alone. In addition, these data indicate that clinical evaluation of HER2-TLR8 agonist conjugates of this disclosure as a single agent and in combination with trastuzumab in relevant HER2-expressing tumor types is warranted.
[0587] While aspects of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such aspects are provided by 5 way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the aspects of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these 10 claims and their equivalents be covered thereby.

Table of Anti-HER2 Antibody Sequences SEQ ID Description Sequence NO
1 Anti-HER2 GFTFTDYTMD
antibody heavy chain (HC) CDR1 2 Anti-HER2 DVNPNSGGSIYNQRFKG
antibody HC CDR2 3 Anti-HER2 NLGPSFYFDY
antibody HC CDR3 4 Anti-HER2 KASQDVSIGVA
antibody light chain (LC) CDR1 Anti4lER2 SASYRYT
antibody LC CDR2 6 Anti-HER2 QQYYIYPYT
antibody LC CDR3 7 1&nti-HER2 EVQLVESGGG
LVQPGGSLRL SCAASGFTFT DYTMDWVRQA
antibody heavy PGKGLEWVAD
VNPNSGGSIY NQRFEGRFTL SVDRSKNTLY
chain variable LQMNSLRAED
TAVYYCARNL GPSFYFDYWG QGTLVTVSS
region (VH) 8 Anti-HER2 DIQMTQSPSS
LSASVGDRVT ITCKASQDVS IGVAWYQQKP
antibody light chain GKAPKLLIYS ASYRYTGVPS RFSGSGSGTD FTLTISSLQP
variable region EDFATYYCQQ
YYIYPYTFGQ GTKVEIK
(VL) 9 Anti-HER2 EVQLVESGGG
LVQPGGSLRL SCAASGFTFT DYTMDWVRQA
antibody heavy PGKGLEWVAD
VNPNSGGSIY NQRFEGRFTL SVDRSKNTLY
chain LQMNSLRAED
TAVYYCARNL GPSFYFDYWG QGTLVTVSSA
STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW
NSGALTSGVE TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY
ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY
VDGVEVHNAK TKPREEQYNS TYRVVSVITV LHQDWLNGKE
YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSREEM
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVI
DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ
KSLSLSPG
Anti-HER2 DIQMTQSPSS LSASVGDRVT ITCKASQUVS IGVAWYQQKP
antibody light chain GKAPKLLIYS ASYRYTGVPS RFSGSGSGTD FTLTISSLQP
EDFATYYCQQ YYIYPYTFGQ GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ
ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG
LSSPVTKSFN RGEC
The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent 5 applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, including U.S. Patent Application No. 62/908,881, filed October 1, 2019, U.S. Patent Application No. 62/935,789, filed November 15, 2019, and U.S. Patent Application No.
63/018,615, filed May 1, 2020, are incorporated herein by reference, in their entirety.
Aspects of the 5 embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.
These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification 10 and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims (103)

PCT/1JS2020/053870WHAT IS CLAIMED IS:
1. A method of treating cancer or viral infection, comprising administering to a subject with cancer or viral infection a conjugate and an immune checkpoint inhibitor that inhibits PD-1 and/or PD-L1; wherein the conjugate is represented by Formula (I):
= 4> Dx (j);
wherein:
A is an antibody that binds a tumor associated antigen or a liver cell antigen, L is a linker;
Dx is a TLR8 agonist, wherein the TL118 agonist is a benzazepine compound;
n is selected from 1 to 20; and z is selected from 1 to 20.
2. The method of claim 1, wherein the immune checkpoint inhibitor is an antibody.
3. The method of claim 1 or 2, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.
4. The method of claim 3, wherein the anti-PD-1 antibody is selected from pembrolizumab, nivolumab, cemiplimab, and biosimilars thereof.
5. The method of claim 3, wherein the anti-PD-L1 antibody is selected from avelumab, durvalumab, atezolizumab, and biosimilars thereof.
6. The method of any one of claims 1-5, wherein n is 1 and z is from 1 to 8.
7. The method of any one of claims 1-6, wherein the TLR8 agonist is a compound of Category A, Formula (IIB):

R5'1_1 (IIB) or a pharmaceutically acceptable salt thereof, wherein:
12 is -Xt -;
L2 is selected from -X2-, -x2-c 1-6 alkylene-X2-, -X2-C2-6 alkeny1ene-X2-, and -X2-C 2-6 alkynylene-X2-, each of which is optionally substituted on alkylene, alkenylene or alkynylene with one or more Rt2;
Xt is selected from -C(0)-, and -C(0)N(Rm)-*, wherein * represents where Xth is bound to R5;
X2 at each occurrence is independently selected from a bond, -0-, -S-, -N(Rw)-, -C(0)-, -C(0)0-, -0C(0)-, -0C(0)0-, -C(0)N(114 )-, -C(C)N(R10)C(0)-, -C(0)N(Rm)C(0)N(Itn, -N(R"))C(0)-, -N(Rw)C(0)N(Rn-, -Not tow(0)0_, -0C(0)N(Rn-, -N(Rw)C(NRw)-, -C(NR' )N(Rt )-, -N(R4 )C(NR')N(R4 )-, -S(0)2-, -0S(0)-, -S(0)0-, -S(0), -OS(0)2-, -S(0)20, -N(RnS(0)2-, -S(0)2N(Rt0)-, -N(Rm)S(0)-, -S(0)N(R1o)_, Ncr.ts. k iS(0)2N(Rw)-, and -N(Rth)S(0)N(R1 )-;
RI- and R2 are independently selected from hydrogen; and Ct-to alkyl, C2-to alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OW , -C(0)N(R10)2, -N(114- )2, -S(0)Rm, -S(0)2114- , -C(0)R1 , -C(0)0Rt , -0C(0)10 , -NO2, =0, =S, =N(Rw), and -CN, R4 is selected from: -OR', -N(Rm)2, -C(0)N(Rw)2, -C(0)Rm, -C(0)0Rw, -S(0)Rm, and -S(0)2101); C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -Coltm, -C(0)N(R0)2, -N(Rm)C(0)Ftw, frk.,(0)N(R10)2, -N(R10)2, -C(0)Rm, -C(0)0R1-0, -0C(0)R", -NO2, =0, =S, =MR"), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle, and 3- to 12-membered heterocycle in R4 is optionally substituted with one or more substituents independently selected from halogen, -OR", -SR', -C(0)N(Rto)2, -N(RICI)C (0 )R1-", -Ncle )C(0)N(R")2, -N(Rn2, -C(D)RM, -C(C)ORKI, -0C(0)10 , -NO2, =0, =S, =N(R"), -CN, Ct-salkyl, C2-6 alkenyl, and C2-6 alkynyl;
R5 is selected from unsaturated C4-8 carbocycle; bicyclic carbocycle; and fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle, wherein R5 is optionally substituted and wherein substituents are independently selected at each occurrence from:
halogen, -OR", -SR", -C(0)N(RI-0)2, _ N(10 )C(0)R", -N(R")C(0)N(Rto)2, _N(t10)2, -C(0)R", -C(0)0R", -0C(0)R", -NO2, 0,=S, =N(R"), and -CN;
CI-toalkyl, C2-10 alkenyl, C2-to alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR", -SR", -C(0)N(R")2, -m(Rto),c(o)Rto, --is(Rto),c(c)Nt-Rict,2, _ N(R")2, -C(0)R", -C(0)0R", -0C(0)R", -NO2, =0, =S, =N(R"), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle, and 3- to 12-membered heterocycle in R5 is optionally substituted with one or more substituents independently selected from halogen, -OR", -SR", -C(0)N(R")2, -N(IVIC(0)R", -N(Rto)C(c)mR10)2, _mato)2, _Cor K
- C(0)0R", -0C(0)Rth, -NO2, =0, =S, =N(R"), -CN, C1.6alkyl, C2-6alkenyl, and C2-6alkynyl;
R" is independently selected at each occurrence from hydrogen, -NH2, -C(0)0CH2C61-15; and CI-to alkyl, C2-10 alkenyl, C2-to alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, -C(0)0CH2C6Els, -NHC(0)0CH2C6H5, Ci.to alkyl, -Ct-to haloalkyl, -0-C 1-to alkyl, C2.10 alkenyl, C2-to alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and habalkyl;
and 102 is independently selected at each occurrence from halogen, -OR", _sRio, _N(Rio)2, -C(0)R10, -C(0)N(R10)2, -N(R1 )C(Or - 10, K 20)0e), -0C(0)R1-0, -SOW , -S(0)2Rio., -P(0)(011.10)2, -0P(0)(010)2, -NO2, =0, =S, =N(Rm), and -CN;
Ct-to alkyl, C2-10 alkenyl, C2-11) alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORM, _SRI , _N(R10)2, -C(0)Rm, -C(C)N(R1 lc (0) 0)2, _mR10-)cor 10, _lc ORM, _ocoor _ 10, S(0)0-1), -S(0)2Ri , -P(0)(0R112, -0P(0)(ORIM)2, -NO2, =0, =S, =N(111 ), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-to carbocycle and 3- to 10-membered heterocycle in R12 is optionally substituted with one or more substituents independently selected from halogen, -OW , _sRio, _N(Rio)2, -C(0)'K 10, - C(0)N(R10)2, _ot_l In Ngorto, _ ts. C(0)0R10, -0C(0)R1 , -S(0)Rw, -S(0)2Rm, -P(0)(010 )2, -0P(0)(010 )2, -NO2, =0, =S, =N(R1 ), -CN, C1-6 alkyl, C24 alkenyl, C2-6 alkynyl;
wherein any substitutable carbon on the benzazepine core is optionally substituted by a substituent independently selected from Ry or two substituents on a single carbon atom combine to form a 3- to 7- membered carbocycle;
R20, R21, R22, and n23 n are independently selected from hydrogen, halogen, -OW , -SR10, -N(Rm)2, -S(0)10, -S(0)21tm, -C(0)Rm, -C(0)011m, -0C(0)Rm, -NO2, 1:0, =S, =N(Rm), -CN, Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl; and R24 and Kn25 are independently selected from hydrogen, halogen, -ORm, -SRI', -N(Rm)2, -S(0)11.1 , -S(0)2Rio, _icor , _ lO
it.
C(0)0111 , -0C(0)1110, -NO2, =0, =S, =N(Rick _ ), CN, Ci-io alkyl, C2-io alkenyl, and C2-io alkynyl; or R24 and R25 taken together form an optionally substituted saturated C3-7 carbocycle.
8. The method of any one of claims 1-7, wherein the TLR8 agonist is a compound of Category A, Formula IIC:

N
co N -R2, ..---(IIC) or a pharmaceutically acceptable salt thereof, wherein:

RI- and R2 are hydrogen;
L2 is -C(0)-;
R4 is -N(R1 )2;
is independently selected at each occurrence from hydrogen, -NH2, -C(0)0CH2C6H5; and Ci-to alkyl, C2-10 alkenyl, C2-to alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, -C(0)0C1tC6E15, -NHC(0)0CH2C6H5, Ci-to alkyl, -Ct-to haloalkyl, -0-C1-to alkyl, C2-to alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and haloalkyl;
L10 is _C(c)mR10%_*, wherein * represents where L11 is bound to R5; and R5 is a fused 5-5, fused 5-6, or fused 6-6 bicyclic heterocycle, wherein R5 is optionally substituted and wherein substituents are independently selected at each occurrence from:
halogen, -OR', -SR', -C(0)N(10 )2, -N(R' )C(0)R1- , -N(10 )C(0)N(Rw)2, -N(10 )2, -C(0)10 , -C(0)0Rw, -0C(0)Rw, -NO2, =0, =S, =N(11.10), and -CN;
CI-toalkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -010 , -C(0)N(11.112, -N(R10)C(0)Rw, -mR10)Coosi(Rto)2, 4,(R10)2, _Cow, -C(0)0Rm, -0C(0)Rw, -NO2, =0, =S, =N(10 ), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OW , -C(0)N(Rm)2, -N(R1 )C(0)R1 , -N(R1 )C(0)N(Rw)2, -N(Rw)2, -C(0)10 , -C(0)010 , -0C(0)10 , -NO2, =0, =S, =N(R1. ), -CN, 0.-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.
9. The method of claim 8, wherein R4 is -N(Ct4 alky1)2 and 12 is -C(0)N(H)-*.
10. The method of claim 8 or 9, wherein:

v.NI
R4 is CH3.
11. The method of any one of claims 1 to 10, wherein the TLR8 agonist is selected from:
oo os 0 0 SID o ..... NH2 N.....
M N
* N
H
0 -- T----\
N
N

OH
0011 N N..... NH2 0 4 0 NI, NH2 H IP N
H
OH -- /----\
N
N
0 \--\ , 0 \--\ , H
N

N, N
II
so -- r-N
11 *-- r-=
N
N
0 \¨\
0 \--\

N
N
HN
, N N
H

- r"-\
- r"-\
N
N
0 \---\
0 µ-----\
, , As 0 N, NH2 A.
ift- EiN toN*.

N, -- r--\.
11 10 , , N

0 \--\
, , cci N 0 _...N N, N._ Cbz"
N *
H
rm.\ NH2 --- r¨\sõ
N
N
0 \---\
0 \----\

ci.......,:_cx 0 ....N
ciIL 0 N

N.., õ
N---N

H
NHCbz --- r---\ --- r---\
N
N
, , caN 0 N.õ

N N
CbzHN
HILIH
re \\ H2N
---h(----\
N
, N
O. 0 = Nai, N N NH2 N
HN,. H
H
az ---- f---\
--- NrTh N
, , H
ouN 0 CbleNaiN
..-= , 0 HN -====._ N__ N, N
N
H
H
.--- /---\
---- NT- \
N
c .....ra 0 HN

, az N
N
H
--- Nr--\
, H
N
ilk 0--( N
4N (3 t HO H
--- /Th N
0 \----\
, Si o Nõ
aNteCILIXN N
.
H H *0 .----Nr- \
, CbzHN
\ 4coLN 0 HN *
' Nr-\
0 \----\
, H2N,..1 LN * CCX N NH2 N ...e , N
H
..---rs, N

1 rt.. 0 NH2 NH:
Mail N, HiraiN N
11 ill H Sil H3C0 a..... r--\
F --- re-\
N N
0 \Th 0 \Th H2N------CN so ,a5s, 0 F F " N ' ----m N, ii 0---- 1---\
N
and 0 \--\\ ,and pharmaceutically acceptable salts thereof.
12. The method of any one of claims 1-11, wherein Dx is a compound of Formula (IVB):

N.õ

,)LçfR24 R21 1 22 _R4 (IVB) or a pharmaceutically acceptable salt thereof, wherein:
I22 is selected from -V-, -V-C1-6alkylene-r-, -V-C2-salkenylene-X3-, and -V-C2-6alkynylene-X3-, each of which is optionally substituted on alkylene, alkenylene, or alkynylene with one or more substituents independently selected from R'2, L22 is independently selected from -X4-, -X4-Ci-6alkylene-r-, -X4-C2-6 alkenylene-X4-, and -r-C2-6alkynylene-r-, each of which is optionally substituted on alkylene, alkenylene, or alkynylene with one or more substituents independently selected from R";
X3 and X4 are independently selected at each occurrence from a bond, -0-, -S-, -N(R")-, -C(0)-, -C(0)0-, -0C(0)-, -0C(0)0-, -C(0)N(RION_ ), C(0)N(R")C(0)-, -C(0)N(Rm)C(0)N(R' )-, -N(R")C(0)-, -N(Rt )C(0)N(RtG)-, -N(R")C(0)0-, -0C(0)N(R")-, -g-NRtoy, 41/44(t10),G(NR10)_, -,c(NR Joy,4(Rto)-, -N(R")C(NRIIN(R")-, -S(0)2-, -OS(0)-, -S(0)0-, -S(0)-, -OS(0)2-, -S(0)20-, -N(RnS(0)2-, -S(0)2N(R10)_, NatnS(C)-, -S(0)N(Rm)-, -N(RnS(0)2N(Rm)-, and -N(RnS(0)N(R")-;
RI- and R2 are independently selected from 1,3, and hydrogen; and Ci-to alkyl, C2-10 alkenyl, and C2-t0 alkynyl, each of which is optionally bound to 1-3 and each of which is optionally substituted with one or more substituents independently selected from halogen, -ORD, -SR", -C(0)N(R")2, -N(Rw)2, -S(C)R", -S(0)2R", -C(0)R", -C(0)0R"), -0C(0)Rm, -NO2, =0, =S, =N(R"), and -CN;
R.4 and le are independently selected from: -OR", -N(141 )2, -C(C)N(Rm)2, -C(0)R", -C(0)0R", -S(0)R", and -S(0)2R"; Ci-to alkyl, C2-10 alkenyl, C2-to alkynyl, each of which is optionally bound to I-3 and each of which is optionally substituted with one or more substituents independently selected from halogen, -OR", -SR", -C(0)N(R1 )2, -N(R1 )C(0)Rt , -N(10 )C(C)N(Rm)2, -N(R")2, -C(0)Rm, -C(0)0R", -0C(0)Rm, -NO2, =0, =S, =N(R")), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle, and 3- to 12-membered heterocycle in le and le is optionally bound to L3 and each C3-12 carbocycle, and 3- to 12-membered heterocycle in R4 and le is optionally substituted with one or more substituents independently selected from halogen, -OR', -SR", -C(0)N(Rm)2, -N(RnC(0)R", -N(Rm)C(0)N(R")2, -N(R")2, -C(Otto, ) -C(0)010 , -0C(0)10 , -NO2, =0, =S, =N(R"), -CN, CI-6alkyl, C2-6alkenyl, and C2-6alkynyl;
Rm is independently selected at each occurrence from L3, hydrogen, -N112, -C(0)0CH2C6H5; and Ci-to alkyl, C2-10 alkenyl, C2-to alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -NH2, =0, =S, -C(0)0CH2C6H5, -NHC(0)0CH2C6H5, C1-10 alkyl, C2-143 alkenyl, C2-to alkynyl, C3-carbocycle, 3- to 12-membered heterocycle, and haloalkyl;
L3 iS a linker moiety, wherein there is at least one occurrence of L3; and R12 is independently selected at each occurrence from halogen, -0R1 , -SW , -N(Rm)2, -C(0)Rto, -C(0)N(Rm) - 2 , N(Rm)C(0)R1 1-C(0)0Rto, -0,c(c)Rtio, _so:ow , 2n 10, --S(0) K P(0)(010 )2, -0P(0)(0R112, -NO2, =0, =S, =N(Rm), and -CN; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORD), ) _ C(0)R1 , -C(0)N(R1 13)2, -N(R1G)C(0)tc.n 1 , -C(0)0R1 , -0C(0)141 , -S(0)11.1 , -S(0)211.10, _powaRto)2, -0P(0)(010 )2, -NO2, =0, =S, -N(Rm), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle in R12 is optionally substituted with one or more substituents independently selected from halogen, -ORR', mwo)2, to, _ -C(0)Rm, -C(0)N(Rto)2, -N(R1 )C(0)R1 , -C(0)0R10, -0C(0)Rm, -S(0)Rm, -S(0)2R1o, _p(:woRto)2, -0P(OXORm)2, -NO2, =0, =S, =N(Rm), -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl;
wherein any substitutable carbon on the benzazepine core is optionally substituted by a substituent independently selected from R12 or two substituents on a single carbon atom combine to form a 3- to 7- membered carbocycle;
R20, R21, K n22, and R23 are independently selected from hydrogen, halogen, -OW , - N(Rm)2, -S(0)1110, -S(0)2R1 , -C(0)Rm, -C(0)0Rm, -0C(0)Rm, -NO2, =0, =S, =N(Rm), -CN, Ct-to alkyl, C2-10 alkenyl, and C2-10 alkynyl; and R24, and R25 are independently selected from hydrogen, halogen, _Ow , am, -N(Rm)2, -S(0)Rm, -S(0)2Rm, -C(0)Rm, -C(0)0Rm, -0C(0)Rm, -NO2, =0, =S, =Novo% _ CN, Ci-to alkyl, C2-to alkenyl, and C2-to alkynyl; or R24 and R25 taken together form an optionally substituted saturated C3-7 carbocycle.
13. The method of any one of claims 1-12, wherein Dx is a compound of Formula (1VC):
N¨R2 (IVC) or a pharmaceutically acceptable salt thereof, wherein:
RI and R2 are hydrogen;
L22 is _C(0)-R4 is -N(Rm)2;
RR' is independently selected at each occurrence from hydrogen, -NH2, -C(0)0CH2C6H5; and Ci-loalkyl, C2-10 alkenyl, C2-to alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -NH2, =0, =S, -C(0)0CH2C6H5, -NHC(0)0CH2C61-15, Ci-to alkyl, C2-143alkenyl, C2-113alkynyl, carbocycle, 3- to 12-membered heterocycle, and haloalkyl;
L1-2 is -C(0)N(Rto)*_, wherein * represents where L'2 is bound to le;
R8 is an optionally substituted fused 5-5, fused 5-6, or fused 6-6 bicyclic heterocycle bound to linker moiety L3, and wherein optional substituents are independently selected at each occurrence from:
halogen, -ORto, _situ% -,c(c)mRto)2, 4.4(Rto),c(c)Rto, -N(RnC(0)N(Rm)2, _mato)2, -C(0)Rm, -C(0)ORt , -0C(0)Rt0, -NO2, 0,=S, =N(R1 ), and -CN;
CI-toalkyl, C2-10 alkenyl, C2-to alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR', -C(0)N(Rm)2, -N(Rm)C(0)Rm, - mRto)Con-Rto,), - MR112, -C(0)R1171, -C(0)0Rt0, -0C(0)R1 , -NO2, =0, =S, =N(R11"), -CN, C3-12 carbocycle, and 3- to membered heterocycle; and C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -Ole , -SRI , -C(0)N(11.1 )2, -N(11.1 )C(0)Ri , -N(R1 )C(0)N(RIO)2, -N(R10)2, _Cow , _C(0)0Rw, -0C(0)R1 , -NO2, =0, =S, =N(R11, -CN, C 1-6alkyl, C2-6 alkenyl, and C2-6 alkynyl.
14. The method of claim 13, wherein R4 is -N(Ci4 alky1)2 and L12 is -C(0)N(1-1)-*.
15. The method of claim 13 or 14, wherein:

v.NI
R4 is CH3.
16. The method of any one of claims 1-15, wherein L and Dx together have a structure selected from:
H2N y0 HN
H H
IsiCIRri N N N

0 0 1. 0..õtr ill H
N
H

---- r---=
N
H2N y0 HN

issCFOCIFNIIAN Fri : H NH2 ...v., Ell jiji..; M, II
N
H

N

N

AN
licilõ.......1j N, N

Thle -. N

=---." r\
H H
N

0 NI-a\
Hi y , N

H
N;:(J 0 N, 0 Xllii 0 0 0A NThrN
N
.v.RX:õ........,,,,,...,,,..A
N N-yeit-N H 0 H
H H
N
Of 0 \-"---\
HN

i * N

0 Nii2 A
kilm.jc...11 N, 0 4"%riiii 0 1. 0 N
N

N
--"--. r---\
H H
N

0 \Th NH
OgH2 , . N

A rill.,..../U1 0 Y H 0 00 0 ri N
H
VRX:õ......................",.....A
NThrINK:AN
H i H
N
0 .=,..1...
0 \.-*\
NH

, 1-12Ny0 HN
H H
FRX-1111;1a14;-N

H

1 yl'il -%--e---Iil * re.N*1:-11 0 NH2 W,N N.
H
, 02Nyo liN

- N

N
= 0 H
Oa 0 0 O N
y , HLJNr-Ths.

H2Ny0 FIN

Nt\
11-Rn N

Hit n 0 --- re\

H2N Nei HN

jk\ 111 N

H

LLNN, NH2 0 \ 5 H2N tO
HN
H
RTN

N
C1NU o \--Th tO
HN

1 ) 11( tsittcr N
= H

N
CINU

N, 0 \---\
H2Ny.0 HN

'R A
0 H 0 N 40 0.....e,NOLIN

reN, H2N tO
HN

caN 0 - H 0 Nõ

\---rN
o 0 * re o NH2 141i HFFH
H H
HIjfJ0 rsk HN
0 \---\
H2N--%0 and o o oIN^-2CN * o NH, F F
N
H - H
re \
HN

and salts thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody.
17. The method of claim 16, wherein L and Dx together have a structure selected from:
H2Ny0 HN

Oy N * 0 N__ - rm.
0 \
H2Ny0 HN
1 ,1Aki _ N
0 141) o Jr\

Nt, -LJÇ

\Th r H2N y0 HN

0 * 0 NC\

H2N y0 HN

Rnj13y b- N

_ H 0 1010 0 \¨\
o * 0 = NH2 VRXIC.---A-X-ry-N HFF H
H H
HN

=
0 0 Ns.--)C-N

F F
H E H
Ill 0 al 111111' fTh HN
0 \Th and H2W--LO

and salts thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody.
18. The method of claim 16 or 17, wherein RX* comprises a succinamide moiety and is bound to a cysteine residue of the antibody.
19. The method of claim 16 or 17, wherein RX* comprises a hydrolyzed succinamide moiety and is bound to a cysteine residue of the antibody.
20. The method of any one of claims 1-19, wherein the tumor antigen is selected from YIER2, Nectin4, MSLN, LIV-1, MUC16, CEACAM1, CEACAM3, CEACAM4, CEACAM5, CEACAM6, CEACAM7, CEACAM8, CEACAM16, CEACAM18, CEACAMI9, CEACAM20, CEACAM2I, VEGFRI, VEGFR2, MUCI, PSMA, PSA, MUC-2, and LRRC15 WO 2021(067644
21. The method of any one of claims 1-20, wherein the tumor associated antigen is selected from:
a) an antigen present on breast cancer, wherein the antigen is optionally selected from ITER2, LIV-I, CDH3 (p-cadherin), MUC I, Sialo-epitope CA6, PTK7, GPNMB, LAMP-1, LRRC15, ADAM12, EPHA2, TNC, LYPD3, EFNA4, Nectin-4, and CLDN6;
b) an antigen present on lung cancer, wherein the antigen is optionally selected from mesothelin, HER2, EGFR, PD-L1, MSLN, LY6K, CD56, PTK7, FOLR1, DLL3, SLC34A2, CECAM5, MUC16, LRRCI5, ADAM12, EGFRvIII, LYPD3, EFNA4, Nectin-4, and MUCl;
c) an antigen present on stomach/gastric cancer, wherein the antigen is optionally selected from HER2, EPHB2, TMEM238, CECAM5, and EFNA4;
d) an antigen present on colorectal cancer, wherein the antigen is optionally selected from EPHB2, TMEM238, CECAM5, LRRC15, ADAM12, EFNA4, Nectin-4, and GPA33;
e) an antigen present on liver cancer, wherein the antigen is optionally selected from GPC3, EPCAM, and CECAM5;
0 an antigen present on lcidney cancer, wherein the antigen is optionally selected from HAVCR1, ENPP3, CD116, CD70, and cMET;
g) an antigen present on ovarian cancer, wherein the antigen is optionally selected from MUC16, MUC I, MSLN, FOLRI, sTN, VTCN1, HER2, PTK7, FAP, TMEM238, LRRC15, CLDN6, SLC34A2, and EFNA4;
h) an antigen present on head and neck cancer, wherein the antigen is optionally selected from LY6K, PTK7, LRRC15, ADAM12, LYPD3, EFNA4, Nectin-4, and TNC;
i) an antigen present on bone cancer, wherein the antigen is optionally selected from EPHA2, LRRCI5, ADAM12, GPNMB, TP-3, and CD248;
I) an antigen present on mesothelioma, wherein the antigen is optionally MSLN;

WO 2021(067644 k) an antigen present on bladder cancer, wherein the antigen is optionally selected from LY6K, PTK7, UPK1B, UPK2, TNC, Nectin4, SLITRK6, LYPD3, EFNA4, and 1-IER2;
l) an antigen present on prostate cancer, wherein the antigen is optionally selected from PSMA, FOLH1, PTK7, STEAP, TMEFF2 (TENB2), OR51E2, SLC30A4, and EFNA4;
m) an antigen present on thyroid cancer, wherein the antigen is optionally PTK7;
n) an antigen present on uterine cancer, wherein the antigen is optionally selected from LY6K, PTK7, EPFIB2, FOLR1, ALPPL2, MUC16, Nectin-4, and EFNA4;
o) an antigen present on cervical/endometrial cancer, wherein the antigen is optionally selected from LY6K, PTK7, MUC16, LYPD3, EFNA4, Nectin4, and muc 1;
and 13) an antigen present on pancreatic cancer, wherein the antigen is optionally selected from PTK7, MUC16, MSLN, LRRC15, ADAM12, EFNA4, MUC5A, Nectin-4, and MUC1.
22. The method of any one of claims 1-21, wherein the antibody is an anti-HER2 antibody.
23. The method of any one of claims 1-22, wherein the antibody is pertuzumab, trastuzumab, or ladiratuzumab, or a biosimilar thereof; or comprises the CDRs of pertuzumab, trastuzumab, or ladiratuzumab; or comprises an antigen binding fragment of pertuzumab, trastuzumab, or ladiratuzumab.
24. The method of any one of claims 1-23, wherein the antibody comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ 1:13 NOs: 1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comptising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
25. The method of any one of claims 1-24, wherein the method comprises administering an additional therapeutic agent.
26. The method of claim 25, wherein the additional therapeutic agent comprises a chemotherapy agent, a kinase inhibitor, a therapeutic antibody, or any combination thereof.
27. The method of claim 25 or 26, wherein the additional therapeutic agent comprises a therapeutic agent targeting HER2.
28. The method of any one of claims 25-27, wherein the additional therapeutic agent is selected from trastuzumab, trastuzumab-qyyp, trastuzumab-pkrb, trastuzumab-dttb, trastuzumab-anns, trastuzumab-dkst, trastuzumab, deruxtecan-nxki, ado-trastuzumab emtansine, trastuzumab duocarmazine, margetuximab, zenocutuzumab , tucatinib, cabozantinib, pyrotinib, and poziotinib.
29. The method of any one of claims 25-28, wherein the additional therapeutic agent comprises an anti-IIER2 antibody, optionally wherein the therapeutic agent comprising the anti-HER2 antibody is selected from trastuzumab, trastuzumab-qyyp, trastuzumab-pkrb, trastuzumab-dtth, trastuzumab-anns, trastuzumab-dkst, trastuzumab deruxtecan-nxki, ado-trastuzumab emtansine, trastuzumab duocarmazine, margetuximab, and zenocutuzumab
30. The method of claim 26, wherein the kinase inhibitor is a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor.
31. The method of claim 30, wherein the kinase inhibitor is a tyrosine kinase inhibitor selected from tucatinib, cabozantinib, afatinib, erlotinib, pyrotinib, poziotinib, dacomitinib, gefitinib, lapatinib, osimertinib, larotrectinib, axitinib, lenvatinib, pazopanib, regorafenib, and sunitinib.
32. The method of claim 30, wherein the kinase inhibitor is a serine/threonine kinase inhibitor that is a CDK4/6 inhibitor selected from abemaciclib, palbociclib, and ribociclib.
33. The method of claim 26, wherein the chemotherapy agent comprises:
(a) a hormone-based compound, optionally wherein the hormone based compound comprises anastrozole, exemestane, letrozole, fulvestrant, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, darolutamide, degarelix, toremifene, goserelin, triptorelin, histrelin, leuprolide, or tamoxifen citrate;
(b) a platinum coordination complex, optionally wherein the platinum coordination complex comprises cisplatin, oxaliplatin, or carboplatin;
(c) a folic acid analog, optionally wherein the folic acid analog comprises pemetrexed, methotrexate, or trimetrexate;
(d) a primidine analog, optionally wherein the pyrimidine analog comprises fluorouracil, capecitabine, fluorodeoxyuridine, tezacitabine, gemcitabine, cytosine arabinoside, cytarabine, 5-azacytidine, or 2,2'-difluorodeoxycytidine;
(e) a microtubule inhibitor, optionally wherein the microtubule inhibitor comprises paclitaxel, docetaxel, and eribulin;
or any combination thereof.
34. The method of claim 25, wherein the additional therapeutic agent comprises a chemotherapy protective agent, optionally wherein the chemotherapy protective agent comprises leucovorin.
35. The method of any one of claims 1-4 and 6-34, wherein:

(a) L and Dx together have a stnrcture selected from:
FI2N yO
HN
H
x11-11\-14 H"
0 O 0,1,4 õLa....N.-p 0 i N__ and H2Ny0 HN

1/1A1:11 0 H 0 1. ONCLJLN NH2, and salts thereof;
(b) the immune checkpoint inhibitor is pembrolizumab;
(c) optionally comprising an additional therapeutic agent, wherein the additional therapeutic agent comprises fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine; and (d) optionally, wherein the antibody comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ NOs: 1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
36, The method of claim 1-4 and 6-34, wherein:

(a) L and Dx together have a structure selected from:
H2Ny0 HN
H 0\ 0 hRXr H H

0 NYLN 0 lkit OyN..,N *
N
H
--.

MN N, H
¨ it----\
hi and H2N tO
HN

kli)yl 411) ill N
1---roc<s------------Thr N

H

0.õ..NOLIN NNH2, H
N
and salts thereof (b) the immune checkpoint inhibitor is nivolumab;
(c) optionally, wherein the antibody comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ [13 NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
37. The method of any one of claims 25-29, and 33, wherein:

(a) L and Dx together have a structure selected from:
H2Ny0 HN
H
1--RXINX1111%N
*

0 O OyN.N

....1µ1õzsi LJÇ

r¨ss, and H2N yO
HN
ARINXTL)INH

14, 0 \---\
and salts thereof (b) optionally wherein the immune checkpoint inhibitor that inhibits PD-1 and/or PD-L1 is pembrolizumab, nivolumab, or atezolizumab;
(c) the additional therapeutic agent comprises:
trastuzumab, a pyrimidine analog, optionally wherein the pyrmidine analog is fluorouracil or capecitabine, and a platinum coordination complex, optionally wherein the platinum coordination complex is oxaliplatin, or cisplatin; and (d) optionally wherein the cancer is gastric cancer;
(e) optionally, wherein the antibody comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
38. The method of any one of claims 25-29, and 33, wherein:
(a) L and Dx together have a structure selected from:
H2N,f0 HN

0 H 0 OyNN *

N
0 \
and H2Ny0 HN

0 11;11?\11 0 PI 40 ;
and salts thereof;
(b) the immune checkpoint inhibitor that inhibits PD-1 and/or PD-Ll is pembrolizumab, nivolumab, or atezolizumab;
(c) the additional therapeutic agent comprises:
(i) trastuzumab; and (ii) a chemotherapy regimen comprising lencovorin, fluorouracil, and oxaliplatin (FOLFOX);
(c) optionally, wherein the cancer is gastric cancer; and (d) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
39. The method of any one of claims 25-29, and 33, wherein:
(a) L and Dx together have a structure selected from:
HaN y.0 HN

1.-1RX1141;CS1(11:11 N
roC1 N, /Th 0 \----\\
and H2Nto HN

Alt\ 111 N, 0 41 o 0 r-\
0 ;
and salts thereof;
(b) the immune checkpoint inhibitor that inhibits PD-1 and/or PD-L1 is pembrolizumab, nivolumab, or atezolizumab;
(c) the additional therapeutic agent comprises:
trastuzumab;
(ii) leucovorin, (iii) fluorouracil; and (iv) cisplatin;
(d) optionally, wherein the cancer is gastric cancer; and (e) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
40. The method of any one of claims 25-29, and 33, wherein:
(a) L and Dx together have a structure selected from:
H2Ny0 HN

AyL\irril FRXtr11 HN

CLIIN-*%="----"N
rall 0 NH2 N I N, ra\
and FI2N tO
HN
ÚRÇLÇH
N

it_ NH2 rC
0 ;
and salts thereof;
(b) the immune checkpoint inhibitor that inhibits PD-1 and/or PD-L1 is pembrolizumab, nivolumab, or atezolizumab;
(c) the additional therapeutic agent comprises:
trastuzumab;
(ii) capecitabine;

(iii) oxaliplatin; and (c) optionally, wherein the cancer is gastric cancer; and (d) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
41. The method of any one of claims 25-29 and 33, wherein:
(a) L and Dx together have a structure selected from:
H2Nr HN
H
1"-RX
0 0 le jt N, N
and H2N tO
HN
H
A in N

r-Thõ
0 \
and salts thereof;
(b) the immune checkpoint inhibitor that inhibits PD-1 and/or PD-Ll is pembrolizumab, nivolumab, or atezolizumab;
(c) the additional therapeutic agent comprises:

trastuzumab; and (ii) optionally capecitabine;
(d) optionally, wherein the cancer is gastric cancer; and (e) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
42. The method of any one of claims 25-29 and 33, wherein:
(a) L and Dx together have a stmcture selected from:
H2N y0 HN
H
hR>6.1-N N N sah "pi 0 0 O OyNNio HJ
r--0 N\-Th r and H2N tO
HN
rj?\ri 0 1411 0 M..N
N

, and salts thereof;
(b) the immune checkpoint inhibitor that inhibits PD-1 and/or PD-Ll comprises pembrolizumab, and optionally atezolizumab;

(c) the additional therapeutic agent comprises:
(i) trastuzumab; and (ii) docetaxel or paclitaxel;
(d) optionally, wherein the cancer is breast cancer; and (e) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
43. The method of any one of claims 25-29 and 33, wherein:
(a) L and Dx together have a structure selected from:
H2NtO
HN

ERXrdsadlir4,)Ci::1)rN sit mpi o NI&NATINK, o and H2Nto HN

1.N 0 N, 0 N\Th;
and salts thereof;

(b) the immune checkpoint inhibitor that inhibits PD-1 and/or PD-L1 is atezolizumab or durvalumab;
(c) the additional therapeutic agent comprises fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine;
(d) optionally wherein the cancer is breast cancer; and (e) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
44. The method of any one of claims 25, 26, and 33, wherein:
(a) L and Dx together have a structure selected from:
H2Ny.0 HN

" 140 0 -õle o 0 so Ca 0 N NH2 - r-and H2NyO
HN
HN:11LaH

0 X Hlie 0 110N

0 \-- rTh.
-\
and salts thereof;
(b) the immune checkpoint inhibitor is pembrolizumab;
(c) the additional therapeutic agent comprises:
pemetrexed; and (ii) carboplatin or cisplatin;
(c) optionally, wherein the cancer is non-small cell lung cancer;
and/or (d) optionally, wherein the antibody comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
45. The method of any one of claims 25, 26, and 33, wherein:
(a) L and Dx together have a structure selected from:

tO
HN

14:2111111 cp r..,N,2:71 111N)L,40A.-N
N, and H2Ny.0 HN
H
H 140 ONCLIì

N., =
and salts thereof;
(b) the immune checkpoint inhibitor is atezolizumab;
(c) the additional therapeutic agent comprises:
paclitaxel;
(ii) carboplatin; and (iii) bevacizumab;
(c) optionally, wherein the cancer is non-small cell lung cancer;
and/or (d) optionally, wherein the antibody comprises FIC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
46. The method of claim 25-29, wherein the conjugate comprises pertuzumab or a biosimilar thereof, or comprises the CDRs of pertuzumab, or comprises an antigen binding fragment of pertuzumab, and the additional therapeutic agent comprises trastuzumab or comprises the CDRs of trastuzumab, or comprises an antigen binding fragment of trastuzumab.
47. The method of any one of claims 1-46, wherein the cancer expresses HER2 at a level of 2+ or 3+ as determined by immunohistochemistry.
48. The method of claim 47, wherein the cancer expresses HER2 at a level of 3+ as determined by immunohistochemistry.
49. The method of any one of claims 1-48, wherein the antibody of the conjugate comprises an antigen binding domain and an Fc domain.
50. The method of claim 49, wherein the Fc domain exhibits the same or substantially similar binding affinity to at least one Fcgamma receptor and/or an FcRn receptor as compared to a wild-type IgG1 Fc domain.
51. The method of claim 49, wherein the Fc domain has increased binding affinity to at least one Fcgamma receptor as compared to a wild-type IgG Fc domain.
52. The method of any one of claims 49-51, wherein the Fc domain is an IgG1 Fc domain.
53. The method of any one of claims 1-52, wherein the method comprises administering an effective regimen of the conjugate, wherein the effective regimen results in a Tmax of the conjugate in the subject of greater than 4 hours following each administration of the conjugate.
54. The method of any one of claims 1-53, wherein the method comprises administering an effective regimen of the conjugate, wherein the effective regimen comprises at least two cycles of administration of the conjugate to the subject and a total dose of greater than 0.4 mg/kg of the conjugate per cycle.
55. The method of any one of claims 1-54, wherein the conjugate is administered subcutaneously.
56. The method of any one of claims 1-54, wherein the conjugate is administered intravenously.

WO 2021(067644
57. A method of treating a HER2-expressing cancer, comprising administering to a subject with a HER2-expressing cancer a conjugate and an additional therapeutic agent comprising a kinase inhibitor, a therapeutic agent comprising an anti-HER2 antibody, or both; wherein the conjugate is represented by Formula (I):
4) 4>
11:0õ )n (I);
wherein:
A is an antibody that binds HER2, L is a linker;
Dx is a TLR8 agonist, wherein the TLR8 agonist is a benzazepine compound;
n is selected from 1 to 20; and z is selected from 1 to 20.
58. The method of claim 57, wherein n is 1 and z is from 1 to 8.
59. The method of claim 57 or claim 58, wherein the antibody of the conjugate is pertuzumab or trastuzumab, or a biosimilar thereof; or comprises the CDRs of pertuzumab or trastuzumab; or comprises an antigen binding fragment of pertuzumab or trastuzumab.
60. The method of any one of claims 57-59, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs: 1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ lD NO: 10.
61. The method of any one of claims 57-60, wherein the additional therapeutic agent comprises an anti-HER2 antibody that binds to a different epitope as compared to the conjugate antibody that binds HER2.
62. The method of any one of claims 57-61, wherein the additional therapeutic agent is selected from trastuzumab, trastuzumab-qyyp, trastuzumab-pkrb, trastuzurnab-dttb, trastuzumab-anns, trastuzumab-dkst, trastuzumab deruxtecan-nxki, ado-trastuzumab emtansine, trastuzumab duocarmazine, margetuximab, zenocutuzumab , tucatinib, cabozantinib, pyrotinib, and ponotinib.
63. The method of any one of claims 57-60, wherein the kinase inhibitor is a tyrosine kinase inhibitor, optionally wherein the tyrosine kinase inhibitor is tucatinib, cabozantinib, afatinib, erlotinib, pyrotinib, poziotinib, dacomitinib, gefitinib, lapatinib, osimertinib, larotrectinib, axitinib, lenvatinib, pazopanib, regorafenib, or sunitinib.
64 The method of any one of claims 57-60, wherein the kinase inhibitor is a CDK4/6 kinase inhibitor, optionally wherein the CDK4/6 kinase inhibitor is palbociclib, abemaciclib, or ribociclib.
65. The method of any one of claims 57-64, the additional therapeutic agent further comprises a chemotherapy agent, an immune checkpoint inhibitor, chemotherapy protective agent, or any combination thereof
66. The method of any one of claims 57-65, wherein the conjugate comprises pertuzumab or comprises the CDRs of pertuzumab, or comprises an antigen binding fragment of pertuzumab; and the additional therapeutic agent comprises trastuzumab, or a biosimilar thereof, or comprises the CDRs or trastuzumab; or comprises an antigen binding fragment of trastuzumab.
67. The method of any one of claims 57-66, wherein the cancer expresses HER2 at a level of 2+ or 3+ as determined by immunohistochemistry.
68. The method of claim 67, wherein the cancer expresses HER2 at a level of 3+ as determined by immunohistochemistry.
69. The method of any one of claims 57-68, wherein the TLR8 agonist is a compound of Category A, Formula (IlB):

%

---in L2-R4 (116) or a pharmaceutically acceptable salt thereof, wherein:
Li() is _xto_;
L2 is selected from -X2-, -X2-C1-6 alkylene-X2-, -X2-C2-6 alkenylene-X2-, and -X2-C2-6 alkynylene-X2-, each of which is optionally substituted on alkylene, alkenylene or alkynylene with one or more 102;
XI is selected from -C(0)-, and -C(C)N(Rm)-*, wherein * represents where X1 is bound to R5;
X2 at each occurrence is independently selected from a bond, -0-, -S-, -N(R10)-, -C(0)-, -C(0)0-, -0C(0)-, -0C(0)0-, -C(0)N(R10)-, -C(0)N(Rw)C(0)-, -C(0)N(Rm)C(0)N(It'o), _N(tto)ccv.)-,_, _ N(R1 )C(0)N(Ri )-, -N(R')C(0)0-, -0C(0)N(IV,:)_, _(Nitio)_, _N(Rio),G(NRKI,_ ), -C(NR"))N(Rm)-, -N(Rw)C(NR"))N(Rm)-, -S(0)2-, -0S(0)-, -S(0)0-, -S(0), -OS(0)2-, -S(0)20, -N(Rt5S(0)2-, -S(0)2N(Rl0)-, _Nattowc.)_, -S(0)N(10- )-, -N(R10)S(0)2N(R10)-, and -N(RnS(0)N(R1 )-;
RI and R2 are independently selected from hydrogen; and CI-toalkyl, C2-to alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0100, -SR', -C(0)N(R10)2, _N(tt0)2, -S(0)Rm, -S(0)2Itt , -C(0)Rw, -C(0)0Rm, -0C(0)10- , -NO2, =0, =S, =N(11.1 ), and -CN;
It4 is selected from: -OW , -N(11."))2, -C(0)N(R10)2, -C(0)R1 , -C(0)0Rw, -S(0)Rm, and -S(0)2R10; Ci-to alkyl, C2-lo alkenyl, C2-10a1kyny1, each of which is optionally substituted with one or more substituents independently selected from halogen, 10 -OR, -SR", -C(0)N(R")2, -N(R")C(0)R", -N(R1 )C(0)N(R10)2, -N(R10)2, _C(D)on 10, _ OC(0)R", -NO2, =0, =S, =N(R"), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle, and 3- to 12-membered heterocycle in R4 is optionally substituted with one or more substituents independently selected from halogen, -OR', ts_ _ C(0)N(Rm)2, -N(Rw)C(0)R"), -N(R1 )C(0)N(R10)2, _m(R10)2, _C(D)R1o, -,c(c)Or.K lo, _ OC(0)R", -NO2, =0, =S, =MR"), -CN, C1-6alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R5 is selected from unsaturated C4-8 carbocycle; bicyclic carbocycle; and fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle, wherein R5 is optionally substituted and wherein substituents are independently selected at each occurrence from:
halogen, _ORto, _sn to, _ C(0)N(R112, -N(R")C(0)R", -NOVIC(C)N(Rto)2, _ C(0)Rm, -C(0)011", -0C(0)11", -NO2, 0,-S, =TAR"), and -CN;
Ct-w alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substiments independently selected from halogen, -OR", -SR` , 2 -C(0)N(R113)µ, TARM)C(C)R1- , - N(WIC(0)N(R10)2, _N(R10)µ, _ C(0)Rt , -C(0)0R", -0C(0)Rm, -NO2, =0, =S, =N(11"), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle, and 3- to 12-membered heterocycle in R5 is optionally substituted with one or more substituents independently selected from halogen, -OR", -SR", -C(0)N(Rt )2, _mRtoycor 10, _ N(Rm)C(0)N(Rn2, -N(R")2, -C(0)R", -C(0)0R", -00(c)Rto, -NO2, =0, =S, =N(R"), -CN, Cboalkyl, C2-6 alkenyl, and C2-6 alkynyl;
It" is independently selected at each occurrence from hydrogen, -NH2, -C(0)0CH2C6H5; and Ci-to alkyl, C2-10 alkenyl, C2-to alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, -C(0)0CH2C6H5, -NHC(0)0CH2C6H5, C1-10 alkyl, -C t- to haloalkyl, -0-C 1-10 alkyl, C2-10 alkenyl, C2-to alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and haloalkyl;
and R12 is independently selected at each occurrence from halogen, -Or, _sRto, _N(Rio)2, _icor , _ to C(0)N(R10)2, _N(R10)Cor _ 10, K
C(C)OR10, -0C(0)Rm, -S(0)Rm, -S(0)2R10, -P(0)(0111 )2, -0P(0)(0141 )2, -NO2, =0, =S, =N(Rm), and -CN;
Ct-to alkyl, C2-10 alkenyl, C2-to alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORm, -N(R1 )2, _C(D)Rto, -,c(c)mR10)2, _NRIonor , _ to K
0(0)ORW, _Gc(0)R10, _soy.K _ S(D)2R10, _PoxiaR10,), -0P(0)(010 )2, -NO2, =0, =S, -N(R1 ), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle in R12 is optionally substituted with one or more substituents independently selected from halogen, -OW , mR)2,to _ -C(0)R1 , -C(0)N(Rto)2, -N(R1 )C(0)R1 , -C(0)0R10, -0C(0)R1o, _sor to, _ S(0)21:01, -P(0)(0R1 )2, -0P(0)(01e)2, -NO2, =0, =S, =N(R1 ), -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl;
wherein any substitutable carbon on the benzanpine core is optionally substituted by a substituent independently selected from R12 or two substituents on a single carbon atom combine to form a 3- to 7- membered carbocycle;
R20, R21, R22, and E. n23 are independently selected from hydrogen, halogen, at , _(Rt0)2, _s(0)Rto, _s(0)2Rto, -,c(c)Rto, _c(c)loRto, -0C(0)R1 , -NO2, =0, =S, =N(111 ), -CN, Ct-to alkyl, C2-10 alkenyl, and C2-10 alkynyl;
and n K. and R25 are independently selected from hydrogen, halogen, -ORD', -SRm, - N(R1 )2, -S(0)Rm, -S(0)2R10, _C(D)R10, _C(o)on 10, _ OC(0)R1 , -NO2, =0, -S, _Notto,, _ CN, Ci-to alkyl, C2-to alkenyl, and C2-to alkynyl; or R24 and R25 taken together form an optionally substituted saturated C3-7 carbocycle.
70.
The method of any one of claims 57-69, wherein the TLR8 agonist is a compound of Category A, Formula IIC:

N¨R2 co N , -----(IIC) or a pharmaceutically acceptable salt thereof, wherein:
RI- and R2 are hydrogen;
L2 is -C(0)-;
R4 is -N(R1. )2;
RR' is independently selected at each occurrence from hydrogen, -NH2, -C(0)0C1tC6H5; and Chto alkyl, C2-10 alkenyl, C2-io alkynyl, C312 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, =0, =S, -C(0)0CH2C6H5, -NI-1C(0)0CH2C6H5, Ci-io alkyl, -Ct-io haloalkyl, -0-C 1-10 alkyl, C2-lo alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and haloalkyl;
Lio is -C(0)N(R'-) *, wherein * represents where Lm is bound to R5; and R5 is a fused 5-5, fused 5-6, or fused 6-6 bicyclic heterocycle, wherein R5 is optionally substituted and wherein substituents are independently selected at each occurrence from:
halogen, -ORM, _SRI , _C(D)TARICI)2, _NotiowecoRio, -N(R10)C(0)N(R10)2, -N(R.....,)2, _ 1n C(0)R10, -0(0)0R1-(1, -00(0)R1n, -NO2, 1:7:0, =S, =N(11.1 ), and -CN;
CI-io alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OW , am, -,c(c)N(Rio)2, _N(Rio),c(0)Rio, 2 _TARilicopk-Rio,), _ N(R"))2, -C(0)R1 , -C(0)0Rm, -0C(0)10 , -NO2, =0, =S, =MR"), -CN, C3-12 carbocyde, and 3- to 12-membered heterocycle; and C342 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -Ole, -SRI , -C(0)N(11.1 )2, -N(11.1 )C(0)Ri , -N(R1 )C(0)N(RIO)2, -N(R10)2, _Cow , _Cowl , -0C(0)R1 , -NO2, =0, =S, =N(R11, -CN, C 1-6alkyl, C2-6 alkenyl, and C2-6 alkynyl.
71. The method of claim 70, wherein R4 is -N(Ci4 alky1)2 and LI is -C(0)N(1-1)-*.
72. The method of claim 70 or 71, wherein:

v.NI
R4 is CH3.
73. The method of any one of claims 57-72, wherein the TLR8 agonist is selected from:
o els .
N
N

N NH, 0 N *
H
-- r--\
N
OH
es . N NH2 00 0 Nõ. NH2 OH M *
-- /-----\
N
H
' iTh 0 N\---\\

NH * 0 NH2 HN 41) 0 N
N
*1-1 --- re\
N *
--r-s..
N
N
0 \----\
0 \----\

. 0 N.

HN

N
H
N
H
__.- cs, --- NiTh N
0 \Th 0 \Th , , =
o AO N
N__ NH2 . 1 * 0A N 011 N, --- .----\\
ri --- Nr---\

crsi 10 .õN _ N, Cbz N N.
*
N
H
H N r-,,N, NH2 --- NC\
0 µ---\
0 \--\
, , cp N

ca. 0 N
N

H
NHCbz ---N/Th --- r---\
N
, , c: C.)., 0.1 N.__ NH2 N
N
CbzHN H H
r--\\ H2N
--r--s\
N N
, raN....x es, 0 N___ NH2 * N ".... 1 N NH2 N
N
HNs. H
H
Cbz -- /Th --- Nr\
N
, , H
oCi CbleN
N
se I NH2 I CI N

HN --...
N
N
H
H
--- 1--\
--- r's\
N
N
N
ad -,._.
_C ..Ø, HN I
N N
H
---Nr---\
0 \----\
, H
e s 0, RB *
N, N
HO H
---rThsi N
, 0 0 ....1 rAMN Cl N__ u 11 *

--- r---\
N

\---\ , CbzliN,i o t.... pi so ......N.,......õ , ri,11........4...ri * N, NH2 ---r---\
0 N\--\ , H2N...1 LN
* OCX H CI NH2 N
...."' 0 N, ...õ
r--\
N
N
N
C., 0 1 '%. 0 HIWN. N Ha:1.N N, VI lb H3C0 r---\
F --- Nr-\
N
0 \--\
0 \---\

H2N-----r N = ratil 0 F F H N
....-- pd N, ii 0 ---ra- \
N
\
0 --\
and , and pharmaceutically acceptable salts thereof.
74.
The method of any one of claims 57-73, wherein Dx is a compound of Formula (IVB):

R2o x R8,c2 N--(IVB) or a pharmaceutically acceptable salt thereof, wherein:
Lu is selected from -X3-, -X3-C1-6alkylene-X3-, -X3-C2-6alkenylene-X3-, and -X3-C2-6 alkynylene-X3-, each of which is optionally substituted on alkylene, alkenylene, or alkynylene with one or more substituents independently selected from R12;
L22 is independently selected from -r-, -r-Ci.-6 alkylene-r-, -X4-C2-6 alkenylene-r-, and -X4-C2-6 alkynylene-r-, each of which is optionally substituted on alkylene, alkenylene, or alkynylene with one or more substituents independently selected from Rw;
X3 and X4 are independently selected at each occurrence from a bond, -0-, -S-, -N(Rm)-, -C(0)-, -C(0)0-, -0C(0)-, -0C(0)0-, -C(0)N(Rn-, -C(0)N(It'c)c(0)_, -C(C)N(Rm)C(C)N(R"))-, -N(R')C(0)-, -N(Rt5C(0)N(R")-, -N(t' )C(0)0-, -0C(0)N(Rw)-, -C(NR` )-, -N(Rw)C(NIV )-, -C(NR"))N(R")-, -N(Rw)C(NRI1N(Rw)-, -S(0)2-, -0S(0)-, -S(0)0-, -S(0)-, -OS(0)2-, -S(0)20-, -N(RnS(0)2-, -S(0)2N(Rth)-, -N(RnS(0)-, -S(0)N(Rm)-, -N(Rm)S(0)2N(R'o)_, and -N(RnS(0)N(10 )-;
RI- and R2 are independently selected from L3, and hydrogen; and Chio alkyl, alkenyl, and C2-10 alkynyl, each of which is optionally bound to L3 and each of which is optionally substituted with one or more substituents independently selected from halogen, -OW , -SRI , -C(0)N(Rm)2, -N(Rn2, -S(0)Rw, -S(0)2Rm, -C(0)Rw, -C(0)0Rm, -0C(0)11.1 , -NO2, =0, =S, =N(R1 ), and -CN;
R4 and R8 are independently selected from: -Ole , -N(R10)2, -C(C)N(R"))2, -C(0)Rm, -C(0)0R1- , -S(0)R'', and -S(0)2Rm; C1-10 alkyl, C2-10 alkenyl, C2-to alkynyl, each of which is optionally bound to L3 and each of which is optionally substituted with one or more substituents independently selected from halogen, -OW , -SRI , -C(0)N(R10)2, 4õ4(R10),c(0)Rto, -N(R10)C(0)N(R10)2, -Nen ttc10)2, -C(0)11.1 , -C(0)0Rm, -0C(C)RY), -NO2, =0, =S, =N(Rw), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle, and 3- to 12-membered heterocycle in R4 and R8 is optionally bound to L3 and each C3-12 carbocycle, and 3- to 12-membered heterocycle in re and 11.8 is optionally substituted with one or more substituents independently selected from halogen, -OW , -SR', -C(0)N(R"))2, -N(RnC(0)Rw, -N(R'')C(0)N(Rt )2, ,n10 -N(R"))2, -C(0)Kõ -C(0)0R11), -0C(0)Rffi, -NO2, =0, =S, =N(R'"), -CN, 0.-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
Ril) is independently selected at each occurrence from L3, hydrogen, -NI12, -C(0)0CH2C6H5; and Chia alkyl, C2-10 alkenyl, C2-to alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -NH2, =0, =S, -C(0)0CH2C6H5, -NHC(0)0CH2C6H5, Ci-toalkyl, C2-10 alkenyl, C2-to alkynyl, C3-carbocycle, 3- to 12-membered heterocycle, and haloalkyl;
L3 is a linker moiety, wherein there is at least one occurrence of and RI-2 is independently selected at each occurrence from halogen, -OR', -SR', -N(Rw)2, -C(0)Rto, -C(0)N(R11)2, -N(Rw)C(0)10.0, -C(0)0Rw, -0C(0)Rw, -S(0)Rw, -S(0) K10, - P(0)(0R10)2, -OP(0)(OR112, -NO2, =0, =S, =MR"), and -CN; C1-10 alkyl, C2-10alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORM, _SR10, _N(R113µ), _ C(0)Rm, -C(0)N(Rm)2, -N(R'orroyn 10, -C(0)ORKI, -0C(0)Rw, -S(0)Rm, -S(0)2R"), _p(p)(0R10µ), -0P(0)(0R10)2, -NO2, =0, =S, =N(RID), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocyde and 3- to 10-membered heterocycle init.' is optionally substituted with one or more substituents independently selected from halogen, -OW , -SW , -MR112, -C(0)Rt0, -C(0)N(R10)2, -N(11 )C(0)R1-0, -20)0R11), -0C(0)RM, -SOW"), -S(0)2R10, -P(0)(0R10)2, -0P(0)(0R10)2, -NO2, =0, =S, =N(1.1 ), -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl;
wherein any substitutable carbon on the benzazepine core is optionally substituted by a substituent independently selected from RI' or two substituents on a single carbon atom combine to form a 3- to 7- membered carbocycle;
R20, R21, lc .22, and R23 are independently selected from hydrogen, halogen, -SR' , -N(Rm)2, -S(0)Rw, -S(0)2Rm, -C(0)Rm, -C(0)0Rw, -0C(0)Rm, -NO2, =S, =N(Rm), -CN, Ct-to alkyl, C2-to alkenyl, and C2-10 alkynyl; and R24, and R25 are independently selected from hydrogen, halogen, -OR', -Sle , -N(Rn2, -S(0)2Rt , -C(0)Rt , -C(0)OR', -0C(0)Rm, -NO2, =0, =S, =Me), -CN, Ci-to alkyl, C2-to alkenyl, and C2-to alkynyl; or R24 and R25 taken together form an optionally substituted saturated C3-7 carbocycle.
75.
The method of any one of claims 57-74, wherein Dx is a compound of Formula (1VC).

N
L12 N -R2, R8 =
-a--(IVC) or a pharmaceutically acceptable salt thereof, wherein:
IV and R2 are hydrogen;
L22 is _C(0)-R4 is -N(Rm)2;
Rm is independently selected at each occurrence from hydrogen, -Nth, -C(0)0CH2C6H5; and CI-to alkyl, C2-10 alkenyl, C2-to alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -NH2, =0, =S, -C(0)0C1tC6H5, -NHC(0)0CH2C6H5, C1-10 alkyl, C2-to alkenyl, C2-to alkynyl, C3-carbocycle, 3- to 12-membered heterocycle, and haloalkyl;

L1-2 is -C(0)N(Rto)*_, wherein * represents where lan is bound to RK;
Rg is an optionally substituted fused 5-5, fused 5-6, or fused 6-6 bicyclic heterocycle bound to linker moiety 12 , and wherein optional substituents are independently selected at each occurrence from:
halogen, -OR", -SRI , -,c(c)mRtc)2p., _ N(R1 )C(0)R10, -N(Rm)C(0)N(Rm)2, -N(R10)2, -C(0)R10, -C(0)0R11 , -0C(0)11.1 , -NO2, :20, =S, =MR"), and -CN;
Ci-io alkyl, C2-10 alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR", am, _Conkto)z, _Nothc(0)Rio, _mkto)C(3)Nt-Rto.,2, _ N(R")2., -C(0)R", -C(0)0R", -0C(0)R", -NO2, =0, =S, =N(R"), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR", -SR", -C(0)N(R")2, -N(10)C(0)R", -N(R1 )C(0)N(R")2, -N(R113)2, -C(D)RM, -C(0)0R10, -0C(0)Rto, -NO2, =0, =S, =MR"), -CN, C1-6alkyl, C2-6 alkenyl, and C2-6alkynyl.
76. The method of claim 75, wherein R4 is -N(C1-1 alky1)2 and I,' is -C(0)N(1-1)-*.
77. The method of claim 75 or 76, wherein:

R4 is CH3.
78.
The method of any one of claims 57-77, wherein L and Dx together have a structure selected from:
FuN ,,,r0 HN

caõ.....õ,....a....õ...õ...Thr NHxitiliril IssCRX N
N..... 0 H

0,.....,[=11 .,,...1)..... N N, H
N
0 \----\ , H2N tO
HN

N
RX*Wir 111 JL- r%)Y[sl - H
N, 0 ......7..õ... 0 410 H

---N

(Ni 0 N ciF1 0 0Aflr" ' H
N

Hy ri H2N--.0 , N

0 0N-----yG
A
N N.__ 0 Xllii 0 ----U
---vRX:`,...............õ,.....õ.õ..A. N......", N - N
H - H
is¨\ .
N
Of HN

, Ill .,.14,.1/4 --11--.
11-4LA , NH2 V
0 yiiii 0 40 0 N
N NI
N N...,N

-H H
N

NH
0.4-NH2 , = N

A.
II ..... _LI' NH2 N
H
H
VRilerisL}L
ri 0 - N
C\
N H
E H
0 -s......L
NH

, H 2N tO
H N
1:11ily,11 1.-Rir%----...--%---.Thre5 1;1 N

H

0 = yr41,...........\ %II 0 1,...aaN 0 N ,--- N, N
H
- r- \
N
H2NtO
HN

RX iril ll r H 0 4 H
0 õAõ.....
OyN,,,---,N so n 1µ1,-41 0 H

IN N ......../A, N NH2 H
-=-" rThs.
N
H2Ny0 HN

1(11xy 11:5iRli ARXC..............hµ'''...Thr N

H H
0 0 mit OyN....,....Thq .VI 0 c.f....A.' ..N
N, H

H2Ny0 HN
=
N.

H

N
I), 0 0 \¨\
I-12N tO
HN
H
es" NXLIN I
0 0 *

N
NU N

---re-\

H2Ny0 HN

z H

N
'%1 0 N, H2N-f0 HN
H
Nxillik 0 le 0.õ,e.NOUN
N

, /Th H2N y0 HN
N= co% 0 H_ 0 /---\\
o \-\
o H o o Rt1 o NH2 F F

HN
0 N\--Ths1/4 Fl2tr1/40 and =
NJL
rXrri op) Ainn CC) NH2 F F
N
H H
o HN

and salts thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein )4 on RX* represents the point of attachment to the residue of the antibody.

WO 2021(067644
79. The method of claim 78, wherein L and Dx together have a structure selected from:
H2N,r0 HN
H H
tLIRX"Wir NY% )YN0 H 0 0 . 1 0 Oy N .,......,..-NN * rõ... Nõ,...ti 0 W. N Nõ
H
----Csµ, N
H2Ny0 HN
_Ai,:
iscR,,,N. N

o z H H
0 ......A......
OyN..........--.1,4 * r,..,L N,.AN...., 0 H N,NH2 Nj H
N
H2NtO
HN
H.2:111( H
N N
N
ARX<--.%-------------ir N

H
0 s 0 , II
H

/---\
.--N
H2N yp HN
H H
/....Rn N 4.N N 5 r....m.....i 0 I

0 ,,..5...... H 0 0............ NI j4-,--,..AN N, H
H
.---N

o o A
crii 0 ri2c11 * CO, N NH2 N aN.d.AN
N ...-- N, H H
H

rTh---- .
N

and Rxz_eõ....õ%.õ....õ..)fir NH it, 40 0 friC
so , 0 NH2 F F
- N
H E H
Nrs HN
0 \
H N
and salts thereof, wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, wherein on RX* represents the point of attachment to the residue of the antibody.
80. The compound or salt of claim 78 or 79, wherein RX* comprises a succinamide moiety and is bound to a cysteine residue of the antibody.
81. The compound or salt of claim 78 or 79, wherein RX* comprises a hydrolyzed succinamide moiety and is bound to a cysteine residue of the antibody.
82. The method of any one of claims 57-81, wherein:
(a) L and Dx together have a structure selected from:
H2N,re HN
H
Rxcwir Nt4\ N

0 = y NH, 14_ =
LJÇJ

and HN

ARACWY
0 140 0Nal. .N
NI, NH2 \--Ths =
and salts thereof;
(b) the additional therapeutic agent comprises trastuzumab; and (c) optionally, wherein the antibody of the conjugate comprises 11C-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
83. The method of any one of claims 57-81, wherein:
(a) L and Dx together have a structure selected from:
H2NtO
HN
H

OyN....õ====,N *
(Yi 0 N

and tO
HN

15ck\111 0 SO 0..._,NIOLIN N NH2, fe-\\
0 \¨\\
and salts thereof;
(b) the additional therapeutic agent comprises fam-trastuzumab deruxtecan-nxki; and (c) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
84. The method of any one of claims 57-81, wherein:
(a) L and Dx together have a structure selected from:
H2Ny0 HN
H oH
O hR)CiN N

0 H 0.,1e-N4 N._ rThs.
and HN

NçN H2 =
and salts thereof;
(b) the additional therapeutic agent comprises ado-trastuzumab emtansine; and (c) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ 1D NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
85. The method of any one of claims 57-81, wherein:
(a) L and Dx together have a stmcture selected from:
HAtp HN
H

O 0 Oy (...1114t.:1 LJJ

0 \
and H2Ny0 HN
H
Rr X
H Wy NIL N

N., and salts thereof;
(b) the additional therapeutic agent comprises tucatinib; and (c) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, 11C-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
86. The method of any one of claims 57-81, wherein:
(a) L and Dx together have a structure selected from:
1-12Ny0 HN

ERX'r!xi\ 1:11 HN 0 Fl 0 O OyN.aN
N'", 0 N, r¨Ths, and H2Ny0 HN
H

0 HNi 0 411 NL_ o and salts thereof;
(b) the additional therapeutic agent comprises palbociclib, abemaciclib, or ribociclib;
(c) optionally wherein the HER2-expressing cancer is breast cancer;
and (d) optionally, wherein the antibody comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ LD NOs: 1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
87.
The method of any one of claims 57-81, wherein:
(a) L and Dx together have a structure selected from:
1-12Ny0 HN

0 HN 0 = y so , N, r`ss, and H2Ny0 HN
H
H

0 411 N., and salts thereof;
(b) the additional therapeutic agent comprises:
(i) trastuzumab;
(ii) a pyrimidine analog, optionally wherein the pyrimidine analog is fluorouracil or capecitabine;
(iii) a platinum coordination complex, optionally wherein the platinum coordination complex is oxaliplatin, or cisplatin;
(iii) a PD-1 and/or PD-Ll inhibitor, optionally wherein the PD-1 and/or PD-Ll inhibitor is pembrolizumab, nivolumab, or atezolizumab;
(c) optionally wherein the HER2-expressing cancer is gastric cancer;
and (d) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
88. The method of any one of claims 57-81, wherein:

(a) L and Dx together have a stnrcture selected from:
H2NtO
HN
H o hRX

0 o len iso 0 Nre\
and H2N yO
HN

lilt\ 11 A Rn NI

\----\\ =
and salts thereof;
(b) the additional therapeutic agent comprises:
(i) trastuzumab;
(ii) a chemotherapy regimen comprising lencovorin, ftuorouracil, and oxatiplann (FOLFOX); and (iii) optionally pembrolizumab, nivolumab, or atezolizumab;
(c) optionally wherein the HER2-expressing cancer is gastric cancer;
and (d) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
89. The method of any one of claims 57-81, wherein:
(a) L and Dx together have a structure selected from:
H2Ny0 FlN

0 kitil\O-1 0-õwe.R.,--.,N
-..

and H2Ny0 HN
mx\
0 S oNOLì 0 NH, N, rTh, \---\ =
and salts thereof;
(b) the additional therapeutic agent comprises:
trastuzumab;
(ii) leucovorin, (iii) fluorouracil:
(iv) cisplatin; and (iii) optionally pembrolizumab, nivolumab, or atezolizumab;
(c) optionally, wherein the HER2-expressing cancer is gastric cancer; and (d) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
90. The method of any one of claims 57-81, wherein:
(a) L and Dx together have a structure selected from:

tO
HN
H
hR)C<WIt\i N."
m 0 u OyNN*

N, and H2Ny0 HN
LitO\

NCO, \---\ -and salts thereof;
(b) the additional therapeutic agent comprises:
trastuzumab;
(ii) capecitabine;
(iii) oxaliplatin; and (iv) optionally pembrolizumab, nivolumab, or atezolizumab;
(c) optionally, wherein the HER2-expressing cancer is gastric cancer; and (d) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
91. The method of any one of claims 57-81, wherein:
(a) L and Dx together have a structure selected from:

tO
HN
H
x11:5-y.11 ries, iF0err)r-N
0 W oy *

LÇÇN

and H2Ny0 HN
H

and salts thereof;
(b) the additional therapeutic agent comprises:
trastuzumab;
(ii) pembrolizumab, nivolumab, or atezolizumab; and (iii) optionally capecitabine;
(c) optionally, wherein the HER2-expressing cancer is gastric cancer; and (d) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:

1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
92. The method of any one of claims 57-81, wherein:
(a) L and Dx together have a structure selected from:
1-12Nto HN
H
l'IRXWYNYC\
O " 0 * nti,,zi N, and 112N tO
HN
Hi\iõH

0õ.Nia.-1/4.,1,N N, r---\--\ =
and salts thereof;
(b) the additional therapeutic agent comprises:
trastuzumab;
(ii) pembrolizumab;
(iii) docetaxel or paclitaxel; and (iv) optionally, atezolizumab;
(c) optionally, wherein the HER2-expressing cancer is breast cancer;
and (d) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
93. The method of any one of claims 57-81, wherein:
(a) L and Dx together have a structure selected from:
H2N tO
HN
H
*

* 14.zzl 0 N
N, and H2Ny0 HN
H H
0 H 0 le N__ N H2 and salts thereof;
(b) the additional therapeutic agent comprises one of the following combinations:
fam-trastuzumab deruxtecan-nxki and durvalumab, (ii) fam-trastuzumab deruxtecan-nxIci and atezolizumab, (iii) ado-trastuzumab emtansine and durvalumab; and (iv) ado-trastuzumab emtansine and atezolizumab;
(c) optionally wherein the HER2-expressing cancer is breast cancer;
and (d) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
94. The method of any one of claims 57-81, wherein:
(a) L and Dx together have a stmcture selected from:
H2N,r0 HN
H

0 o Ca.
NH

N 2, \
0 NI\
and H2Ny0 HN
HAH
ess,,RnN
= 0 ,,,,NOLI N, -and salts thereof;
(b) the additional therapeutic agent comprises:
(i) trastuzumab;

(ii) a hormone-based compound; and (ii) palbociclib or abemaciclib;
(c) optionally, wherein the HER2-expressing cancer is breast cancer;
and (d) optionally, wherein the antibody of the conjugate comprises HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of SEQ ID NOs:
1-6, respectively; or the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
95. The method of any one of claims 57-94, wherein the antibody of the conjugate comprises an antigen binding domain and an Fc domain.
96. The method of claim 95, wherein the Fc domain exhibits the same or substantially similar binding affinity to at least one Fcgamma receptor and/or an FcRn receptor as compared to a wild-type IgG1 Fc domain.
97. The method of claim 95, wherein the Fc domain has increased binding affinity to at least one Fcgamma receptor as compared to a wild-type IgG Fc domain.
98. The method of any one of claims 95-97, wherein the Fc domain is an IgG1 Fc domain.
99. The method of any one of claims 57-98, wherein the method comprises administering an effective regimen of the conjugate, wherein the effective regimen results in a Tmax of the conjugate in the subject of greater than 4 hours following each administration of the conjugate.
100. The method of any one of claims 57-99, wherein the method comprises administering an effective regimen of the conjugate, wherein the effective regimen comprises at least two cycles of administration of the conjugate to the subject and a total dose of greater than 0.4 mg/kg of the conjugate per cycle.
101. The method of any one of claims 57-100, wherein the conjugate is administered subcutaneously.
102. The method of any one of claims 57-100, wherein the conjugate is administered intravenously.
103. The method of any one of claims 57-102, wherein the HER2-expressing cancer is selected from breast cancer, stomach/gastric cancer, colorectal cancer, non-small cell lung cancer (NSCLC), urothelial cancer, endometrial cancer, and ovarian cancer.
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