WO2023186174A1

WO2023186174A1 - Topical formulation comprising an il-17a binding molecule and uses thereof

Info

Publication number: WO2023186174A1
Application number: PCT/CN2023/085983
Authority: WO
Inventors: Harald REINHART; Eric Yu; Srikanth MANNE; Yali TSAI
Original assignee: Zai Lab Shanghai Co Ltd
Current assignee: Zai Lab Shanghai Co Ltd
Priority date: 2022-04-01
Filing date: 2023-04-03
Publication date: 2023-10-05
Anticipated expiration: 2024-10-01
Also published as: WO2023186174A9

Abstract

Provided herein is a gel composition for topical use, which comprises an IL-17 A binding molecule and suitable excipients.

Description

Topical Formulation Comprising an IL-17A Binding Molecule and Uses Thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to International Application No. PCT/CN2022/084767 filed April 1st, 2022, the content of which is incorporated herein by reference in its entirety.

REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

The contents of the electronic sequence listing (FG00771PCT-seq. xml; Size: 74, 447 bytes; and Date of Creation: April 3rd, 2023) is herein incorporated by reference in its entirety.

FIELD

This application relates to a stable gel composition which comprises an IL-17A binding molecule for topical administration. The application also relates to the use of the gel composition in the treatment of dermatological conditions/diseases.

BACKGROUND

The IL-17 pathway plays a major role in the development of diseases such as psoriasis and asthma. IL-17 over expression promotes psoriasis by contributing to the inflammatory response that damages and overturns the keratinocyte cells of the epidermal layer. Because of their role in disease, IL-17 inhibitors are being investigated as possible treatment for various diseases. IL-17A-targeting antibody has become a therapeutic agent in the treatment of chronic plaque psoriasis (CPP) . So far, three systemically-administered mAbs (secukinumab, ixekizumab and brodalumab) which target IL-17A and IL-7RA have been approved by Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of moderate-to-severe CPP in recent years. There is a need for stable drug topical formulations in this field.

Topical administration via the skin may be transdermal or intradermal (also referred to as local or dermal) . Transdermal administration involves transport of the drug through the skin into the systemic blood circulation. Intradermal administration of a drug occurs with little or no systemic absorption or accumulation. It involves entry of the drug across the stratum corneum for a cutaneous or local skin effect. In other words, the pharmacological effect of the drug via intradermal delivery is localized to the intracutaneous regions of drug penetration and deposition. Intradermal absorption of a drug involves partitioning of the drug from the applied vehicle into the stratum corneum; diffusion of the drug through the stratum corneum; and partitioning of the drug from the stratum corneum into the epidermis. In contrast, transdermal absorption further involves diffusion of the drug through the epidermis; and capillary uptake of the drug for circulation in the blood.

Intradermal delivery can be desired because it would be expected to result in an improved safety profile due to reduced off-target toxicity over the systemic treatment. However, it is complicated and may require innovative approaches to design a topical formulation that can retain at least the majority of the drug dermally such that it does not enter the blood stream in significant amounts. Several factors can determine the permeability of the skin or of specific layers to drug compounds. These factors include the characteristics of the skin, the characteristics of the drug compound itself (size, lipophilicity/hydrophilicity) , the dosage of the drug compound applied, interactions between the drug compound and the delivery vehicle, interactions between the drug compound and the skin. As a result, it is generally accepted that whether intradermal delivery of a drug compound can be achieved in an amount sufficient for therapy is uncertain. Penetration enhancers are commonly used in transdermal delivery to achieve penetration of a drug across the stratum corneum typically to provide for systemic delivery of the drug, rather than its retention in the epidermis or dermis. Thus, topical administration, while desired from a patient convenience and drug delivery view, has been largely unsuccessful for many compounds as evidenced by the relatively few drugs approved for topical administration.

Single variable domain antibodies that bind to human IL-17A are described in WO2016/113557 whose contents are hereby incorporated in its entirety. Due to their small sizes and other features unique to this class of molecules such as improved target affinity, it is hypothesized that this class of antibodies may be able to penetrate the abnormal tissue of CPP when topically-administered with suitable excipients or vehicles. This application provides a intradermal hydrogel formulation comprising a single variable domain antibody that binds to human IL-17A. The intradermal hydrogel formulation results in minimal to no or no significant amount of systemic absorption of the single domain antibody that binds to human IL-17A.

SUMMARY

Provided is a gel composition comprising (1) a single variable heavy chain domain antibody that binds to human IL-17A, (2) a gelling agent, (3) tris, glycine, glutamic acid, arginine, sorbitol, propylene glycol, and (5) water, wherein the pH of the gel composition ranges from 5 to 9.

In some embodiments, the single variable heavy chain domain antibody comprises CDR1 having SEQ ID NO: 2, CDR2 having SEQ ID NO: 3, and CDR3 having SEQ ID NO: 4.

In some embodiments, the single variable heavy chain domain antibody comprises SEQ ID NO: 1 or comprises a sequence sharing at least 75%, 80%, 85%, 90%, or 95%sequence homology to SEQ ID NO: 1. In some embodiments, the single variable heavy chain domain antibody comprises SEQ ID NO: 74 or comprises a sequence sharing at least 75%, 80%, 85%, 90%, or 95%sequence homology to SEQ ID NO: 74. In some embodiments, the single variable heavy chain domain antibody comprises a sequence selected from SEQ ID NOs: 5-73 or comprises a sequence sharing at least 75%, 80%, 85%, 90%, or 95%sequence homology to a sequence selected from SEQ ID NOs: 5-73.

In some embodiments, the gel composition comprises the single variable heavy chain domain antibody that binds to human IL-17A in an amount ranging from 0.01 to 5% (w/w) such as from 0.5 to 5 % (w/w) of the gel composition. In some embodiments, the single variable heavy chain domain antibody that binds to human IL-17A is in an amount of 1-5% (w/w) of the gel composition. In some embodiments, the single variable heavy chain domain antibody that binds to human IL-17A is in an amount of 1, 2, or 3% (w/w) of the gel composition.

In some embodiments, the gelling agent is a cellulose derivative selected from hydroxyethylcellulose (HEC) , hydroxypropyl cellulose (HPC) , and hydroxypropylmethyl cellulose (HPMC) . In some embodiments, the gelling agent is HPMC.

In some embodiments, the gel composition further comprises a preservative. In some embodiment, the preservative is selected from parabens, such as methylparaben and propylparaben and salt thereof.

In some embodiments, the gelling agent is in an amount of less than 5% (w/w) . In some embodiments, the gelling agent is in an amount ranging from 0.5 to 2.0 % (w/w) , such as from 0.6 to 1.5% (w/w) , 0.6 to 1.4% (w/w) , 0.6 to 1.3% (w/w) , 0.6 to 1.2% (w/w) , 0.6 to 1.1% (w/w) , 0.7 to 1.5% (w/w) , 0.7 to 1.4% (w/w) , 0.7 to 1.3% (w/w) , 0.7 to 1.2% (w/w) , 0.7 to 1.1% (w/w) , 0.8 to 1.5% (w/w) , 0.8 to 1.4% (w/w) , 0.8 to 1.3% (w/w) , 0.8 to 1.2% (w/w) , 0.8 to 1.1% (w/w) , 0.9 to 1.5% (w/w) , 0.9 to 1.4% (w/w) , 0.9 to 1.3% (w/w) , 0.9 to 1.2% (w/w) , or 0.9 to 1.1% (w/w) . In some embodiments, the gelling agent is in an amount of 1% (w/w) .

In some embodiments, tris is in an amount ranging from 0.5 to 2.0% (w/w) , such as from 0.6 to 1.5% (w/w) , 0.6 to 1.4% (w/w) , 0.6 to 1.3% (w/w) , 0.6 to 1.2% (w/w) , 0.6 to 1.1% (w/w) , 0.7 to 1.5% (w/w) , 0.7 to 1.4% (w/w) , 0.7 to 1.3% (w/w) , 0.7 to 1.2% (w/w) , 0.7 to 1.1% (w/w) , 0.8 to 1.5% (w/w) , 0.8 to 1.4% (w/w) , 0.8 to 1.3% (w/w) , 0.8 to 1.2% (w/w) , 0.8 to 1.1% (w/w) , 0.9 to 1.5% (w/w) , 0.9 to 1.4% (w/w) , 0.9 to 1.3% (w/w) , 0.9 to 1.2% (w/w) , or 0.9 to 1.1% (w/w) . In some embodiments, tris is in an amount of 1% (w/w) .

In some embodiments, glycine is in an amount ranging from 0.2 to 1.5% (w/w) , such as from 0.3 to 1.5% (w/w) , 0.3 to 1.0% (w/w) , 0.3 to 0.9% (w/w) , 0.3 to 0.8% (w/w) , 0.3 to 0.7% (w/w) , 0.4 to 1.5% (w/w) , 0.4 to 1.0% (w/w) , 0.4 to 0.9% (w/w) , 0.4 to 0.8% (w/w) , 0.4 to 0.7% (w/w) , 0.5 to 1.5% (w/w) , 0.5 to 1.0% (w/w) , 0.5 to 0.9% (w/w) , 0.5 to 0.8% (w/w) , or 0.5 to 0.7% (w/w) . In some embodiments, glycine is in an amount of 0.7% (w/w) .

In some embodiments, arginine is in an amount ranging from 1.0 to 3.0% (w/w) , such as from 1.1 to 3.0% (w/w) , 1.1 to 2.5% (w/w) , 1.1 to 2.0% (w/w) , 1.2 to 3.0% (w/w) , 1.2 to 2.5% (w/w) , 1.2 to 2.0% (w/w) , 1.3 to 3.0% (w/w) , 1.3 to 2.5% (w/w) , 1.3 to 2.0% (w/w) , 1.4 to 3.0% (w/w) , 1.4 to 2.5% (w/w) , 1.4 to 2.0% (w/w) , 1.5 to 3.0% (w/w) , 1.5 to 2.5% (w/w) , 1.5 to 2.0% (w/w) , 1.6 to 3.0% (w/w) , 1.6 to 2.5% (w/w) , 1.6 to 2.0% (w/w) , 1.7 to 3.0% (w/w) , 1.7 to 2.5% (w/w) , 1.7 to 2.0% (w/w) , 1.8 to 3.0% (w/w) , 1.8 to 2.5% (w/w) , 1.8 to 2.0% (w/w) , 1.9 to 3.0% (w/w) , 1.9 to 2.5% (w/w) , or 1.9 to 2.0% (w/w) . In some embodiments, arginine is in an amount of 1.9% (w/w) .

In some embodiments, glutamic acid is in an amount ranging from 1.0 to 3.0% (w/w) , such as from 1.1 to 3.0% (w/w) , 1.1 to 2.5% (w/w) , 1.1 to 2.0% (w/w) , 1.2 to 3.0% (w/w) , 1.2 to 2.5% (w/w) , 1.2 to 2.0% (w/w) , 1.3 to 3.0% (w/w) , 1.3 to 2.5% (w/w) , 1.3 to 2.0% (w/w) , 1.4 to 3.0% (w/w) , 1.4 to 2.5% (w/w) , 1.4 to 2.0% (w/w) , 1.5 to 3.0% (w/w) , 1.5 to 2.5% (w/w) , 1.5 to 2.0% (w/w) , 1.6 to 3.0% (w/w) , 1.6 to 2.5% (w/w) , 1.6 to 2.0% (w/w) , 1.7 to 3.0% (w/w) , 1.7 to 2.5% (w/w) , 1.7 to 2.0% (w/w) , 1.8 to 3.0% (w/w) , 1.8 to 2.5% (w/w) , 1.8 to 2.0% (w/w) , 1.9 to 3.0% (w/w) , 1.9 to 2.5% (w/w) , or 1.9 to 2.0% (w/w) . In some embodiments, glutamic acid is in an amount of 1.6% (w/w) .

In some embodiments, sorbitol is in an amount of less than 15% (w/w) . In some embodiments, sorbitol is in an amount ranging from 5.0 to 15% (w/w) , such as from 5.5 to 15% (w/w) , 5.5 to 10% (w/w) , 5.5 to 9.5% (w/w) , 5.5 to 9.0% (w/w) , 6.0 to 15% (w/w) , 6.0 to 10% (w/w) , 6.0 to 9.5% (w/w) , 6.0 to 9.0% (w/w) , 6.5 to 15% (w/w) , 6.5 to 10% (w/w) , 6.5 to 9.5% (w/w) , 6.5 to 9.0% (w/w) , 7.0 to 15% (w/w) , 7.0 to 10% (w/w) , 7.0 to 9.5% (w/w) , 7.0 to 9.0% (w/w) , 7.5 to 15% (w/w) , 7.5 to 10% (w/w) , 7.5 to 9.5% (w/w) , 7.5 to 9.0% (w/w) , 8.0 to 15% (w/w) , 8.0 to 10% (w/w) , 8.0 to 9.5% (w/w) , 8.0 to 9.0% (w/w) , 8.5 to 15% (w/w) , 8.5 to 10% (w/w) , 8.5 to 9.5% (w/w) , or 8.5 to 9.0% (w/w) . In some embodiments, sorbitol is in an amount of 8.8% (w/w) .

In some embodiments, propylene glycol is in an amount ranging from 5.0 to 25% (w/w) , such as from 5.0 to 20% (w/w) , 5.0 to 15% (w/w) , 5.0 to 14% (w/w) , 5.0 to 13% (w/w) , 5.0 to 12% (w/w) , 5.0 to 11% (w/w) , 6.0 to 25% (w/w) , 6.0 to 20% (w/w) , 6.0 to 15% (w/w) , 6.0 to 14% (w/w) , 6.0 to 13% (w/w) , 6.0 to 12% (w/w) , 6.0 to 11% (w/w) , 7.0 to 25% (w/w) , 7.0 to 20% (w/w) , 7.0 to 15% (w/w) , 7.0 to 14% (w/w) , 7.0 to 13% (w/w) , 7.0 to 12% (w/w) , 7.0 to 11% (w/w) , 8.0 to 25% (w/w) , 8.0 to 20% (w/w) , 8.0 to 15% (w/w) , 8.0 to 14% (w/w) , 8.0 to 13% (w/w) , 8.0 to 12% (w/w) , 8.0 to 11% (w/w) , 9.0 to 25% (w/w) , 9.0 to 20% (w/w) , 9.0 to 15% (w/w) , 9.0 to 14% (w/w) , 9.0 to 13% (w/w) , 9.0 to 12% (w/w) , or 9.0 to 11% (w/w) . In some embodiments, propylene glycol is in an amount of 10% (w/w) .

In some embodiments, the pH of the gel composition ranges from 6 to 9. In some embodiments, the pH of the gel composition ranges from 7 to 9. In some embodiments, the pH of the gel composition is 8.

Provided is a gel composition comprising (1) a single variable heavy chain domain antibody that binds to human IL-17A which comprises CDR1 having SEQ ID NO: 2, CDR2 having SEQ ID NO: 3, and CDR3 having SEQ ID NO: 4, (2) HPMC, (3) 0.5 to 2.0% (w/w) tris, 0.2 to 1.5% (w/w) glycine, 1.0 to 3.0% (w/w) glutamic acid, 1.0 to 3.0% (w/w) arginine, 5.0 to 10% (w/w) sorbitol, 5.0 to 25% (w/w) propylene glycol, and (5) water, wherein the pH of the gel composition ranges from 5 to 9.

In some embodiments, HPMC is in an amount of less than 5% (w/w) . In some embodiments, HPMC is in an amount ranging from 0.5 to 2.0 % (w/w) , such as from 0.6 to 1.5% (w/w) , 0.6 to 1.4% (w/w) , 0.6 to 1.3% (w/w) , 0.6 to 1.2% (w/w) , 0.6 to 1.1% (w/w) , 0.7 to 1.5% (w/w) , 0.7 to 1.4% (w/w) , 0.7 to 1.3% (w/w) , 0.7 to 1.2% (w/w) , 0.7 to 1.1% (w/w) , 0.8 to 1.5% (w/w) , 0.8 to 1.4% (w/w) , 0.8 to 1.3% (w/w) , 0.8 to 1.2% (w/w) , 0.8 to 1.1% (w/w) , 0.9 to 1.5% (w/w) , 0.9 to 1.4% (w/w) , 0.9 to 1.3% (w/w) , 0.9 to 1.2% (w/w) , or 0.9 to 1.1% (w/w) . In some embodiments, HPMC is in an amount of 1% (w/w) .

Provided is a method of preparing the gel composition as disclosed herein, comprising mixing a gel preparation with an active pharmaceutical ingredient (API) solution, wherein the gel preparation comprises glycine, tris, glutamic acid, arginine, sorbitol, propylene glycol, and HPMC, and the API solution comprises the single variable heavy chain domain antibody that binds to human IL-17A as disclosed herein, glycine, tris, glutamic acid, arginine, sorbitol, and propylene glycol.

Provided is a method of treating an autoimmune disease or skin disorder in a subject in need thereof comprising topically administering to the subject a therapeutically effective amount of the gel composition as disclosed herein.

In some embodiments, the skin disorder is psoriasis, spondyloarthropathies, uveitis, gingivitis, or atopic dermatitis.

In some embodiments, psoriasis is mild-to-moderate chronic plaque psoriasis (CPP) .

In some embodiments, before the treatment, the subject has Psoriasis Area and Severity Index (PASI) score ≤ 15.

In some embodiments, before the treatment, the subject has a lesion size of > 9 cm² to 100 cm².

In some embodiments, the method comprises administering to the subject a dose of 0.15-0.3 mg of the single variable heavy chain domain antibody that binds to human IL-17A as disclosed herein per square centimeter of the lesion size.

In some embodiments, the gel composition is delivered intradermally with no or without major systemic exposure.

DETAILED DESCRIPTION

I. Definitions

As used herein, the singular forms “a, ” “an, ” and “the” include plural referents unless the context clearly indciates otherwise.

Tirs refers to tromethamine. Glycine, glutamic acid, and arginine as used herein can be the L or D isomer. Sorbitol is D-sorbitol.

The term "antibody" , broadly refers to any immunoglobulin (Ig) molecule, or antigen binding portion thereof, comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains, or any functional fragment, mutant, variant, or derivation thereof, which retains the essential epitope binding features of an Ig molecule. Such mutant, variant, or derivative antibody formats are known in the art. In a full-length antibody, each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or V_H) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, C_H1, C_H2 and C_H3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or V_L) and a light chain constant region. The light chain constant region is comprised of one domain, C_L. The V_H and V_L regions can be further subdivided into regions of hypervariability, termed complementarity-determining regions (CDR) , interspersed with regions that are more conserved, termed framework regions (FR) . Each V_H and V_L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy terminus in the following order: FR1, CDR1 , FR2, CDR2, FR3, CDR3, FR4. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY) , class (e.g., IgG 1, lgG2, IgG 3, lgG4, IgAI and lgA2) or subclass.

The term "CDR" refers to the complementarity determining region within antibody variable sequences. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions. The term "CDR set" refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat is used herein. The terms "Kabat numbering" , "Kabat definitions" and "Kabat labeling" are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues which are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen binding portion thereof (Kabat et al., (1971) Ann. NY Acad. Sci. 190: 382-391 and Kabat, et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) .

The term "antigen binding site" refers to the part of the antibody or antibody fragment that comprises the area that specifically binds to an antigen. An antigen binding site may be provided by one or more antibody variable domains. Preferably, an antigen binding site is comprised within the associated V_H and V_L of an antibody or antibody fragment.

An antibody fragment is a portion of an antibody, for example as F (ab') 2 , Fab, Fv, sFv and the like. Functional fragments of a full length antibody retain the target specificity of a full length antibody. Recombinant functional antibody fragments, such as Fab (Fragment, antibody) , scFv (single chain variable chain fragments) and single domain antibodies (dAbs) have therefore been used to develop therapeutics as an alternative to therapeutics based on mAbs. scFv fragments (～25kDa) consist of the two variable domains, V_H and V_L. Naturally, V_H and V_L domain are non-covalently associated via hydrophobic interaction and tend to dissociate. However, stable fragments can be engineered by linking the domains with a hydrophilic flexible linker to create a single chain Fv (scFv) .

The smallest antigen binding fragment is the single variable fragment, namely the V_H or V_L domain. Binding to a light chain/heavy chain partner respectively is not required for target binding. Such fragments are used in single domain antibodies. A single domain antibody (-12 to 15 kDa) therefore consists of or comprises either the V_H or V_L domain.

The terms "single domain antibody, variable single domain or immunoglobulin single variable domain (ISV) " are all well known in the art and describe the single variable fragment of an antibody that binds to a target antigen. These terms are used interchangeably herein. As explained below, in preferred embodiments of the various aspects of the present disclosure, the single variable domain may be a domain antibody ("dAb" ) or an amino acid sequence that is suitable for use as a domain antibody, a single domain antibody (or an amino acid sequence that is suitable for use as a single domain antibody) other single variable domains, or any suitable fragment of any one thereof. Single domain antibodies have been described in the art; they are antibodies whose complementary-determining regions are part of a single domain polypeptide, for example a variable domain, such as a human heavy chain variable domain (V_H) polypeptide. Single variable domain antibodies wherein the variable domain is a V_HH domain are also within the scope of the present disclosure. V_HH domains are generally understood to designate camelid variable heavy chain domains For a general description of (single) domain antibodies, reference is also made to Ward et al. 1989 (Nature 341 (6242) : 544-546) and to Holt et al. 2003 (Trends Biotechnol. 21 (11) : 484-490) .

As used herein, the term V_H or "variable domain" refers to immunoglobulin variable domains defined by Kabat et al. (1991) . The numbering and positioning of CDR amino acid residues as used herein is in accordance with the well-known Kabat numbering convention.

Each single V_H domain antibody comprises three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1-CDR1-FR2-CDR2-FR3- CDR3-FR4. Thus, in one embodiment, the domain is a V_H domain with the following formula FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

"Homology" generally refers to the percentage of amino acid residues in the candidate sequence that are identical with the residues of the polypeptide with which it is compared, after aligning the sequences and in some embodiments after introducing gaps, if necessary, to achieve the maximum percent homology, and not considering any conservative substitutions as part of the sequence identity. Neither N-or C-terminal extensions, tags or insertions shall be construed as reducing identity or homology. Methods and computer programs for the alignment are well known.

“Psoriasis” is a chronic relapsing and remitting inflammatory skin disease affecting 2-3%of the world's population (～125m sufferers) that causes significant morbidity and decreased quality of life, largely due to clinical flare-ups and disfiguring lesions in visible areas of the skin, systemic manifestations and drug-related side effects. The common form of the disease, termed 'plaque psoriasis vulgaris' , is observed in more than 80%of patients and is characterized by erythematous scaly plaques (typically on elbows, knees, scalp and buttocks) which can vary in size from minimal to the involvement of the entire skin surface. Depending on the degree of body surface area (BSA) involvement, psoriasis can be categorized into mild (<3%BSA involvement) , moderate (3-10%BSA) and severe (>10%BSA) disease.

The term “subject” as used herein refers to animal (such as mammal) or human.

As used herein, a “therapeutically effective amount” refers to the amount that, when administered to a subject for treatment of a disease, is sufficient to cause a desired treatment effect in the subject, including for example, alleviation of the symptoms or stop of the progression of the disease.

The terms “treating” , “treatment” , or “treat” (of) a disease refers to slowing or arresting the development of a disease, providing relief from the symptoms or side-effects of the disease, and/or causing regression of the disease. The terms also refers to reduction of the occurrence of the disease in the subject when compared with a subject without the treatment.

As used herein, “w/w” refers to percentage "by weight, " which is synonymous with the term "by mass, " and indicates that a ratio or percentage defined herein is done according to weight rather than volume, thickness, or some other measure. Each numeric weight percentage is to be construed to include the interval under the ordinary-meaning of significant-figure based on rules of rounding.

“Topical delivery” , “topical administration, ” or “topically administering” is used herein to describe administration to a particular spot of the body and includes administration to the surface of the body as well as pulmonary administration by topical agents. Topical administration can be to the skin, eye, gums, a membrane or lung.

As used herein, glutamic acid, arginine, or sorbitol can be in any stereoisomers thereof. For example, each of glutamic acid, arginine, and sorbitol can be L-or D-form.

As used herein, the terms "formulation" or "composition" describe the active molecule in combination with a pharmaceutically acceptable excipient. The terms "pharmaceutical composition" or "pharmaceutical formulation" refer to preparations which are in such form as to permit the biological activity of the active ingredients to be effective. The term "pharmaceutically acceptable" refers to a compound or protein that can be administered to an animal (for example, a mammal) without significant adverse medical consequences.

II. Single Variable Heavy Chain Domain Antibody That Binds To Human IL-17A

In one embodiment, the single variable heavy chain domain antibody that binds to human IL-17A refers to a single domain antibody comprising a V_H domain capable of binding human IL-17A wherein said V_H domain has a sequence comprising a CDR3 sequence having the amino acid residues GEILPLYFDY (SEQ ID NO: 4) or sequence comprising a CDR3 with a sequence having at least 80%, for example at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%homology to SEQ ID NO: 4. In one embodiment, said CDR3 sequence is a variant of SEQ ID NO: 4 and comprises substitutions, insertions, additions or deletions of one or more amino acid residue of said SEQ ID NO: 4. V_H domains are generally understood to designate human variable heavy chain domains.

In one embodiment, said V_H domain comprises a CDR1 having the amino acid residues SYSMY (SEQ ID NO: 2) or a sequence with a sequence with 1, 2, 3, 4 or 5 amino acid modifications. In one embodiment, said CDR1 sequence is a variant of SEQ ID NO: 2 and comprises substitutions, insertions, additions or deletions of one or more amino acid residue of said SEQ ID NO: 2. In one embodiment, said V_H domain comprises a CDR2 having the amino acid residues EIKQDGSVQYYVSDVKG (SEQ ID NO: 3) or a sequence with at least 80%, for example at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%homology to SEQ ID NO: 3. In one embodiment, said CDR2 sequence is a variant of SEQ ID NO: 3 and comprises substitutions, additions, insertions or deletions of one or more amino acid residue of said SEQ ID NO: 3. In one embodiment, the V_H domain has a CDR1 , CDR2 and CDR3, wherein said CDR1 has SEQ ID NO: 2 or a variant thereof that comprises substitutions, additions or deletions of one or more amino acid residue, said CDR2 has SEQ ID NO: 3 or a variant thereof that comprises substitutions additions, insertions or deletions of one or more amino acid residue and said CDR3 has SEQ ID NO: 4 or a variant thereof that comprises substitutions additions, insertions or deletions of one or more amino acid residue. In one embodiment, the V_H domain has a CDR1, CDR2 and CDR3, wherein said CDR1 has SEQ ID NO: 2, said CDR2 has SEQ ID NO: 3 and said CDR3 has SEQ ID NO: 4.

In another embodiment, said V_H domain comprises or consists of SEQ ID NO: 1 or a sequence having at least 50%, 55%, 60%, 65%, 70%or 75%homology thereto. SEQ ID NO: 1 is shown below:

SEQ ID NO: 1 (CDR1, 2 and 3 in bold and underlined)

The IL-17 family of cytokines includes six members, IL-17/IL-17A, IL-17B, IL-17C, IL-17D, IL-17E/IL-25, and IL-17F, which are produced by multiple cell types. Members of this family have a highly conserved C-terminus containing a cysteine-knot fold structure. Most IL-17 proteins are secreted as disulfide-linked dimers, with the exception of IL-17B, which is secreted as a non-covalent homodimer.

Signaling by IL-17 family cytokines is mediated by members of the IL-17 receptor family, IL-17 R/IL-17 RA, IL-17 B R/IL-17 RB, IL-17 RC, IL-17 RD, and IL-17 RE. Activation of these receptors triggers intracellular pathways that induce the production of pro-inflammatory cytokines and anti-microbial peptides. IL-17A, IL-17F, and IL-17A/F are produced primarily by activated T cells and signal through an oligomerized receptor complex consisting of IL-17 RA and IL-17 RC. Ligand binding to this complex leads to recruitment of the intracellular adaptor proteins, Act1 and TRAF-6, and downstream activation of the transcription factors, NF kappa B, AP-1 , and C/EBP. IL-17E activates similar signaling pathways through a receptor complex formed by IL-17 RA and IL-17 B R/IL-17RB. Signaling by IL-17E induces Th2-type immune responses and may be involved in promoting the pathogenesis of asthma. Less is known about the signaling pathways activated by other IL-17 family cytokines. Recent studies suggest that IL-17C is produced primarily by epithelial cells and binds to a receptor complex consisting of IL-17 RA and IL-17 RE. Autocrine signaling by IL-17C in epithelial cells stimulates the production of anti-microbial peptides and pro-inflammatory cytokines, but like IL-17A, overexpression of IL-17C may contribute to the development of autoimmune diseases. Similar to IL-17E, IL-17B binds to IL-17 B R/IL-17 RB, but the major target cells and effects of IL-17B signaling have not been reported. In addition, the receptor for IL-17D and the ligand for IL-17 RD are currently unknown.

An IL-17A binding molecule as used herein binds to human IL-17A (Accession number Q16552 (Swiss-Prot) showing the full-length precursor IL-17A including the signal peptide, SEQ ID NO: 75) and/or cynomolgus monkey IL-17 (Uniprot G7P4U9) . Human IL-17A is a homodimer consisting of two 155 amino acid chains. Each polypeptide chain includes a 23 amino acid N-terminal peptide which is cleaved to produce a mature polypeptide of 132 residues. IL-17A binds to and exerts its effects via activation of the IL-17 receptors A and C. SEQ ID NO: 75

The terms "IL-17 binding molecule" , "anti-IL-17 binding molecule" "IL-17 binding protein" "anti-IL-17 single domain antibody" or "anti-IL-17 antibody" all refer to a molecule capable of binding to the human IL-17A antigen. Thus, as used herein, IL-17 usually refers to IL-17A, unless otherwise stated or unless the context directs otherwise. The binding reaction may be shown by standard methods (qualitative assays) including, for example, a binding assay, competition assay or a bioassay for determining the inhibition of IL-17 binding to its receptor or any kind of binding assays, with reference to a negative control test in which an antibody of unrelated specificity. The term "IL-17 binding molecule" includes an IL-17 binding protein or a part thereof that is capable of binding human IL-17A. In preferred embodiments, the IL-17 binding molecule is an antibody or fragment thereof, for example an anti-IL-17 single domain antibody. In a more preferred embodiment, the IL-17 binding molecule is an anti-IL-17 single domain antibody comprising a VH domain as described herein.

In one embodiment, the binding molecules of the present disclosure comprise a single variable domain antibody wherein said variable domain is a V_H domain. Such molecules are termed V_H single domain antibody or single V_H domain antibody. Human heavy chain variable domain antibodies are particularly preferred. Binding molecules that comprise a single variable domain antibody wherein said domain is a human VH domain are also termedV_H herein. Thus, in one embodiment, the IL-17A binding molecule is aV_H. is a registered trademark of Crescendo Biologics Ltd.

In one embodiment, the isolated binding molecules used in the formulation and other aspects of the present disclosure comprise or consist of at least one single domain antibody wherein said domain is a human V_H domain. Thus, in one aspect, the binding molecules of the disclosure comprise or consist of at least one immunoglobulin single variable heavy chain domain antibody that has a V_H domain, but is devoid of V_L domains.

IL17A binding molecules including single domain antibodies used in the compositions according to the present disclosure are isolated molecules. The term "isolated" single domain antibody refers to a single domain antibody that is substantially free of other single domain antibodies, antibodies or antibody fragments having different antigenic specificities. Moreover, an isolated single domain antibody may be substantially free of other cellular material and/or chemicals. As explained further herein, in preferred embodiments, the single V_H domain antibodies are generated in transgenic mice that express human V, D and J regions are used according to the present disclosure.

According to the various aspects and embodiments of the present disclosure, the variable domain of the single domain antibodies is preferably a human variable domain (human variable domains are typically termed V_H) . As used herein, a human V_H domain includes a fully human or substantially fully human V_H domain. As used herein, the term human V_H domain also includes V_H domains that are isolated from heavy chain only antibodies made by transgenic mice expressing fully human immunoglobulin heavy chain loci, in particular in response to an immunization with an antigen of interest, for example as described in WO2016/062990 and in the examples. In one embodiment, a human V_H domain can also include a V_H domain that is derived from or based on a human V_H domain amino acid or nucleic acid sequence encoding such V_H domain. Thus, the term includes variable heavy chain regions derived from or encoded by human germline immunoglobulin sequences. A substantially human V_H domain or V_H domain that is derived from or based on a human V_H domain may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced in vitro, e.g. by random or site-specific mutagenesis, or introduced by somatic mutation in vivo) . The term "human V_H domain" therefore also includes a substantially human V_H domain wherein one or more amino acid residue has been modified. For example, a substantially human V_H domain may include up to 10, for example 1, 2, 3, 4 or 5 amino acid modifications compared to a fully human sequence.

However, the term "human V_H domain" or "substantially human V_H domain" , as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. In some embodiments, the term "human V_H domain" , as used herein, does not include camelized V_H domains, that is human V_H domains that have been specifically modified, for example in vitro by conventional mutagenesis methods to select predetermined positions in the V_H domains sequence and introduce one or more point mutation at the predetermined position to change one or more predetermined residue to a specific residue that can be found in a camelid V_HH domain.

Thus, in one embodiment, the IL-17A binding molecule is selected from at least one single domain antibody comprising a human V_H domain capable of binding human IL-17A. In one embodiment, the IL-17A binding molecule is selected from at least one single V_H domain antibody capable of binding human IL-17A. In another embodiment, the V_H domain comprises or consists of SEQ ID NO: 1 or a sequence having at least 50%, 55%, 60%, 65%, 70%or 75%homology thereto.

Modifications to the V_H framework may be made to improve binding and/or other properties. For example, the V_H domain may comprise C or N terminal extensions.

As set out herein, in one embodiment, the compositions of the present disclosure comprise an effective amount of at least one single V_H domain antibody capable of binding human IL-17A wherein said V_H domain comprises SEQ ID NO: 1 or a sequence having at least 50%, 55%, 60%, 65%, 70%or 75%homology thereto. In one embodiment, said sequence homology or identity is at least 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%.

In some embodiments, the present disclosure provides a single V_H domain antibody that is a variant of the single VH domain antibody as defined in SEQ ID NO: 1 having one or more amino acid modifications compared to SEQ ID NO: 1 and which retains a biological function of the single domain antibody. The modification can be one or more substitution, deletion, insertion or other addition of an amino acid residue. Variants can be selected from SEQ ID NOs: 5 to 73 as shown in Table 1.

In one embodiment, a variant single V_H domain antibody can be sequence engineered. Modifications include at least one substitution, deletion or insertion of one or more codons encoding the single domain antibody or polypeptide that results in a change in the amino acid sequence as compared with the native sequence V_H single domain antibody or polypeptide. Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine, i.e., conservative amino acid replacements. Insertions or deletions may optionally be in the range of about 1 to 10, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids. The variation allowed may be determined by systematically making insertions, deletions or substitutions of amino acids in the sequence and testing the resulting variants for activity exhibited by the full-length or mature native sequence. A variant of the V_H single domain antibody defined in SEQ ID NO: 1 has preferably at least 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence homology to the non-variant molecule, preferably at least 95%, 96%, 97%, 98%or 99%sequence homology.

In one embodiment, the modification is a conservative sequence modification. As used herein, the term "conservative sequence modifications" is intended to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody of the present disclosure by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine) , acidic side chains (e.g., aspartic acid, glutamic acid) , uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan) , nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine) , beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine) . Thus, one or more amino acid residues within the CDR regions of a single domain antibody of the present disclosure can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested for retained function (i.e., the functions set forth in (c) through (I) above) using the functional assays described herein.

In some embodiments, a variant of V_H single domain antibody as defined in SEQ ID NO: 1 can be used in the composition as disclosed herein wherein the variant comprises one or more sequence modification and has improvements in one or more of a property such as binding affinity, specificity, thermostability, expression level, effector function, glycosylation, reduced immunogenicity, or solubility as compared to the unmodified single domain antibody.

In one embodiment, modifications can be made to decrease the immunogenicity of the single domain antibody. For example, one approach is to revert one or more framework residues to the corresponding human germline sequence. More specifically, a single domain antibody that has undergone somatic mutation may contain framework residues that differ from the germline sequence from which the single domain antibody is derived. Such residues can be identified by comparing the single domain antibody framework sequences to the germline sequences from which the single domain antibody is derived.

To return one or more of the amino acid residues in the framework region sequences to their germline configuration, the somatic mutations can be "backmutated" to the germline sequence by, for example, site-directed mutagenesis or PCR-mediated mutagenesis.

Another type of framework modification involves mutating one or more residues within the framework region, or even within one or more CDR regions, to remove T cell epitopes to thereby reduce the potential immunogenicity of the antibody.

In still another embodiment, the glycosylation of an antibody is modified. For example, an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation) . Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen. Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence. For example, one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such aglycosylation may increase the affinity of the antibody for antigen.

In one embodiment, the V_H domain comprises or consists of SEQ ID NO: 1, but comprises one or more amino acid substitutions, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In one embodiment, the one or more amino acid substitution is in one or more of the framework areas, for example FR1, FR2, FR3 and/or FR4. In another embodiment, the one or more amino acid substitution is in one or more of the CDRs. In another embodiment, the V_H domain comprises or consists of SEQ ID NO: 1, but comprises 1 , 2, 3, 4 or 5 amino acid substitutions in a CDR sequences, for example a CDR1 , CDR2 or CDR3. For example, in CDR3 (SEQ ID NO: 4) of SEQ ID NO: 1 or a variant thereof, one or more Y may be replaced with H.

In one embodiment, the V_H single domain antibody is selected from one of the amino acid sequences shown below in Table 1 (Table 1 shows the full length VH amino acid sequence; sequences for FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4 respectively are shown in the separate columns of Table 1 for ease of reference) .

Table 1.

The C terminus of a V_H domain ends in VTVSS (SEQ ID NO: 77) . In one embodiment of the binding molecules described herein, the V_H domain comprises additional C terminal residues, for example 1 to 15 additional C terminal residues, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 additional amino acids. In one embodiment, the V_H domain comprises additional C terminal residues of from 1 to 15 amino acid residues, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 wherein said residues are residues of the C_H1 domain. In other words, the V_H domain is extended into the C_H1 domain. In one embodiment, said extension comprises at least one alanine residue, for example a single alanine residue, a pair of alanine residues or a triplet of alanine residues. Such extended V_H domains are within the scope of the present disclosure. In one embodiment, the C terminus of a V_H domain is truncated and one or more of VTVSS (SEQ ID NO: 77) may be deleted. In one embodiment, one or more of VTVSS (SEQ ID NO: 77) may be substituted for another residue.

Also within the scope of the present disclosure are V_H domains that comprise additional C or N terminal residues, for example linker residues and /or labels of tags, such as His tags, e.g., hexa-His. In one embodiment, the V_H domain comprises or consists of a variant of SEQ ID NO.1 and is designated V_H 1.1 (SEQ ID NO: 74) having the following amino acid sequence as shown in the examples.

III. Gel Composition

In some embodiments, the gel composition comprises at least one anti-IL-17A binding molecule, for example a V_H single domain antibody as described herein. In some embodiments, more than one anti-IL-17A V_H single domain antibody may be present. In one embodiment, the gel composition comprises a biparatopic or bivalent anti-IL-17A V_H single domain antibody. In another embodiment, the composition further comprises a second antibody or antibody fragment which is not a V_H single domain antibody. The anti-IL-17A V_H single domain antibody can also be used and administered in conjunction with other agents that serve to enhance and/or complement the effectiveness of the antibodies.

Multispecific binding molecules for use in the formulation of the present disclosure can be constructed using methods known in the art. In biparatopic or multispecific binding molecules, the moieties are generally joined by a linker, for example a polypeptide linker. Suitable linkers, for example comprising linker including GS residues such as (Gly4Ser) n, where n=from 1 to 10, e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10, are known in the art.

If desired, bispecific or multispecific binding molecules can be linked to an antibody Fc region or a fragment thereof, comprising one or both of C_H2 and C_H3 domains, and optionally a hinge region. For example, vectors encoding bispecific or multispecific binding molecules linked as a single nucleotide sequence to an Fc region or a fragment thereof can be used to prepare such polypeptides. Exemplary second antigen targets include leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD4, CD45, CD58, CD80, CD86 or their ligands; TNF, IL-1 IL-15, IL-23, IL-6 or CD20. This list is not limited to the agents mentioned.

In one embodiment, a second (or third, fourth, fifth etc) moiety can be linked to the V_H domain that binds IL-17A, for example to prolong the half-life of the binding molecule. This moiety may comprise a protein, for example an antibody, or part thereof that binds a serum albumin, e.g., human serum albumin (HSA) . In one embodiment, the second moiety may comprise a V_H domain that binds serum albumin, e.g. human serum albumin (HSA) .

The second moiety may comprise a serum albumin, e.g. a human serum albumin (HSA) or a variant thereof such as C34S. Further provided is a binding molecule as described herein comprising a V_H domain and an Fc domain or a fragment thereof, e.g., wherein the V_H domain is connected to an Fc domain or a fragment thereof. Further provided is a binding molecule that comprises a second variable domain that specifically binds a second antigen, where the second antigen is an antigen other than human IL-17A. The second antigen may be a cluster of differentiation (CD) molecule or a Major Histocompatibility Complex (MHC) Class II molecule.

Binding molecules described herein can be obtained by using transgenic knock out (KO) rodents, for example mice, that lack endogenous immunoglobulins. Preferably, the mouse does not comprise a functional heavy chain, lambda light chain and kappa light chain locus. The loci may be rendered non-functional through deletion, insertion, gene editing or other techniques known in the art. A mouse having a non-functional endogenous lambda and kappa L-chain loci may, for example, be made as disclosed in WO 2003/000737, which is hereby incorporated by reference in its entirety. A mouse having a non-functional heavy chain locus may, for example, be made as disclosed in WO 2004/076618, which is hereby incorporated by reference in its entirety. For example, the transgenic mouse comprises a vector, for example a Yeast Artificial Chromosome (YAC) for expressing a heterologous heavy chain locus. YACs are vectors that can be employed for the cloning of very large DNA inserts in yeast. As well as comprising all three cis-acting structural elements essential for behaving like natural yeast chromosomes (an autonomously replicating sequence (ARS) , a centromere (CEN) and two telomeres (TEL) ) , their capacity to accept large DNA inserts enables them to reach the minimum size (150 kb) required for chromosome-like stability and for fidelity of transmission in yeast cells. The construction and use of YACs is well known in the art (e.g., Bruschi, C. V. and Gjuracic, K. Yeast Artificial Chromosomes, Encyclopaedia of Life Sciences 2002 Macmillan Publishers Ltd, Nature Publishing Group /www. els. net) .

For example, the YAC may comprise a plethora of human V_H, D and J genes in combination with mouse immunoglobulin constant region genes lacking C_H 1 domains, mouse enhancer and regulatory regions, as disclosed in WO2016/062990, which is hereby incorporated by reference in its entirety.

Transgenic mice can be created according to standard techniques. The transgenic mouse may be immunized with an IL-17A antigen and a library of sequences comprising V_H domain sequences from said mouse is then generated. Sequences comprising V_H domain sequences from said libraries are isolated using standard techniques.

As shown in the examples, gel compositions according to the present disclosure are stable under various conditions. As used herein, the term "stability" generally relates to maintaining the integrity or to minimizing the degradation, denaturation, aggregation or unfolding of a biologically active agent, i.e. the IL-17 binding molecule described herein. Stability of the active molecule in the composition can be determined by various means known to the skilled person.

In some embodiments, stability refers to a formulation having low to undetectable levels of aggregation, containing no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1 %and no more than 0.5%aggregation by weight of protein as measured by high performance size exclusion chromatography (HPSEC) , static light scattering (SLS) , Fourier Transform Infrared Spectroscopy (FTIR) , circular dichroism (CD) , urea-induced protein unfolding techniques, intrinsic tryptophan fluorescence, differential scanning calorimetry, l-anilino-8-naphthalenesulfonic acid (ANS) protein binding techniques or other techniques known in the art.

In one embodiment, the compositions of the present disclosure maintain an improved stability and/or aggregation profile when stored for extended periods of time at room temperature (between about 20℃ to about 25℃) . In one embodiment, the compositions of the present disclosure maintain an improved stability and/or aggregation profile when stored for extended periods of time at reduced temperatures (below about 10℃, between about 2℃ to about 8℃, for example, at 5℃) , for up to about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years or 5 years.

In another embodiment, the compositions of the present disclosure maintain an improved stability and/or aggregation profile when stored for extended periods at low temperatures, for example 0℃ or below, such from 0℃ to -70℃, such as -1 ℃, -2℃, -3℃, -4℃, -5℃, -6℃, - 7℃, -8℃, -9℃ or -10℃ for up to about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years or 5 years.

The gel composition as disclosed herein comprises (1) a single variable heavy chain domain antibody that binds to human IL-17A as disclosed herein, (2) a gelling agent, (3) tris, glycine, glutamic acid, arginine, sorbitol, propylene glycol, and (5) water, wherein the pH of the gel composition ranges from 5 to 9. The gel composition can be in the form of sprayable hydrogel, roll on formulations of the same, occlusive hydrogel patches, and /or any patch forms.

In some embodiments, the gel composition comprises 0.5 to 2.0% (w/w) tris, 0.2 to 1.5% (w/w) glycine, 1.0 to 3.0% (w/w) glutamic acid, 1.0 to 3.0% (w/w) arginine, 5.0 to 10% (w/w) sorbitol, and 5.0 to 25% (w/w) propylene glycol.

The gelling agent is in an amount of less than 5% (w/w) of the gel composition. While there are many known gelling agents, the art of forming a desired gel can be viewed as being unpredictable. As Example 2 demonstrates, xanthan gum and Carbopol 980 resulted in cloudy gels and Sepineo P 600 failed to form a gel. HPC can provide a clear gel when purified water was used to make up the formulation but cannot form a gel when inactive buffer was used as make-up. Among the three cellulose derivatives (HPC, HEC, and HPMC) , HPMC led to the formation of a more stable and clear gel. The types of HPMC that can be used in the gel formulation as disclosed herein include those with nominal viscosity ranging from 3-200,000 (mPA·s) as measured using NF/EP/JP viscosity method (e.g., based on a standard Brookfield method, using the RVT spindle at 20 rpm on 2%solutions maintained at 20 C, based on dried product) . Examples of HPMC can be Hypromellose 2906 “F” types, 2910 “E” types, and 2208 “K” types, all available from Ashland.

In some embodiments, the gel composition further comprises preservative. The experiments also showed that, compared to benzyl alcohol or phenoxyethanol as a preservative, parabens and/or their salt forms lead to the formation of a clear gel which is physically and chemically stable.

The gel composition can further comprise known pharmaceutically acceptable excipients as deemed appropriate, such as antioxidant. Additional known pharmaceutical excipients, such as physiologically acceptable carriers and/or additives suitable for use in the formulations of the present disclosure are known in the art, e.g., as listed in "The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003) incorporated herein by reference.; and Remington: the Science and Practice of Pharmacy, 21 st edition, Gennaro, Ed., Lippincott Williams &Wilkins (2005) incorporated herein by reference. The term "physiologically acceptable carrier" refers to a carrier which does not have a significant detrimental impact on the treated host and which retains the therapeutic properties of the compound with which it is administered.

In one embodiment, the gel composition as disclosed herein is formulated for topical administration to the skin, gum or surface of the eye.

IV. Method of Use

The present disclosure further relates to a method for the prevention and/or treatment of a disease comprising administering a gel composition disclosed herein to a subject in need thereof.

The term "subject" for purposes of treatment includes any subject, and preferably is a subject who is in need of the treatment of the targeted pathologic condition for example autoimmune disease. For purposes of prevention, the subject is any subject, and preferably is a subject that is at risk for, or is predisposed to, developing the targeted pathologic condition for example autoimmune disease. The term "subject" is intended to include living organisms, e.g., prokaryotes and eukaryotes. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the subject is a human. More in particular, provided is a method for the prevention and/or treatment of a disease selected from the non-limiting group consisting of the diseases and disorders listed herein, said method comprising administering, to a subject in need thereof, a pharmaceutically effective amount of the gel composition as disclosed herein. Examples of the immune related diseases that can be treated will be clear to the skilled person based on the disclosure herein, and for example include autoimmune diseases, inflammatory conditions, allergies and allergic conditions, hypersensitivity reactions, severe infections, and organ or tissue transplant rejection.

In another aspect, the present disclosure relates to the use of the gel composition as disclosed herein in the manufacture of a medicament for the treatment of a disease, selected from the non-limiting group consisting of the diseases and disorders listed herein, for example autoimmune disease, inflammatory conditions, allergies and allergic conditions, hypersensitivity reactions, severe infections, and organ or tissue transplant rejection.

According to the different aspects above, the disease may be selected from the following non-limiting list: psoriasis, systemic lupus erythematosis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, spondyloarthropathies, systemic sclerosis, idiopathic inflammatory myopathies, Sjogren's syndrome, systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, thyroiditis, diabetes mellitus, immune-mediated renal disease, demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain Barre syndrome, and chronic inflammatory demyelinating polyneuropathy, hepatobiliary diseases such as infectious, autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis, inflammatory bowel disease, gluten-sensitive enteropathy, and Whipple's disease, autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria, immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis, autoimmune haematological disorders (including e.g., hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia) , autoimmune inflammatory bowel disease (including e.g., ulcerative colitis, Crohn's disease and Irritable Bowel Syndrome) , transplantation associated diseases including graft rejection and graft-versus-host-disease.

The gel composition as disclosed herein is also useful for the treatment, prevention, or amelioration of asthma, bronchitis, pneumoconiosis, pulmonary emphysema, and other obstructive or inflammatory diseases of the airways.

In some embodiments, the disease is a skin disease. In some embodiments, the disease is selected from psoriasis, spondyloarthropathies, uveitis, gingivitis atopic dermatitis and asthma. In some embodiments, psoriasis that can be treated is mild-to-moderate chronic plaque psoriasis (CPP) .

The gel composition as disclosed herein is useful for treating undesirable acute and hyperacute inflammatory reactions which are mediated by IL-17, or involve IL-17 production, or the promotion of TNF release by IL-17, e.g., acute infections, for example septic shock (e.g., endotoxic shock and adult respiratory distress syndrome) , meningitis, pneumonia; and severe burns; and for the treatment of cachexia or wasting syndrome associated with morbid TNF release, consequent to infection, cancer, or organ dysfunction, especially AIDS-related cachexia, e.g., associated with or consequential to HIV infection. A composition of the present disclosure are particularly useful for treating diseases of bone metabolism including osteoarthritis, osteoporosis and other inflammatory arthritis, and bone loss in general, including age-related bone loss, and in particular periodontal disease.

The gel composition as disclosed herein may be administered as the sole active ingredient or in combination with one or more other drug, e.g., an immunosuppressive or immunomodulating agent or other anti-inflammatory agent, e.g., for the treatment or prevention of diseases mentioned above. For example, the gel composition as disclosed herein maybe used in combination with immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40. CD45, CD58, CD80, CD86 or their ligands; other immunomodulatory compounds, e.g., a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g., an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g., CTLA4lg (e.g., designated ATCC 68629) or a mutant thereof, e.g., LEA29Y; adhesion molecule inhibitors, e.g., LFA-I antagonists, ICAM-I or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or a chemotherapeutic agent, e.g., paclitaxel, gemcitabine, cisplatinum, doxorubicin or 5-fluorouracil; anti TNF agents, e.g., monoclonal antibodies to TNF, e.g., infliximab, adalimumab, CDP870, or receptor constructs to TNF-RI or TNF-RII, e.g., PEG-TNF-RI; blockers of proinflammatory cytokines, IL-I blockers, e.g., Anakinra or IL-I trap, AAL160, ACZ 885, IL-6 blockers; chemokines blockers, e.g., inhibitors or activators of proteases, e.g., metalloproteases, anti-IL-15 antibodies, anti-IL-6 antibodies, anti-CD20 antibodies, NSAIDs, such as aspirin or an anti-infectious agent. This list is not limited to the agents mentioned.

The gel composition as disclosed herein may be administered and/or co-administered at the same time or at a different time as the other drug e.g., simultaneously, separately or sequentially. The gel compositions as disclosed herein are of particular use in topical delivery.

In some embodiments, it can be desirable to administer the gel composition as disclosed herein locally to the area in need of treatment.

Thus, in some embodiments, administration of the gel composition as disclosed herein is by topical administration to healthy or diseased skin. The active agent, e.g., the single variable heavy chain domain antibody that binds to human IL-17A is capable of penetrating at least the outer layer of the skin and can therefore be delivered intradermally or transdermally.

Accordingly, in one embodiment of the various aspects of the present disclosure, topical delivery of the composition or binding molecule of the present disclosure to the skin is direct delivery into the skin for local non-systemic exposure. In another embodiment, topical delivery of the composition or binding molecule of the present disclosure to the skin is direct delivery to the skin to provide systemic exposure following penetration through all layers of the skin. The skin that is treated may be diseased or healthy skin. In a preferred embodiment, the skin disease is psoriasis or atopic dermatitis.

In some embodiments, the surface area to which it is applied is 1 %-30%of the body surface area, for example 1 %-10%or 1-20%. Administration may thus be to 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24%, 25%, 27%, 26%, 28%, 29%or 30%of body surface area. In one embodiment, the disease state is mild. In another embodiment, the disease state is moderate. In another embodiment, the disease state is severe. For the treatment of psoriasis, administration is to areas affected, typically one or more area selected from elbows, knees, palms of hands, scalp, soles of feet, genitals, upper thighs, groin, buttocks, face and torso. For the treatment of atopic dermatitis administration is to areas affected, typically one or more area selected from face, forearms and wrists.

The amount of the active agent (e.g., the single variable heavy chain domain antibody that binds to human IL-17A as disclosed herein) of the present disclosure that is effective/active in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. The compositions of the present disclosure comprise an effective amount of the active agent as disclosed herein such that a suitable dosage will be obtained. The correct dosage of the compounds will vary according to the particular formulation, the mode of application, and its particular site, host and the disease being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account.

According to one embodiment, the dose contains an amount of the active agent that is about 1 μg/kg, about 10 μg/kg, about 20 μg/kg, about 25 μg/kg, about 50 μg/kg, about 100 μg/kg, about 200 μg/kg, about 250 μg/kg, about 500 μg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, or about 1 1 mg/kg (of mass of the mammal to which the dose it to be administered) . In some embodiments, the dose contains about 20 μg/kg, about 25 μg/kg, about 50 μg/kg, about 100 μg/kg, about 200 μg/kg, about 250 μg/kg, 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg of the active agent. Dosage regimens may depend on the pattern of pharmacokinetic decay that the practitioner wishes to achieve. For example, in some embodiments, dosing from one-four times a week is contemplated. Even less frequent dosing may be used. In some embodiments, the dose is administered once every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 15 weeks, every 20 weeks, every 25 weeks, or longer. In some embodiments, the dose is administered once every 1 month, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, or longer. The progress of this therapy is easily monitored by conventional techniques and assays. The dosing regimen can vary over time. The IL17 binding molecule used in the compositions of the present disclosure for medical treatment is as described elsewhere herein. For example, it can be selected from a VH single domain antibody comprising the CDR1, CDR2 and CDR3 sequences SEQ ID NOs. 2, 3 and 4 as described herein. In one embodiment, the VH single domain antibody is selected from Table 1. In one embodiment, the V_H single domain antibody comprises SEQ ID NO: 1 or a sequence having at least 75%homology thereto, for example SEQ ID NO: 74.

In some embodiments, the dose is in an amount relative to the lesion size of the skin disorder to be treated. For example, the dose can be 0.1-0.5 mg/cm², such as 0.15-0.3 mg/cm² of the lesion size.

In another aspect, the present disclosure provides a kit or article of manufacture comprising a composition of the present disclosure useful for the treatment of a disease described above. The kit can comprise a container with the composition of interest, for example in the form suitable for topical administration and optionally instructions for use.

The IL17 binding molecule used in each embodiments/aspects can be selected from a VH single domain antibody comprising the CDR1 , CDR2 and CDR3 sequences SEQ ID Nos. 2, 3 and 4 as described herein. In one embodiment, the VH single domain antibody is selected from Table 1. In one embodiment, the VH single domain antibody comprises SEQ ID NO: 1 or a sequence having at least 75%homology thereto, for example SEQ ID NO: 74.

V. Method of Preparation

In another aspect, the present disclosure provides a method of preparing the gel composition as disclosed herein, comprising mixing a gel preparation with an aqueous active pharmaceutical ingredient (API) solution, wherein the gel preparation comprises glycine, tris, glutamic acid, arginine, sorbitol, propylene glycol, HPMC, and water, the API solution comprises the single variable heavy chain domain antibody that binds to human IL-17A as disclosed herein, glycine, tris, glutamic acid, arginine, sorbitol, propylene glycol, and water.

In some embodiments, the gel preparation is in an amount of 15-75 % (w/w) relative to the weight of the gel composition, and the aqueous API solution is in an amount of 25-85% (w/w) relative to the weight of the gel composition.

In some embodiments, the gel preparation comprises (1) an aqueous buffer comprising a) glycine, tris, glutamic acid, arginine, and sorbitol, (2) propylene glycol, and (3) HPMC, wherein glycine, tris, glutamic acid, arginine, sorbitol, propylene glycol, and HPMC are in a respective amount such that the mixed composition of the gel preparation and the API solution is within the scope of the gel composition as disclosed herein. In some embodiment, the aqueous buffer is in an amount of 10-65% (w/w) relative to the weight of the gel composition.

In some embodiments, tris in the gel preparation is in an amount ranging from 0.5 to 2.0% (w/w) relative to the weight of the aqueous buffer, such as from 0.6 to 1.5% (w/w) , 0.6 to 1.4% (w/w) , 0.6 to 1.3% (w/w) , 0.6 to 1.2% (w/w) , 0.6 to 1.1% (w/w) , 0.7 to 1.5% (w/w) , 0.7 to 1.4% (w/w) , 0.7 to 1.3% (w/w) , 0.7 to 1.2% (w/w) , 0.7 to 1.1% (w/w) , 0.8 to 1.5% (w/w) , 0.8 to 1.4% (w/w) , 0.8 to 1.3% (w/w) , 0.8 to 1.2% (w/w) , 0.8 to 1.1% (w/w) , 0.9 to 1.5% (w/w) , 0.9 to 1.4% (w/w) , 0.9 to 1.3% (w/w) , 0.9 to 1.2% (w/w) , or 0.9 to 1.1% (w/w) . In some embodiments, tris is in an amount of 1.2% (w/w) .

In some embodiments, glycine in the gel preparation is in an amount ranging from 0.2 to 1.5% (w/w) relative to the weight of the aqueous buffer, such as from 0.3 to 1.5% (w/w) , 0.3 to 1.0% (w/w) , 0.3 to 0.9% (w/w) , 0.3 to 0.8% (w/w) , 0.3 to 0.7% (w/w) , 0.4 to 1.5% (w/w) , 0.4 to 1.0% (w/w) , 0.4 to 0.9% (w/w) , 0.4 to 0.8% (w/w) , 0.4 to 0.7% (w/w) , 0.5 to 1.5% (w/w) , 0.5 to 1.0% (w/w) , 0.5 to 0.9% (w/w) , 0.5 to 0.8% (w/w) , or 0.5 to 0.7% (w/w) . In some embodiments, glycine is in an amount of 0.8% (w/w) .

In some embodiments, arginine in the gel preparation is in an amount ranging from 1.0 to 3.0% (w/w) relative to the weight of the aqueous buffer, such as from 1.1 to 3.0% (w/w) , 1.1 to 2.5% (w/w) , 1.1 to 2.0% (w/w) , 1.2 to 3.0% (w/w) , 1.2 to 2.5% (w/w) , 1.2 to 2.0% (w/w) , 1.3 to 3.0% (w/w) , 1.3 to 2.5% (w/w) , 1.3 to 2.0% (w/w) , 1.4 to 3.0% (w/w) , 1.4 to 2.5% (w/w) , 1.4 to 2.0% (w/w) , 1.5 to 3.0% (w/w) , 1.5 to 2.5% (w/w) , 1.5 to 2.0% (w/w) , 1.6 to 3.0% (w/w) , 1.6 to 2.5% (w/w) , 1.6 to 2.0% (w/w) , 1.7 to 3.0% (w/w) , 1.7 to 2.5% (w/w) , 1.7 to 2.0% (w/w) , 1.8 to 3.0% (w/w) , 1.8 to 2.5% (w/w) , 1.8 to 2.0% (w/w) , 1.9 to 3.0% (w/w) , 1.9 to 2.5% (w/w) , or 1.9 to 2.0% (w/w) . In some embodiments, arginine is in an amount of 2.2% (w/w) .

In some embodiments, glutamic acid is in an amount ranging from 1.0 to 3.0% (w/w) relative to the weight of the aqueous buffer, such as from 1.1 to 3.0% (w/w) , 1.1 to 2.5% (w/w) , 1.1 to 2.0% (w/w) , 1.2 to 3.0% (w/w) , 1.2 to 2.5% (w/w) , 1.2 to 2.0% (w/w) , 1.3 to 3.0% (w/w) , 1.3 to 2.5% (w/w) , 1.3 to 2.0% (w/w) , 1.4 to 3.0% (w/w) , 1.4 to 2.5% (w/w) , 1.4 to 2.0% (w/w) , 1.5 to 3.0% (w/w) , 1.5 to 2.5% (w/w) , 1.5 to 2.0% (w/w) , 1.6 to 3.0% (w/w) , 1.6 to 2.5% (w/w) , 1.6 to 2.0% (w/w) , 1.7 to 3.0% (w/w) , 1.7 to 2.5% (w/w) , 1.7 to 2.0% (w/w) , 1.8 to 3.0% (w/w) , 1.8 to 2.5% (w/w) , 1.8 to 2.0% (w/w) , 1.9 to 3.0% (w/w) , 1.9 to 2.5% (w/w) , or 1.9 to 2.0% (w/w) . In some embodiments, arginine is in an amount of 1.8% (w/w) .

In some embodiments, sorbitol is in an amount of less than 15% (w/w) relative to the weight of the aqueous buffer. In some embodiments, sorbitol is in an amount ranging from 5.0 to 15% (w/w) , such as from 5.5 to 15% (w/w) , 5.5 to 10% (w/w) , 5.5 to 9.5% (w/w) , 5.5 to 9.0% (w/w) , 6.0 to 15% (w/w) , 6.0 to 10% (w/w) , 6.0 to 9.5% (w/w) , 6.0 to 9.0% (w/w) , 6.5 to 15% (w/w) , 6.5 to 10% (w/w) , 6.5 to 9.5% (w/w) , 6.5 to 9.0% (w/w) , 7.0 to 15% (w/w) , 7.0 to 10% (w/w) , 7.0 to 9.5% (w/w) , 7.0 to 9.0% (w/w) , 7.5 to 15% (w/w) , 7.5 to 10% (w/w) , 7.5 to 9.5% (w/w) , 7.5 to 9.0% (w/w) , 8.0 to 15% (w/w) , 8.0 to 10% (w/w) , 8.0 to 9.5% (w/w) , 8.0 to 9.0% (w/w) , 8.5 to 15% (w/w) , 8.5 to 10% (w/w) , 8.5 to 9.5% (w/w) , or 8.5 to 9.0% (w/w) . In some embodiments, sorbitol is in an amount of 10% (w/w) .

In some embodiments, propylene glycol in the gel preparation is in an amount to make the gel composition comprises propylene glycol in an amount as disclosed herein.

In some embodiments, HPMC in the gel preparation is in an amount to make the gel composition comprises HPMC in an amount as disclosed herein.

In some embodiments, In some embodiments, tris in the aqueous API solution is in an amount ranging from 0.5 to 2.0% (w/w) relative to the weight of the aqueous API solution, such as from 0.6 to 1.5% (w/w) , 0.6 to 1.4% (w/w) , 0.6 to 1.3% (w/w) , 0.6 to 1.2% (w/w) , 0.6 to 1.1% (w/w) , 0.7 to 1.5% (w/w) , 0.7 to 1.4% (w/w) , 0.7 to 1.3% (w/w) , 0.7 to 1.2% (w/w) , 0.7 to 1.1% (w/w) , 0.8 to 1.5% (w/w) , 0.8 to 1.4% (w/w) , 0.8 to 1.3% (w/w) , 0.8 to 1.2% (w/w) , 0.8 to 1.1% (w/w) , 0.9 to 1.5% (w/w) , 0.9 to 1.4% (w/w) , 0.9 to 1.3% (w/w) , 0.9 to 1.2% (w/w) , or 0.9 to 1.1% (w/w) . In some embodiments, tris is in an amount of 1% (w/w) .

In some embodiments, glycine in the aqueous API solution is in an amount ranging from 0.2 to 1.5% (w/w) relative to weight of the aqueous API solution, such as from 0.3 to 1.5% (w/w) , 0.3 to 1.0% (w/w) , 0.3 to 0.9% (w/w) , 0.3 to 0.8% (w/w) , 0.3 to 0.7% (w/w) , 0.4 to 1.5% (w/w) , 0.4 to 1.0% (w/w) , 0.4 to 0.9% (w/w) , 0.4 to 0.8% (w/w) , 0.4 to 0.7% (w/w) , 0.5 to 1.5% (w/w) , 0.5 to 1.0% (w/w) , 0.5 to 0.9% (w/w) , 0.5 to 0.8% (w/w) , or 0.5 to 0.7% (w/w) . In some embodiments, glycine is in an amount of 0.7% (w/w) .

In some embodiments, arginine in the aqueous API solution is in an amount ranging from 1.0 to 3.0% (w/w) relative to the weight of the aqueous API solution, such as from 1.1 to 3.0% (w/w) , 1.1 to 2.5% (w/w) , 1.1 to 2.0% (w/w) , 1.2 to 3.0% (w/w) , 1.2 to 2.5% (w/w) , 1.2 to 2.0% (w/w) , 1.3 to 3.0% (w/w) , 1.3 to 2.5% (w/w) , 1.3 to 2.0% (w/w) , 1.4 to 3.0% (w/w) , 1.4 to 2.5% (w/w) , 1.4 to 2.0% (w/w) , 1.5 to 3.0% (w/w) , 1.5 to 2.5% (w/w) , 1.5 to 2.0% (w/w) , 1.6 to 3.0% (w/w) , 1.6 to 2.5% (w/w) , 1.6 to 2.0% (w/w) , 1.7 to 3.0% (w/w) , 1.7 to 2.5% (w/w) , 1.7 to 2.0% (w/w) , 1.8 to 3.0% (w/w) , 1.8 to 2.5% (w/w) , 1.8 to 2.0% (w/w) , 1.9 to 3.0% (w/w) , 1.9 to 2.5% (w/w) , or 1.9 to 2.0% (w/w) . In some embodiments, arginine is in an amount of 2% (w/w) .

In some embodiments, glutamic acid in the aqueous API solution is in an amount ranging from 1.0 to 3.0% (w/w) relative to the weight of the aqueous API solution, such as from 1.1 to 3.0% (w/w) , 1.1 to 2.5% (w/w) , 1.1 to 2.0% (w/w) , 1.2 to 3.0% (w/w) , 1.2 to 2.5% (w/w) , 1.2 to 2.0% (w/w) , 1.3 to 3.0% (w/w) , 1.3 to 2.5% (w/w) , 1.3 to 2.0% (w/w) , 1.4 to 3.0% (w/w) , 1.4 to 2.5% (w/w) , 1.4 to 2.0% (w/w) , 1.5 to 3.0% (w/w) , 1.5 to 2.5% (w/w) , 1.5 to 2.0% (w/w) , 1.6 to 3.0% (w/w) , 1.6 to 2.5% (w/w) , 1.6 to 2.0% (w/w) , 1.7 to 3.0% (w/w) , 1.7 to 2.5% (w/w) , 1.7 to 2.0% (w/w) , 1.8 to 3.0% (w/w) , 1.8 to 2.5% (w/w) , 1.8 to 2.0% (w/w) , 1.9 to 3.0% (w/w) , 1.9 to 2.5% (w/w) , or 1.9 to 2.0% (w/w) . In some embodiments, arginine is in an amount of 2% (w/w) .

In some embodiments, sorbitol in the aqueous API solution is in an amount of less than 15% (w/w) relative to the weight of the aqueous API solution. In some embodiments, sorbitol is in an amount ranging from 5.0 to 15% (w/w) , such as from 5.5 to 15% (w/w) , 5.5 to 10% (w/w) , 5.5 to 9.5% (w/w) , 5.5 to 9.0% (w/w) , 6.0 to 15% (w/w) , 6.0 to 10% (w/w) , 6.0 to 9.5% (w/w) , 6.0 to 9.0% (w/w) , 6.5 to 15% (w/w) , 6.5 to 10% (w/w) , 6.5 to 9.5% (w/w) , 6.5 to 9.0% (w/w) , 7.0 to 15% (w/w) , 7.0 to 10% (w/w) , 7.0 to 9.5% (w/w) , 7.0 to 9.0% (w/w) , 7.5 to 15% (w/w) , 7.5 to 10% (w/w) , 7.5 to 9.5% (w/w) , 7.5 to 9.0% (w/w) , 8.0 to 15% (w/w) , 8.0 to 10% (w/w) , 8.0 to 9.5% (w/w) , 8.0 to 9.0% (w/w) , 8.5 to 15% (w/w) , 8.5 to 10% (w/w) , 8.5 to 9.5% (w/w) , or 8.5 to 9.0% (w/w) . In some embodiments, sorbitol is in an amount of 9% (w/w) .

In some embodiments, propylene glycol in the aqueous API solution is in an amount ranging from 5.0 to 25% (w/w) relative to the weight of the aqueous API solution, such as from 5.0 to 20% (w/w) , 5.0 to 15% (w/w) , 5.0 to 14% (w/w) , 5.0 to 13% (w/w) , 5.0 to 12% (w/w) , 5.0 to 11% (w/w) , 6.0 to 25% (w/w) , 6.0 to 20% (w/w) , 6.0 to 15% (w/w) , 6.0 to 14% (w/w) , 6.0 to 13% (w/w) , 6.0 to 12% (w/w) , 6.0 to 11% (w/w) , 7.0 to 25% (w/w) , 7.0 to 20% (w/w) , 7.0 to 15% (w/w) , 7.0 to 14% (w/w) , 7.0 to 13% (w/w) , 7.0 to 12% (w/w) , 7.0 to 11% (w/w) , 8.0 to 25% (w/w) , 8.0 to 20% (w/w) , 8.0 to 15% (w/w) , 8.0 to 14% (w/w) , 8.0 to 13% (w/w) , 8.0 to 12% (w/w) , 8.0 to 11% (w/w) , 9.0 to 25% (w/w) , 9.0 to 20% (w/w) , 9.0 to 15% (w/w) , 9.0 to 14% (w/w) , 9.0 to 13% (w/w) , 9.0 to 12% (w/w) , or 9.0 to 11% (w/w) . In some embodiments, propylene glycol is in an amount of 6% (w/w) .

In some embodiments, the IL-17A binding single domain is in an amount of 35-45 mg/mL in the API aqueous solution. In some embodiments, the IL-17A binding single domain is in an amount of 40 mg/mL.

In some embodiments, the molar concentration of glycine, tris, glutamic acid, or arginine in the aqueous buffer is the same as that of glycine, tris, glutamic acid, or arginine in the API solution, respectively.

The IL17 binding molecule used in the gel compositions is as described herein. can be selected from a VH single domain antibody comprising the CDR1, CDR2 and CDR3 sequences SEQ ID Nos. 2, 3 and 4 as described herein. In one embodiment, the V_H single domain antibody is selected from Table 1. In one embodiment, the V_H single domain antibody comprises SEQ ID NO: 1 or a sequence having at least 75%homology thereto, for example SEQ ID NO: 74.

Illustration of the development and use of the gel compositions are provided in the Example section below. The examples are provided as a guide to a practitioner of ordinary skill in the art and are not meant to be limiting in any way.

EXAMPLES

Example 1 Generation of V_H Domain

The IL-17A binding V_H single domains as described herein can be prepared as described in Example 1 of WO2018/011555.

Example 2 Gel Compositions

Formulations in Table 2 below containing different gelling agents were tested for their gelling ability.

Table 2: Gelling agent tested

Unless otherwise indicated, the drug substance in the drug solution of Table 2 and any other applicable tables in section EXAMPLES (i.e., the drug substance used in the whole EXAMPLES section) was an IL-17A binding V_H single domain comprising CDR1 having SEQ ID NO: 2, CDR2 having SEQ ID NO: 3, and CDR3 having SEQ ID NO: 4. More specifically, the IL-17A binding V_H single domain comprises a sequence of SEQ ID NO: 74. The drug solution also comprised inactive buffer comprising 100mM Tris/glycine pH 8.0, 125mM arginine/glutamic acid, 6% (v/v) propylene glycol, and 10% (w/v) sorbitol. Unless otherwise indicated, arginine and glutamic acid used in the EXAMPLES section are L-arginine and L-glutamic acid, and sorbitol is D-sorbitol.

The results indicated that Xanthan gum and Carbopol 980 led to cloudy gels and that Sepineo P 600 and HPC failed to form a gel. Additional gelling agent tested included poloxamer 407, HMPC, and polycarbophil. Polycarbophil gave hazy gel and poloxamer 407 failed to form gel when its concentration was 10%or lower. Only HMPC and HEC resulted in a clear gel at low concentrations (about 1 or 2%w/w) .

Table 3 below tested another set of formulations based on the results above. In this set, no sucrose or mannitol and electrolytes were used. Similarly, both HEC and HPMC provided clear gel.

Table 3: No sucrose or mannitol and electrolytes were used

Table 4 below used purified water to replace inactive buffer and gel stability after the gel formation was observed.

Table 4: Purified water was used for make-up

Compared to placebo gel (containing no drug substance) which remained clear at T5 days, the gel formulation in Table 4 above became slightly hazy or cloudy. This indicated possible protein aggregation. It was also noted that HPC resulted in a clear gel when purified water instead of inactive buffer was used as the make-up solution and that HPMC provided a clear gel regardless of purified water or inactive buffer as the make-up solution.

Example 3: Freeze Thaw Study

The formulation in Table 5 were subjected to freeze thaw study for three cycles. All formulations were subjected to freezing conditions for 24 hours at -20 ℃ and thaw to room temperature for 6-8 hours.

Table 5: Gel formulations subjected to freeze-thaw study

The results of the freeze thaw study were shown in Table 6 and 7 below

Table 6: Freeze thaw study results of the gel containing drug substance

*all pH values measured at temperatures 21.5 ℃ ± 0.5 ℃.

Table 7: Freeze thaw study results of the gel containing no drug substance

*all pH values measured at temperatures 21.5 ℃ ± 0.5 ℃.

The freeze-thaw studies of above showed that HPC and HPMC are promising gelling agents which are compatible with drug substance resulting in a translucent gel with best recoveries.

Example 4: Compatibility Testing

In Table 8 below, HPMC was used as the gelling agent to evaluate the compatibility with Transcutol (penetration enhancer) and benzyl alcohol (preservative) , as well as propylene glycol and another preservative. The inactive buffer comprises 100mM Tris, 100 mM glycine, 125mM arginine, 125 mM glutamic acid and 10% (w/v) sorbitol. Existing simple HPMC gel comprises HPMC and drug substance solution (DS soln) . DS Soln comprises 100mM Tris/glycine pH 8.0, 125mM arginine/glutamic acid, 6% (v/v) propylene glycol, 10% (w/v) sorbitol, and DS of about 37 mg/mL.

Table 8: Compatibility testing

The results indicated that as a penetration enhancer, propylene glycol is more compatible with HMPC than transcutol and that thimersol is better than benzyl alcohol in terms of compatibility with HPMC.

Due to toxicity concerns over thimersol, additional preservatives were explored. As shown in Table 9, parabens were tested in HPMC gel formulations using propylene glycol, trancutol, or DMI as the penetration enhancer.

Table 9: Parabens as preservatives

*The slight haziness could be caused by air bubbles trapped in the solution as later batches were clear at T0.

Further stability study conducted on the three formulations in Table 9 showed that no major difference in impurity profiles between the different formulations were observed and that pH was stable for all three formulations and are at about 8.0-8.1.

Example 5: Clinical Study on the Treatment of Psoriasis with Gel Formulation

A multi-center, double-blind, randomized, placebo-controlled, First-in-Human study was conducted to evaluate the safety, tolerability, and efficacy of a topical gel formulation as disclosed herein in adults with mild-to-moderate chronic plaque psoriasis.

The topical gel formulation used in this study corresponds to a composition comprising ingredients set forth in Table 10 below.

Table 10: Exemplary Gel Formulation

Patient Selection

The subjects had mild-to-moderate CPP and the subject recruitment was carried out by following major patient selection criteria as listed in the table below

Study design

A total of 53 subjects were randomized in a 1: 1 ratio to drug substance arm (27 subjects) and Vehicle arm (26 subjects) for a 4-week treatment and a 2-week follow-up period. Safety, tolerability, efficacy, pharmacodynamics (PD) , immunogenicity and PK profile were evaluated.

Subjects who passed screening reported to study sites on Day 1 for baseline evaluations. At this clinic visit, subjects meeting all eligibility criteria were randomized to drug substance or Vehicle arm, and a plaque suitable for treatment was selected. The subject was instructed on how to apply the study treatment twice daily (BID) and how to document any untoward events both locally and generally. The subject was also given a 1-week supply of study medication as per randomization assignment and was instructed to return to clinic weekly for assessments.

At each visit of the subject, the Investigator documented the local Psoriasis Area and Severity Index (PASI) score and treated plaque size, monitored safety, and collected blood samples for PK and ADA determinations as outlined in Schedule of Activities. Safety and efficacy were monitored during and after 28 days of blinded treatments. The efficacy and safety monitoring were concluded in a follow-up visit (Day 43) . The overall treatment duration was 28 days.

Dose

Recommended dosage to target plaque was approximately 0.15 -0.3 mg/cm² (drug substance, 1% [w/w] or matching vehicle, 0% [w/w] ) . The topical application was based on the initial size of target plaque.

Results

Treatment with drug substance showed approximately a 45%relative improvement compared to placebo (vehicle) in the local PASI score of the target lesion at four weeks. A trend of increasing efficacy compared to placebo was observed over time, and clinical benefit was maintained after the end of treatment up to six weeks.

Anti-inflammatory effects were observed, with clear improvement in erythema of the target lesion up to four weeks, maintained after the end of treatment up to six weeks. Clinical improvement in scaling was also observed.

Drug substance showed consistent clinical improvement in target lesion size (reduction in area) compared to an area increase in the placebo arm during the treatment period.

Drug substance showed consistently higher responder rates over time compared to placebo up to four weeks and maintained after the end of treatment up to six weeks. The responder rate in this study was defined as the percentage of patients who achieved a ≥50%reduction compared to baseline in local PASI score of the target lesion, measured weekly.

Safety data showed (1) a benign safety and tolerability profile comparable to placebo, with treatment-emergent adverse events that were few in number and mild. In addition, pharmacokinetic studies confirmed lack of systemic absorption of the compound.

Claims

A gel composition comprising (1) a single variable heavy chain domain antibody that binds to human IL-17A, (2) a gelling agent, (3) tris, glycine, glutamic acid, arginine, sorbitol, propylene glycol, and (5) water, wherein the pH of the gel composition ranges from 5 to 9.
The gel composition of claim 1, wherein the single variable heavy chain domain antibody comprises CDR1 having SEQ ID NO: 2, CDR2 having SEQ ID NO: 3, and CDR3 having SEQ ID NO: 4.
The gel composition of claim 1, wherein the single variable heavy chain domain antibody comprises SEQ ID NO: 1 or a sequence having at least 95%homology thereto.
The gel composition of claim 1, wherein the single variable heavy chain domain antibody comprises SEQ ID NO: 74 or a sequence having at least 95%homology thereto.
The gel composition of claim 1, wherein the single variable heavy chain domain antibody comprises a sequence selected from SEQ ID NOs: 5-73 or a sequence having at least 95%homology to a sequence selected from SEQ ID NOs: 5-73.
The gel composition of any of claims 1-5, wherein the gelling agent is in an amount of less than 5% (w/w) .
The gel composition of claim 6, wherein the gelling agent is in an amount of 0.5 to 2.0 % (w/w) .
The gel composition of claim 7, wherein the gelling agent is in an amount of 0.6 to 1.5% (w/w) , 0.6 to 1.4% (w/w) , 0.6 to 1.3% (w/w) , 0.6 to 1.2% (w/w) , 0.6 to 1.1% (w/w) , 0.7 to 1.5% (w/w) , 0.7 to 1.4% (w/w) , 0.7 to 1.3% (w/w) , 0.7 to 1.2% (w/w) , 0.7 to 1.1% (w/w) , 0.8 to 1.5% (w/w) , 0.8 to 1.4% (w/w) , 0.8 to 1.3% (w/w) , 0.8 to 1.2% (w/w) , 0.8 to 1.1% (w/w) , 0.9 to 1.5% (w/w) , 0.9 to 1.4% (w/w) , 0.9 to 1.3% (w/w) , 0.9 to 1.2% (w/w) , or 0.9 to 1.1% (w/w) .
The gel composition of claim 6, wherein the gelling agent is in an amount of 1% (w/w) .
The gel composition of any of claims 1-9, wherein tris is in an amount ranging from 0.5 to 2.0% (w/w) .
The gel composition of claim 10, wherein tris is in an amount of 0.6 to 1.5% (w/w) , 0.6 to 1.4% (w/w) , 0.6 to 1.3% (w/w) , 0.6 to 1.2% (w/w) , 0.6 to 1.1% (w/w) , 0.7 to 1.5% (w/w) , 0.7 to 1.4% (w/w) , 0.7 to 1.3% (w/w) , 0.7 to 1.2% (w/w) , 0.7 to 1.1% (w/w) , 0.8 to 1.5% (w/w) , 0.8 to 1.4% (w/w) , 0.8 to 1.3% (w/w) , 0.8 to 1.2% (w/w) , 0.8 to 1.1% (w/w) , 0.9 to 1.5% (w/w) , 0.9 to 1.4% (w/w) , 0.9 to 1.3% (w/w) , 0.9 to 1.2% (w/w) , or 0.9 to 1.1% (w/w) .
The gel composition of claim 10, wherein tris is in an amount of 1% (w/w) .
The gel composition of any of claims 1-12, wherein glycine is in an amount ranging from 0.2 to 1.5% (w/w) .
The gel composition of claim 13, wherein glycine is in an amount of 0.3 to 1.5% (w/w) , 0.3 to 1.0% (w/w) , 0.3 to 0.9% (w/w) , 0.3 to 0.8% (w/w) , 0.3 to 0.7% (w/w) , 0.4 to 1.5% (w/w) , 0.4 to 1.0% (w/w) , 0.4 to 0.9% (w/w) , 0.4 to 0.8% (w/w) , 0.4 to 0.7% (w/w) , 0.5 to 1.5% (w/w) , 0.5 to 1.0% (w/w) , 0.5 to 0.9% (w/w) , 0.5 to 0.8% (w/w) , or 0.5 to 0.7% (w/w) .
The gel composition of claim 13, wherein glycine is in an amount of 0.7% (w/w) .
The gel composition of any of claims 1-15, wherein arginine is in an amount ranging from 1.0 to 3.0% (w/w) .
The gel composition of claim 16, wherein arginine is in an amount of 1.1 to 3.0% (w/w) , 1.1 to 2.5% (w/w) , 1.1 to 2.0% (w/w) , 1.2 to 3.0% (w/w) , 1.2 to 2.5% (w/w) , 1.2 to 2.0% (w/w) , 1.3 to 3.0% (w/w) , 1.3 to 2.5% (w/w) , 1.3 to 2.0% (w/w) , 1.4 to 3.0% (w/w) , 1.4 to 2.5% (w/w) , 1.4 to 2.0% (w/w) , 1.5 to 3.0% (w/w) , 1.5 to 2.5% (w/w) , 1.5 to 2.0% (w/w) , 1.6 to 3.0% (w/w) , 1.6 to 2.5% (w/w) , 1.6 to 2.0% (w/w) , 1.7 to 3.0% (w/w) , 1.7 to 2.5% (w/w) , 1.7 to 2.0% (w/w) , 1.8 to 3.0% (w/w) , 1.8 to 2.5% (w/w) , 1.8 to 2.0% (w/w) , 1.9 to 3.0% (w/w) , 1.9 to 2.5% (w/w) , or 1.9 to 2.0% (w/w) .
The gel composition of claim 16, wherein arginine is in an amount of 1.9% (w/w) .
The gel composition of any of claims 1-18, wherein glutamic acid is in an amount ranging from 1.0 to 3.0% (w/w) .
The gel composition of claim 18, wherein glutamic acid is in an amount of 1.1 to 3.0% (w/w) , 1.1 to 2.5% (w/w) , 1.1 to 2.0% (w/w) , 1.2 to 3.0% (w/w) , 1.2 to 2.5% (w/w) , 1.2 to 2.0% (w/w) , 1.3 to 3.0% (w/w) , 1.3 to 2.5% (w/w) , 1.3 to 2.0% (w/w) , 1.4 to 3.0% (w/w) , 1.4 to 2.5% (w/w) , 1.4 to 2.0% (w/w) , 1.5 to 3.0% (w/w) , 1.5 to 2.5% (w/w) , 1.5 to 2.0% (w/w) , 1.6 to 3.0% (w/w) , 1.6 to 2.5% (w/w) , 1.6 to 2.0% (w/w) , 1.7 to 3.0% (w/w) , 1.7 to 2.5% (w/w) , 1.7 to 2.0% (w/w) , 1.8 to 3.0% (w/w) , 1.8 to 2.5% (w/w) , 1.8 to 2.0% (w/w) , 1.9 to 3.0% (w/w) , 1.9 to 2.5% (w/w) , or 1.9 to 2.0% (w/w) .
The gel composition of claim 18, wherein glutamic acid is in an amount of 1.6% (w/w) .
The gel composition of any of claims 1-21, wherein sorbitol is in an amount of less than 15% (w/w) .
The gel composition of claim 22, wherein sorbitol is in an amount ranging from 5.0 to 15% (w/w) .
The gel composition of claim 23, wherein sorbitol is in an amount of 5.5 to 15% (w/w) , 5.5 to 10% (w/w) , 5.5 to 9.5% (w/w) , 5.5 to 9.0% (w/w) , 6.0 to 15% (w/w) , 6.0 to 10% (w/w) , 6.0 to 9.5% (w/w) , 6.0 to 9.0% (w/w) , 6.5 to 15% (w/w) , 6.5 to 10% (w/w) , 6.5 to 9.5% (w/w) , 6.5 to 9.0% (w/w) , 7.0 to 15% (w/w) , 7.0 to 10% (w/w) , 7.0 to 9.5% (w/w) , 7.0 to 9.0% (w/w) , 7.5 to 15% (w/w) , 7.5 to 10% (w/w) , 7.5 to 9.5% (w/w) , 7.5 to 9.0% (w/w) , 8.0 to 15% (w/w) , 8.0 to 10% (w/w) , 8.0 to 9.5% (w/w) , 8.0 to 9.0% (w/w) , 8.5 to 15% (w/w) , 8.5 to 10% (w/w) , 8.5 to 9.5% (w/w) , or 8.5 to 9.0% (w/w) .
The gel composition of claim 23, wherein sorbitol is in an amount of 8.8% (w/w) .
The gel composition of any of claims 1-25, wherein propylene glycol is in an amount ranging from 5.0 to 25% (w/w) .
The gel composition of claim 26, wherein propylene glycol is in an amount of 5.0 to 20% (w/w) , 5.0 to 15% (w/w) , 5.0 to 14% (w/w) , 5.0 to 13% (w/w) , 5.0 to 12% (w/w) , 5.0 to 11% (w/w) , 6.0 to 25% (w/w) , 6.0 to 20% (w/w) , 6.0 to 15% (w/w) , 6.0 to 14% (w/w) , 6.0 to 13% (w/w) , 6.0 to 12% (w/w) , 6.0 to 11% (w/w) , 7.0 to 25% (w/w) , 7.0 to 20% (w/w) , 7.0 to 15% (w/w) , 7.0 to 14% (w/w) , 7.0 to 13% (w/w) , 7.0 to 12% (w/w) , 7.0 to 11% (w/w) , 8.0 to 25% (w/w) , 8.0 to 20% (w/w) , 8.0 to 15% (w/w) , 8.0 to 14% (w/w) , 8.0 to 13% (w/w) , 8.0 to 12% (w/w) , 8.0 to 11% (w/w) , 9.0 to 25% (w/w) , 9.0 to 20% (w/w) , 9.0 to 15% (w/w) , 9.0 to 14% (w/w) , 9.0 to 13% (w/w) , 9.0 to 12% (w/w) , or 9.0 to 11% (w/w) .
The gel composition of claim 26, wherein propylene glycol is in an amount of 10% (w/w) .
The gel composition of any of claims 1-28, wherein the pH of the gel composition ranges from 6 to 9 or from 7 to 9.
The gel composition of any of claims 1-28, wherein the pH of the gel composition is 8.
The gel composition of any of claims 1-30, wherein the gelling agent is selected from hydroxyethylcellulose (HEC) , hydroxypropyl cellulose (HPC) , and hydroxypropylmethyl cellulose (HPMC) .
The gel composition of any of claims 1-30, wherein the gelling agent is HPMC.
The gel composition of any of claims 1-32, which further comprises a preservative selected from methylparaben and propylparaben and salt thereof.
The gel composition of any of claims 1-33, wherein the single variable heavy chain domain antibody that binds to human IL-17A is in an amount ranging from 0.01 to 5 % (w/w) or from 0.5 to 5% (w/w) of the gel composition.
The gel composition of any of claims 1-33, wherein the single variable heavy chain domain antibody that binds to human IL-17A is in an amount of 1, 2, 2.5, or 3% (w/w) of the gel composition.
The gel composition of claim 1, comprising (1) a single variable heavy chain domain antibody that binds to human IL-17A which comprises CDR1 having SEQ ID NO: 2, CDR2 having SEQ ID NO: 3, and CDR3 having SEQ ID NO: 4, (2) HPMC, (3) 0.5 to 2.0% (w/w) tris, 0.2 to 1.5% (w/w) glycine, 1.0 to 3.0% (w/w) glutamic acid, 1.0 to 3.0% (w/w) arginine, 5.0 to 10% (w/w) sorbitol, 5.0 to 25% (w/w) propylene glycol, and (5) water, wherein the pH of the gel composition ranges from 5 to 9.
A method of preparing the gel composition of any of claims 1-36, comprising mixing a gel preparation with an aqueous active pharmaceutical ingredient (API) solution, wherein

the gel preparation comprises glycine, tris, glutamic acid, arginine, sorbitol, propylene glycol, HPMC, and water and

the API solution comprises the single variable heavy chain domain antibody that binds to human IL-17A, glycine, tris, glutamic acid, arginine, sorbitol, propylene glycol, and water.
The method of claim 37, wherein the gel preparation is in an amount of 15-75 % (w/w) relative to the weight of the gel composition, and the aqueous API solution is in an amount of 25-85% (w/w) relative to the weight of the gel composition.
The method of claim 37 and 38, wherein the gel preparation comprises (1) an aqueous buffer comprising glycine, tris, glutamic acid, arginine, sorbitol, water, (2) propylene glycol, and (3) HPMC.
The method of claim 39, wherein the aqueous buffer is in an amount of 10-65% (w/w) relative to the weight of the gel composition.
The method of any of claim 39 or 40, wherein the molar concentration of glycine, tris, glutamic acid, or arginine in the aqueous buffer is the same as that of glycine, tris, glutamic acid, or arginine in the API solution, respectively.
The method of any of claims 37-41, wherein the single variable heavy chain domain antibody that binds to human IL-17A is in an amount of 35-45 mg/mL in the aqueous API solution.
The method of any of claims 37-41, wherein the IL-17A binding single domain is in an amount of 40 mg/mL in the aqueous API solution.
A method of treating a skin disorder in a subject in need thereof comprising topically administering to the subject a therapeutically effective amount of the gel composition of any of claims 1-36.
The method of claim 44, wherein the skin disorder is psoriasis, spondyloarthropathies, uveitis, gingivitis, or atopic dermatitis.
The method of claim 44, wherein the skin disorder is mild-to-moderate chronic plaque psoriasis (CPP) .
The method of claim 46, wherein, before the treatment, the subject has Psoriasis Area and Severity Index (PASI) score ≤ 15.
The method of claim 46 or 47, wherein, before the treatment, the subject has a lesion size of > 9 cm² to 100 cm².
The method of any of claims 46-48, comprising administering to the subject twice daily a dose of 0.15-0.3 mg of the single variable heavy chain domain antibody that binds to human IL-17A per square centimeter of the lesion size.
The method of any of claim 44-49, wherein the gel composition is delivered intradermally with no or without major systemic exposure.