WO2026008525A1

WO2026008525A1 - Stable radionuclide-containing formulations

Info

Publication number: WO2026008525A1
Application number: PCT/EP2025/068438
Authority: WO
Inventors: Corinna WILHELM; Georg ARTEMEW; Abongnui ASANKA'A; Aasmund LARSEN; Alex Papple; Jenny Karlsson; Indrevoll BÅRD
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 2024-07-01
Filing date: 2025-06-30
Publication date: 2026-01-08
Anticipated expiration: 2027-01-01

Abstract

The present disclosure relates to pharmaceutical compositions comprising radionuclide-containing conjugates comprising urea, thiourea or amide linking moieties and methionine and/or cysteamine.

Description

STABLE RADIONUCLIDE-CONTAINING FORMULATIONS

FIELD

The present disclosure relates to pharmaceutical compositions comprising radionuclidecontaining conjugates comprising urea, thiourea or amide linking moieties and methionine and/or cysteamine.

BACKGROUND

Introduction

Radionuclide-containing pharmaceuticals have rapidly established themselves as an indispensable tool for the diagnosis and treatment of diseases such as hyperproliferative diseases. It is therefore of utmost importance that the treatment using radionuclide-containing pharmaceuticals is provided in a safe and efficient manner to a traceable target without intolerable side effects ((Vermeulen K., et al., Design and Challenges of Radiopharmaceuticals, Seminars in Nuclear Medicine, 49 (5), 2019, pp. 339-356)). Rationally designed formulations and dosage forms can stop drug substance degradation e.g. through chemical or physical decomposition (Wu, Z., Drug stability testing and formulation strategies, Pharmaceutical Development and Technology, 23 (10), 2018, p. 941).

In addition to the general degradation pathways pharmaceticals have, radiophamaceuticals can decompose by radioation, i.e. radiolysis. Radiolysis may occur during manufacturing, storage or administration of the radiopharmaceutical (Vermeulen K., et al., Design and Challenges of Radiopharmaceuticals, Seminars in Nuclear Medicine, 49 (5), 2019, pp. 339-356). Radiolysis can release the radiosisoptope or damage the targeting moiety, which can cause the release of the unbound radioisotope. Hence, it is critical to limit radiolysis to the highest extend possible with an adequately chosen formulation, thus making the provision of stable pharmaceutical compositions and formulations comprising radiopharmaceuticals an essential requisite in the development of such drugs.

Description of the prior art, problem to be solved and its solution

Radionuclide-containing drugs typically comprise a so-called targeting moiety (e.g. a small chemical structure, a peptide or an antibody) capable of binding to the desired target and a radionuclide-containing moiety which binds (e.g. complexes) the radionuclide (e.g. a chelating moiety) and delivers the active payload. These two moieties are usually attached to each other by a linking moiety or group. In many cases, the moiety or group linking the targeting moiety and the radionuclide-containing moiety comprises a urea, thiourea or amide because they provide a convenient, straightforward and usually stable way of linking the two components. In most cases, radionuclide-containing drugs contain several such urea, thiourea or amide moieties in their chemical structure.

However, these functional groups and especially thiourea groups are known to be affected by the nearby presence of radionuclides, which may lead to their cleavage and therefore to increased product decomposition and unstable pharmaceutical compositions and/or formulations. Compounds and/or additives that effectively stabilize proteins and peptides are often not effective or practical when used to inhibit the autoradiolysis of radiolabeled peptides and proteins (Deutsch et al., 1995, US patent 5, 384,113).

Complex stabilization has been typically achieved by the addition of radiostabilizers, such as gentisic acid (see, for example: Pluvicto Prescribing Information, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215833s000lbl.pdf), pentetic acid (Pluvicto Prescribing Information), para-aminobenzoic acid and/or ascorbic acid.

However, these methods typically suffer from reduced efficiency in preventing the cleavage of urea, thiourea and amide groups which, given the short shelf-life of radiopharmaceuticals, is a critical issue. Further, the above-mentioned additives are all acidic in nature and may cause additional stability issues in other parts of the conjugate. Lastly, the nature of the radionuclidecontaining moiety and especially of the chelating agent may result in the cleavage of the linking urea, thiourea and amide groups, since oftentimes harsh reaction conditions such as elevated temperatures need to be used to incorporate the corresponding radionuclide to the chelating moiety of the conjugate. This may lead to the need of additional purification steps and therefore to a reduced yield and a reduced process efficiency.

Thus, there is an increased need for the provision of stable compositions and/or formulations comprising radiopharmaceuticals. In particular, given the popularity, versatility and ease of use of a urea, thiourea and amide groups as linking moieties, there is an increased need for the provision of stable radionuclide-containing compositions and/or formulations where the radiopharmaceutical comprises such a linking moiety.

More particularly, there is an increased need for the provision of compositions and/or formulations comprising radiopharmaceuticals which are stable over sufficient periods of time that allow their delivery to the administering physician and the patient without suffering from radiopharmaceutical degradation. Increasing the stability of the radiopharmaceutical in pharmaceutical compositions/and or formulations is especially desirable from a logistical perspective, since this would allow for the reliable delivery of the radiopharmaceutical-containing drug product across countries and/or continents. It would be desirable to have compositions and/or formulations comprising radiopharmaceuticals available which are stable for at least 48 hours, preferably for at least 72 hours and more preferably for at least 96 hours or more and/or which have a monomer content of at least 85% for at least 48 hours, preferably a monomer content of at least 90% for at least 48 hours. The present disclosure solves the above-mentioned issues by providing pharmaceutical compositions with increased stability, said compositions comprising radionuclide-containing conjugates comprising (i) a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a urea, thiourea or amide moiety and (ii) methionine or cysteamine. The compositions of the present disclosure show increased stability due to the diminished degradation of the urea, thiourea or amide link between the conjugates’ targeting and radionuclide-containing chelating moieties. This results in the reduced formation of undesired byproducts (both qualitatively and quantitatively, i.e. , less degradation products are formed and in reduced amounts), which in turn allows for the convenient preparation of drug products suitable for longer storage and a more reliable supply chain which can be easily adapted to provide customers (i.e., doctors and patients) with the desired product conveniently and reliably. In protein formulations, methionine has previously been used to prevent oxidation of the primary amino acid, as the inherent methionine is most susceptible to oxidation (Met-O), (Strickley, R., Lambert W., A review of Formulations of Commercially Available Antibodies, Jorunal of Pharmacuetical Sciences, 110 (7), 2021 , pp. 2590-2608). This is, however, different for radionuclide-containing conjugates, where the focus lies on preventing the cleavage of the urea, thiourea or amide moieties which may be affected by the presence of a nearby radionuclide (autoradiolysis) in the conjugate itself rather than on avoiding the oxidation of the individual components of a protein (i.e., amino acids) by external agents.

Both methionine and cysteamine are suitable compounds which protect the radiolysis (i.e., cleavage) of the urea, thiourea or amide moiety linking the targeting moiety and the radionuclidecontaining chelating moiety. In addition, both methionine and cysteamine, and particularly cysteamine, can be used in low amounts while maintaining their radioprotective effect, thus improving the cost-effectiveness of the final compositions and, more importantly, their safety, since less additive is needed. Cysteamine is also capable of undergoing a self-regeneration cycle via taurine and taurine-related compounds, which enhances its (radio)protective effect.

In particular, the use of methionine or cysteamine yields pharmaceutical compositions which are stable for at least 96 hours and in some cases for up to 120 hours with a monomer content of at least 90%. Thus, the pharmaceutical compositions of the present disclosure are superior to currently available, radionuclide-containing compositions.

DEFINITIONS

The term “comprising” when used in the specification includes “consisting of”.

If within the present text any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present text. In the context of the present disclosure, the term “methionine” refers to 2-amino-4- (methylsulfanyl)butanoic acid of the following structure: and encompasses both the pure (R) and (S) enantiomers as well as mixtures of the (R) and (S) enantiomers in any ratio.

In the context of the present disclosure, the term “cysteamine” refers to 2-aminoethane-1 -thiol of the following structure:

In the context of the present disclosure, the term “targeting moiety” refers to a molecule or part of a molecule that binds to a specific target. The term "tissue targeting" is used herein to indicate that the substance in question (i.e. a tissue-targeting compound, a tissue-targeting actinium complex and/or a tissue-targeting moiety, particularly when in the form of a tissue-targeting complex as described herein), serves to localize itself (and particularly to localize any conjugated actinium complex) preferentially to at least one tissue site at which its presence (e.g. to deliver a radioactive decay) is desired. Thus, a tissue-targeting compound, complex, group or moiety serves to provide greater localization to at least one desired site in the body of a subject following administration to that subject in comparison with the concentration of an equivalent complex not having the targeting moiety. The targeting moiety in the present case will be preferably selected to bind specifically to cell-surface receptors associated with cancer cells or other receptors associated with the tumor microenvironment.

The present disclosure relates to pharmaceutical compositions comprising radionuclidecontaining conjugates comprising urea, thiourea or amide linking moieties and methionine and/or cysteamine. In the context of the present disclosure, the term “pharmaceutical compositions” refers to any composition comprising radionuclide-containing conjugates comprising urea, thiourea or amide linking moieties which are suitable to comprise methionine and/or cysteamine. Preferably, the pharmaceutical compositions according to the present disclosure are in liquid form, i.e., liquid pharmaceutical compositions. More preferably, the pharmaceutical compositions according to the present disclosure are aqueous liquid pharmaceutical compositions.

In the context of the present disclosure, the term “HER2” refers to “Receptor tyrosine-protein kinase erbB”-2 antigen encoded by the ERBB2 gene; UniProt ID: P04626 ■ ERBB2_HUMAN. In the context of the present disclosure, the term “GPC3” refers to “Glypican-3”antigen encoded by the GPC3 gene; UniProt ID: P51654 ■ GPC3_HUMAN.

In the context of the present disclosure, the term “CEACAM5” refers to “Carcinoembryonic antigen-related cell adhesion molecule 5” antigen encoded by the CEACAM5 gene; UniProt ID: P06731 ■ CEAM5_HUMAN.

In the context of the present disclosure, the term “GUCY2C” refers to “Guanylyl cyclase C” antigen encoded by the GUCY2C gene; UniProt ID: P25092 ■ GUC2C_HUMAN.

In the context of the present disclosure, the term “cMet” refers to “Hepatocyte growth factor receptor” antigen encoded by the MET gene; UniProt ID: P08581 ■ MET_HUMAN.

In the context of the present disclosure, the term “FoIRa” refers to “Folate receptor alpha” antigen encoded by the FOLRIgene; UniProt ID: P15328 ■ FOLR1_HUMAN.

In the context of the present disclosure, the term “DLL3” refers to “Delta-like protein 3” antigen encoded by the DLL3 gene; UniProt ID: Q9NYJ7 ■ DLL3_HUMAN.

In the context of the present disclosure, the term “Nectin-4” refers to “Nectin-4” antigen encoded by the NECTIN4 gene; UniProt ID: Q96NY8 ■ NECT4_HUMAN.

In the context of the present disclosure, the term “STEAP1” refers to “Metalloreductase STEAP1” antigen encoded by the STEAP1 gene; UniProt ID: Q9UHE8 ■ STEA1_HUMAN.

In the context of the present disclosure, the term “TROP2” refers to “tumor associated calcium signal transducer 2” antigen encoded by the TASTD2 gene; UniProt ID: P09758 ■ TACD2_HUMAN.

In the context of the present disclosure, “DOTA” refers to 2,2',2",2"'-(1 ,4,7,10- Tetraazacyclododecane-1 ,4,7,10-tetrayl)tetraacetic acid (CAS no. 60239-18-1).

In the context of the present disclosure, the term “Macropa” refers to 6-((16-((6-carboxypyridin-

2-yl)methyl)-1 ,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)picolinic acid (CAS no. 1128304-86-8).

In the context of the present disclosure, the term “HOPO” refers to 4-((4-(3-(Bis(2-(((1 ,2-dihydro-

3-hydroxy-1-methyl-2-oxo-4-pyridinyl)carbonyl)amino)ethyl)amino)-2-((bis(2-(((1 ,2-dihydro-3- hydroxy-1-methyl-2-oxo-4-pyridinyl)carbonyl)amino)ethyl)amino)methyl)propyl)phenyl)amino)-

4-oxobutanoic acid (Corixetan, CAS no. 1952359-26-0).

In the context of the present disclosure, the term “DFO” refers to N1-hydroxy-N1-(5-(4- (hydroxy(5-(3-(4-isothiocyanatophenyl)thioureido)pentyl)amino)-4-oxobutanamido)pentyl)-N4- (5-(N-hydroxyacetamido)pentyl)succinamide (CAS no.1222468-90-7).

In the context of the present disclosure, the term “DFO*” refers to 5,11 ,16,22- Tetraazahexacosanediamide, N¹-[5-(acetylhydroxyamino)pentyl]-N²⁶,5,16-trihydroxy-N²⁶-[5- [[[(4-isothiocyanatophenyl)amino]thioxomethyl]amino]pentyl]-4,12,15,23-tetraoxo (CAS no.1810009-29-0).

In the context of the present disclosure, the term IRF refers to the Immunoreactive Fraction i.e. , the fraction of the labelled product (i.e., the compounds of formula (I) of the present disclosure) which is capable of binding to the target. The Lindmo assay (Lindmo T., et al. (1984) “Determination of the immunoreactive fraction of radiolabeled monoclonal antibodies by linear extrapolation to binding at infinite antigen excess.” J. Immunol. Methods. 72, 77-89) is the most commonly used method for assessing the immunoreactive fraction.

In the context of the present disclosure, the term CAR refers to the Chelator-to-Antigen Ratio, which is a measure of the specific activity of the radiolabeled compound (e.g., the compounds of formula (I) of the present disclosure).

The terms "polypeptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. Unless otherwise indicated, a particular polypeptide sequence also implicitly encompasses conservatively modified variants thereof.

Amino acids may be referred to herein by their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

The term "antibody", as used herein, is intended to refer to immunoglobulin molecules including, but not limited to, full-length antibodies and monovalent antibodies. “Full-length antibodies” are preferably comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains which are typically inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region can comprise e.g., three domains CH1 , CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain (CL). The VH and VL 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 VH and VL is typically composed of three CDRs and up to four FRs arranged from amino-terminus to carboxy-terminus e.g., in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4. “Monovalent antibodies” as used herein are preferably comprised of three polypeptide chains, two heavy (H) chains and one light (L) chain which are typically interconnected by disulfide bonds. One heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region can comprise e.g., three domains CH1 , CH2 and CH3. The other heavy chain is comprised of a heavy chain constant region only. The light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain (CL). The VH and VL 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 VH and VL is typically composed of three CDRs and up to four FRs arranged from amino-terminus to carboxy-terminus e.g., in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.

As used herein, the term "Complementarity Determining Regions” (CDRs; e.g., CDR1 , CDR2, and CDR3) refers to the amino acid residues of an antibody variable domain the presence of which are necessary for antigen binding. Each variable domain typically has three CDR regions identified as CDR1 , CDR2 and CDR3. Each complementarity determining region may comprise amino acid residues from a "complementarity determining region" as defined by Kabat (e.g. about residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the light chain variable domain and SI- 35 (H1), 50-65 (H2) and 95-102 (H3) in the heavy chain variable domain; (Kabat et al., Sequences of Proteins of Immunolological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)) and/or those residues from a "hypervariable loop" (e.g. about residues 26-32 (L1), 50-52 (L2) and 91-96 (L3) in the light chain variable domain and 26- 32 (H1), 53-55 (H2) and 96-101 (H3) in the heavy chain variable domain (Chothia and Lesk; J Mol Biol 196: 901-917 (1987)). In some instances, a complementarity determining region can include amino acids from both a CDR region defined according to Kabat and a hypervariable loop.

Depending on the amino acid sequence of the constant domain of their heavy chains, intact antibodies can be assigned to different "classes". There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these maybe further divided into "subclasses" (isotypes), e.g., lgG1 , lgG2, lgG3, lgG4, lgA1 , and lgA2. A preferred class of immunoglobulins for use in the present disclosure is IgG.

The heavy-chain constant domains that correspond to the different classes of antibodies are called [alpha], [delta], [epsilon], [gamma], and [mu], respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. As used herein antibodies are conventionally known antibodies and functional fragments thereof.

A “functional fragment” or “antigen-binding antibody fragment” of an antibody/immunoglobulin hereby is defined as a fragment of an antibody/immunoglobulin (e.g., a variable region of an IgG) that retains the antigen-binding region. An “antigen-binding region” of an antibody typically is found in one or more hyper variable region(s) of an antibody, e.g., the CDR1 , -2, and/or -3 regions; however, the variable “framework” regions can also play an important role in antigen binding, such as by providing a scaffold for the CDRs. In the context of the present disclosure, the term “antibody fragment” refers to an “antigen-binding antibody fragment”. “Functional fragments”, “antigen-binding antibody fragments”, or “antibody fragments” of the invention include but are not limited to Fab, Fab', Fab'-SH, F(ab')2, and Fv fragments; diabodies; single domain antibodies (DAbs), linear antibodies; single-chain antibody molecules (scFv); and multi-specific, such as bi- and tri-specific, antibodies formed from antibody fragments (C. A. K Borrebaeck, editor (1995) Antibody Engineering (Breakthroughs in Molecular Biology), Oxford University Press; R. Kontermann & S. Duebel, editors (2001) Antibody Engineering (Springer Laboratory Manual), Springer Verlag). An antibody other than a "multi-specific" or "multifunctional" antibody is understood to have each of its binding sites identical. The F(ab’)2 or Fab may be engineered to minimize or completely remove the intermolecular disulfide interactions that occur between the CH1 and CL domains.

The term "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, the C-terminal Lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

Variants of the antibodies or antigen-binding antibody fragments contemplated in the invention are molecules in which the binding activity of the antibody or antigen-binding antibody fragment is maintained.

“Binding proteins” contemplated in the invention are for example antibody mimetics, such as Affibodies, Adnectins, Anticalins, DARPins, Avimers, Nanobodies (reviewed by Gebauer M. et al., Curr. Opinion in Chem. Biol. 2009; 13:245-255; Nuttall S.D. et al., Curr. Opinion in Pharmacology 2008; 8:608-617).

A “human” antibody or antigen-binding fragment thereof is hereby defined as one that is not chimeric (e.g., not “humanized”) and not from (either in whole or in part) a non-human species. A human antibody or antigen-binding fragment thereof can be derived from a human or can be a synthetic human antibody. A “synthetic human antibody” is defined herein as an antibody having a sequence derived, in whole or in part, in silico from synthetic sequences that are based on the analysis of known human antibody sequences. In silico design of a human antibody sequence or fragment thereof can be achieved, for example, by analyzing a database of human antibody or antibody fragment sequences and devising a polypeptide sequence utilizing the data obtained there from. Another example of a human antibody or antigen-binding fragment thereof is one that is encoded by a nucleic acid isolated from a library of antibody sequences of human origin (e.g., such library being based on antibodies taken from a human natural source). Examples of human antibodies include antibodies as described in Sdderlind et al., Nature Biotech. 2000, 18:853-856.

A “humanized antibody” or humanized antigen-binding fragment thereof is defined herein as one that is (i) derived from a non-human source (e.g., a transgenic mouse which bears a heterologous immune system), which antibody is based on a human germline sequence; (ii) where amino acids of the framework regions of a non-human antibody are partially exchanged to human amino acid sequences by genetic engineering or (iii) CDR-grafted, wherein the CDRs of the variable domain are from a non-human origin, while one or more frameworks of the variable domain are of human origin and the constant domain (if any) is of human origin.

A “chimeric antibody” or antigen-binding fragment thereof is defined herein as one, wherein the variable domains are derived from a non-human origin and some or all constant domains are derived from a human origin.

The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible mutations, e.g., naturally occurring mutations, that may be present in minor amounts. Thus, the term "monoclonal" indicates the character of the antibody as not being a mixture of discrete antibodies. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. In addition to their specificity, monoclonal antibody preparations are advantageous in that they are typically uncontaminated by other immunoglobulins. The term "monoclonal” is not to be construed as to require production of the antibody by any particular method. The term monoclonal antibody specifically includes chimeric, humanized and human antibodies.

An "isolated" antibody is one that has been identified and separated from a component of the cell that expressed it. Contaminant components of the cell are materials that would interfere with diagnostic or therapeutic uses of the antibody, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes.

An "isolated" nucleic acid is one that has been identified and separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

As used herein, an antibody “binds specifically to”, is “specific to/for” or “specifically recognizes” an antigen of interest, e.g. a tumor-associated polypeptide antigen target or an antigen-binding polypeptide target (as e.g. an antigen-binding antibody), is one that binds the antigen-target with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting a cell or tissue expressing the antigen or one that binds an antigen-binding polypeptide target with sufficient affinity such that the antibody is useful as a reversal agent to neutralize the therapeutic activity of this antigen-binding polypeptide (e.g. an antigen-binding antibody) and does not significantly cross-react with other proteins or does not significantly cross-react with proteins other than orthologs and variants (e.g. mutant forms, splice variants, or proteolytically truncated forms) of the aforementioned target. The term "specifically recognizes" or "binds specifically to" or is "specific to/for" a particular polypeptide or an epitope on a particular polypeptide target as used herein can be exhibited, for example, by an antibody, or antigen-binding fragment thereof, having a monovalent KD for the antigen of less than about 10-4 M, alternatively less than about 10-5 M, alternatively less than about 10-6 M, alternatively less than about 10-7 M, alternatively less than about 10-8 M, alternatively less than about 10-9 M, alternatively less than about 10-10 M, alternatively less than about 10-11 M, alternatively less than about 10-12 M, or less. An antibody “binds specifically to,” is “specific to/for” or “specifically recognizes” an antigen if such antibody is able to discriminate between such antigen and one or more reference antigen(s). In its most general form, “specific binding”, “binds specifically to”, is “specific to/for” or “specifically recognizes” is referring to the ability of the antibody to discriminate between the antigen of interest and an unrelated antigen, as determined, for example, in accordance with one of the following methods. Such methods comprise, but are not limited to, surface plasmon resonance (SPR), Western blots, ELISA-, RIA-, ECL-, IRMA-tests and peptide scans. For example, a standard ELISA assay can be carried out. The scoring may be carried out by standard color development (e.g., secondary antibody with horseradish peroxidase and tetramethyl benzidine with hydrogen peroxide). The reaction in certain wells is scored by the optical density, for example, at 450 nm. Typical background (=negative reaction) may be 0.1 OD; typical positive reaction may be 1 OD. This means the difference positive/negative is more than 5-fold, 10-fold, 50-fold, and preferably more than 100-fold. Typically, determination of binding specificity is performed by using not a single reference antigen, but a set of about three to five unrelated antigens, such as milk powder, BSA, transferrin or the like.

"Binding affinity" or “affinity” refers to the strength of the total sum of non-covalent interactions between a single binding site of a molecule and its binding partner. Unless indicated otherwise, as used herein, "binding affinity" refers to intrinsic binding affinity which reflects a 1 :1 interaction between members of a binding pair (e.g., an antibody and an antigen). The dissociation constant “KD” is commonly used to describe the affinity between a molecule (such as an antibody) and its binding partner (such as an antigen) i.e., how tightly a ligand binds to a particular protein. Ligand-protein affinities are influenced by non-covalent intermolecular interactions between the two molecules. Affinity can be measured by common methods known in the art, including those described herein. In one embodiment, the "KD" or "KD value" according to this invention is measured by using surface plasmon resonance assays using suitable devices including but not limited to Biacore instruments like Biacore T100, Biacore T200, Biacore 2000, Biacore 4000, a Biacore 3000 (GE Healthcare Biacore, Inc.), or a ProteOn XPR36 instrument (Bio-Rad Laboratories, Inc.).

"Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig bound onto Fc gamma receptors (FcyRs) present on certain cytotoxic cells (e.g. NK cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell e.g. with cytotoxins. To assess ADCC activity of an antibody of interest, an in vitro ADCC assay, such as that described in US Patent No. 5,500,362 or 5,821 ,337 or U.S. Patent No. 6,737,056 (Presta), may be performed. Useful effector cells for such assays include PBMC and NK cells.

"Complement dependent cytotoxicity" or "CDC" refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (of the appropriate subclass), which are bound to their cognate antigen. To assess complement activation, a CDC assay, e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202: 163 (1996), may be performed. Polypeptide variants with altered Fc region amino acid sequences (polypeptides with a variant Fc region) and increased or decreased C1q binding are described, e.g., in US Patent No. 6,194,551 Bl and WO 1999/51642.

"Percent (%) sequence identity" with respect to a reference polynucleotide or polypeptide sequence, respectively, is defined as the percentage of nucleic acid or amino acid residues, respectively, in a candidate sequence that are identical with the nucleic acid or amino acid residues, respectively, in the reference polynucleotide or polypeptide sequence, respectively, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Conservative substitutions are not considered as part of the sequence identity. Preferred are un-gapped alignments. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared.

Substantial sequence identity/similarity may be taken as having a sequence similarity/identity of at least 80% to the complete sequences and/or at least 90% to the specific binding regions (e.g., the CDR regions). Preferable sequence similarity or more preferably identity may be at least 92%, 95%, 97%, 98% or 99%. Sequence similarity and/or identity may be determined using the "BestFit" program of the Genetics Computer Group Version 10 software package from the University of Wisconsin. The program uses the local had algorithm of Smith and Waterman with default values: Gap creation penalty=8, Gap extension penalty=2, Average match=2.912, average mismatch 2.003.

The terms “polynucleotide” or “nucleic acid”, as used interchangeably herein, refer to chains of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a chain by DNA or RNA polymerase. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs.

"Sequence homology" indicates the percentage of amino acids that either is identical or that represent conservative amino acid substitutions.

In addition, the nucleic acid sequences encoding variable regions of the heavy and/or light chains can be converted, for example, to nucleic acid sequences encoding full-length antibody chains, Fab fragments, or to scFv. The VL- or VH-encoding DNA fragment can be operatively linked, (such that the amino acid sequences encoded by the two DNA fragments are in-frame) to another DNA fragment encoding, for example, an antibody constant region or a flexible linker. The sequences of human heavy chain and light chain constant regions are known in the art (see e.g., Kabat, E. A., el al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.

To create a polynucleotide sequence that encodes a scFv, the VH- and VL-encoding nucleic acids can be operatively linked to another fragment encoding a flexible linker such that the VH and VL sequences can be expressed as a contiguous single-chain protein, with the VL and VH regions joined by the flexible linker (see e.g., Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al., Nature (1990) 348:552- 554).

To express the antibodies, antigen binding fragments thereof or variants thereof standard recombinant DNA expression methods can be used (see, for example, Goeddel; Gene Expression Technology. Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990)). For example, DNA encoding the desired polypeptide can be inserted into an expression vector which is then transfected into a suitable host cell. Suitable host cells are prokaryotic and eukaryotic cells. Examples for prokaryotic host cells are e.g., bacteria, examples for eukaryotic hosts cells are yeasts, insects and insect cells, plants and plant cells, transgenic animals, or mammalian cells. In some embodiments, the DNAs encoding the heavy and light chains are inserted into separate vectors. In other embodiments, the DNA encoding the heavy and light chains is inserted into the same vector. It is understood that the design of the expression vector, including the selection of regulatory sequences is affected by factors such as the choice of the host cell, the level of expression of protein desired and whether expression is constitutive or inducible.

Useful expression vectors for bacterial use are constructed by inserting a DNA sequence encoding a desired protein together with suitable translation initiation and termination signals in operable reading phase with a functional promoter. The vector will comprise one or more phenotypic selectable markers and an origin of replication to ensure maintenance of the vector and, if desirable, to provide amplification within the host. Suitable prokaryotic hosts for transformation include but are not limited to E. coli, Bacillus subtilis, Salmonella typhimurium and various species within the genera Pseudomonas, Streptomyces, and Staphylococcus.

Bacterial vectors may be, for example, bacteriophage-, plasmid- or phagemid-based. These vectors can contain a selectable marker and a bacterial origin of replication derived from commercially available plasmids typically containing elements of the well-known cloning vector pBR322 (ATCC 37017). Following transformation of a suitable host strain and growth of the host strain to an appropriate cell density, the selected promoter is de-repressed/induced by appropriate means (e.g., temperature shift or chemical induction) and cells are cultured for an additional period. Cells are typically harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification.

In bacterial systems, a number of expression vectors may be advantageously selected depending upon the use intended for the protein being expressed. For example, when a large quantity of such a protein is to be produced, for the generation of antibodies or to screen peptide libraries, for example, vectors which direct the expression of high levels of fusion protein products that are readily purified may be desirable.

Antibodies of the present disclosure or antigen-binding fragments thereof or variants thereof include naturally purified products, products of chemical synthetic procedures, and products produced by recombinant techniques from a prokaryotic host, including, for example, E. coli, Bacillus subtilis, Salmonella typhimurium and various species within the genera Pseudomonas, Streptomyces, and Staphylococcus, preferably, from E. coli cells.

Preferred regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV) (such as the CMV promoter/enhancer), Simian Virus 40 (SV40) (such as the SV40 promoter/enhancer), adenovirus, (e.g., the adenovirus major late promoter (AdMLP)) and polyoma. Expression of the antibodies may be constitutive or regulated (e.g. inducible by addition or removal of small molecule inductors such as Tetracyclin in conjunction with Tet system). For further description of viral regulatory elements, and sequences thereof, see e.g., U.S. 5,168,062 by Stinski, U.S. 4,510,245 by Bell et al. and U.S. 4,968,615 by Schaffner et al.. The recombinant expression vectors can also include origins of replication and selectable markers (see e.g., U.S. 4,399,216, 4,634,665 and U.S. 5,179,017). Suitable selectable markers include genes that confer resistance to drugs such as G418, puromycin, hygromycin, blasticidin, zeocin/bleomycin or methotrexate or selectable marker that exploit auxotrophies such as Glutamine Synthetase (Bebbington et al., Biotechnology (N Y). 1992 Feb; 10(2): 169-75), on a host cell into which the vector has been introduced. For example, the dihydrofolate reductase (DHFR) gene confers resistance to methotrexate, neo gene confers resistance to G418, the bsd gene from Aspergillus terreus confers resistance to blasticidin, puromycin N-acetyl-transferase confers resistance to puromycin, the Sh ble gene product confers resitance to zeocin, and resistance to hygromycin is conferred by the E. coli hygromycin resistance gene (hyg or hph). Selectable markers like DHFR or Glutamine Synthetase are also useful for amplification techniques in conjunction with MTX and MSX.

Transfection of the expression vector into a host cell can be carried out using standard techniques such as electroporation, nucleofection, calcium-phosphate precipitation, lipofection, polycation-based transfection such as polyethlylenimine (PEI)-based transfection and DEAE- dextran transfection.

Suitable mammalian host cells for expressing the antibodies, antigen binding fragments thereof or variants thereof provided herein include but are not limited to Chinese Hamster Ovary (CHO cells) such as CHO-K1 , CHO-S, CHO-K1SV [including dhfr- CHO cells, described in llrlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220 and Urlaub et al., Cell. 1983 Jun;33(2):405-12, used with a DHFR selectable marker, e.g., as described in R. J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621 ; and other knockout cells exemplified in Fan et al., Biotechnol Bioeng. 2012 Apr;109(4):1007-15], NS0 myeloma cells, COS cells, HEK293 cells, HKB11 cells, BHK21 cells, CAP cells, EB66 cells, and SP2 cells.

Expression might also be transient or semi-stable in expression systems such as HEK293, HEK293T, HEK293-EBNA, HEK293E, HEK293-6E, HEK293-Freestyle, HKB11 , Expi293F, 293EBNALT75, CHO Freestyle, CHO-S, CHO-K1 , CHO-K1SV, CHOEBNALT85, CHOS-XE, CHO-3E7 or CAP-T cells (for instance Durocher et al., Nucleic Acids Res. 2002 Jan 15;30(2):E9).

In some embodiments, the expression vector is designed such that the expressed protein is secreted into the culture medium in which the host cells are grown. The antibodies, antigen binding fragments thereof or variants thereof can be recovered from the culture medium using standard protein purification methods.

Antibodies of the invention or antigen-binding fragments thereof or variants thereof can be recovered and purified from recombinant cell cultures by well-known methods including, but not limited to ammonium sulfate or ethanol precipitation, acid extraction, Protein A chromatography, Protein G chromatography, anion or cation exchange chromatography, phospho-cellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, mixed mode chromatography and lectin chromatography. High performance liquid chromatography (“HPLC”) can also be employed for purification. See, e.g., Colligan, Current Protocols in Immunology, or Current Protocols in Protein Science, John Wiley & Sons, NY, N.Y., (1997-2001), e.g., Chapters 1 , 4, 6, 8, 9, 10, each entirely incorporated herein by reference.

Antibodies of the present disclosure or antigen-binding fragments thereof or variants thereof include naturally purified products, products of chemical synthetic procedures, and products produced by recombinant techniques from an eukaryotic host, including, for example, yeast, higher plant, insect and mammalian cells. Depending upon the host employed in a recombinant production procedure, the antibody of the present disclosure can be glycosylated or can be nonglycosylated. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Sections 17.37-17.42; Ausubel, supra, Chapters 10, 12, 13, 16, 18 and 20.

In preferred embodiments, the antibody is purified (1) to greater than 95% by weight of antibody as determined e.g. by the Lowry method, UV-Vis spectroscopy or by by SDS-Capillary Gel electrophoresis (for example on a Caliper LabChip GXII, GX 90 or Biorad Bioanalyzer device), and in further preferred embodiments more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or, preferably, silver stain. Isolated naturally occurring antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.

DESCRIPTION

In accordance with a first aspect, the present disclosure covers a pharmaceutical composition comprising

(i) a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a urea, thiourea or amide moiety, and

(ii) methionine or cysteamine.

In accordance with a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(ii) methionine or cysteamine in an amount of from 10 to 500 mM. With regard to the targeting moiety, no restrictions apply as long as the the targeting moiety and the radionuclide-containing chelating moiety can be linked to each other by a urea, thiourea or amide moiety.

In the context of the present disclosure, the targeting moiety preferably comprises an antibody, an antibody fragment, a binding peptide, a binding polypeptide, a binding protein, an enzyme, a nucleobase-containing moiety or a lectin. Preferably, the targeting moiety comprises an antibody, an antibody fragment, a binding peptide or a binding polypeptide. More preferably, the targeting moiety comprises an antibody, an antibody fragment, a binding peptide or a binding polypeptide capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GLICY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1 . More preferably, the targeting moiety comprises an antibody, a binding peptide or a binding polypeptide. More preferably, the targeting moiety comprises an antibody, an antibody fragment or a binding peptide.

More preferably, the targeting moiety comprises an antibody or an antigen-binding fragment thereof. More preferably, the targeting moiety comprises an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GLICY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1. More preferably, the targeting moiety comprises a binding peptide or a binding polypeptide. More preferably, the targeting moiety comprises a binding peptide or a binding polypeptide capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GLICY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1. More preferably, the targeting moiety comprises a binding peptide. More preferably, the targeting moiety comprises a binding peptide capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAPI .

When the targeting moiety comprises an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding antibody fragment thereof is preferably selected from Belimumab, Mogamulizumab, Blinatumomab, Ibritumomab, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab, Moxetuinomab, Brentuximab, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Cemiplimab, Nivolumab, Pembrolizumab, Siltuximab, Olaratumab, Trastuzumab, , Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Vandortuzumab, Codrituzumab, Atezolizumab, Avelumab, Durvalumab, Capiomab, Flotuzuinab, Denosumab, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxoinab, Ftaracizumab, or a modified version thereof or an antigen-binding fragment thereof. Even more preferably, the antibody or antibody fragment is preferably selected from Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Codrituzumab and Vandortuzumab. Preferably, the antibody or antigen-binding fragment thereof is Pelgifatamab (PSMA) comprising at least the three CDR heavy chain sequences according to SEQ ID NO. 1 , SEQ ID NO. 2 and SEQ ID NO. 3 and the three CDR light chain sequences according to SEQ ID NO. 4, SEQ ID NO. 5 and SEQ ID NO. 6.

Pelgifatamab CDR heavy chain sequences

SEQ ID NO. 1 : RYGMH

SEQ ID NO. 2: VIWYDGSNKYYADSVKG

SEQ ID NO. 3: GGDFLYYYYYGMDV

Pelgifatamab CDR light chain sequences

SEQ ID NO. 4: RASQGISNYLA

SEQ ID NO. 5: EASTLQS

SEQ ID NO. 6: QNYNSAPFT

Preferably, the antibody or antigen-binding fragment thereof is Trastuzumab (HER2) comprising at least the three CDR heavy chain sequences according to SEQ ID NO. 7, SEQ ID NO. 8 and SEQ ID NO. 9 and the three CDR light chain sequences according to SEQ ID NO. 10, SEQ ID NO. 11 and SEQ ID NO. 12.

Trastuzumab (HER2) CDR heavy chain sequences

SEQ ID NO. 7: DTYIH

SEQ ID NO. 8: RIYPTNGYTRYADSVKG

SEQ ID NO. 9: WGGDGFYAMDY

Trastuzumab (HER2) CDR light chain sequences

SEQ ID NO. 10: RASQDVNTAVA

SEQ ID NO. 11 : SASFLYS

SEQ ID NO. 12: QQHYTTPPT

Preferably, the antibody or antigen-binding fragment thereof is Trastuzumab emtansine (HER2) comprising at least the three CDR heavy chain sequences according to SEQ ID NO. 7, SEQ ID NO. 8 and SEQ ID NO. 9 and the three CDR light chain sequences according to SEQ ID NO. 10, SEQ ID NO. 11 and SEQ ID NO. 12.

Trastuzumab emtansine (HER2) CDR heavy chain sequences SEQ ID NO. 7: DTYIH

SEQ ID NO. 8: RIYPTNGYTRYADSVKG

SEQ ID NO. 9: WGGDGFYAMDY

Trastuzumab emtansine (HER2) CDR light chain sequences

SEQ ID NO. 10: RASQDVNTAVA

SEQ ID NO. 11: SASFLYS

SEQ ID NO. 12: QQHYTTPPT

Preferably, the antibody or antigen-binding fragment thereof is Codrituzumab (GPC3) comprising at least the three CDR heavy chain sequences according to SEQ ID NO. 13, SEQ ID NO. 14 and SEQ ID NO. 15 and the three CDR light chain sequences according to SEQ ID NO. 16, SEQ ID NO. 17 and SEQ ID NO. 18.

Codrituzumab CDR Heavy Chain Sequences

SEQ ID NO. 13: DYEMH

SEQ ID NO. 14: ALDPKTGDTAYSQKFKG

SEQ ID NO. 15: FYSYTY

Codrituzumab CDR Light Chain Sequences

SEQ ID NO. 16: RSSQSLVHSNRNTYLH

SEQ ID NO. 17: KVSNRFS

SEQ ID NO. 18: SQNTHVPPT

Preferably, the antibody or antigen-binding fragment thereof is Labetuzumab (CEACAM5) comprising at least the three CDR heavy chain sequences according to SEQ ID NO. 19, SEQ ID NO. 20 and SEQ ID NO. 21 and the three CDR light chain sequences according to SEQ ID NO. 22, SEQ ID NO. 23 and SEQ ID NO. 24.

Labetuzumab (CEACAM5)CDR heavy chain sequences

SEQ ID NO. 19: TYWMS

SEQ ID NO. 20: EIHPDSSTINYAPSLKD

SEQ ID NO. 21: LYFGFPWFAY

Labetuzumab (CEACAM5) CDR light chain sequences SEQ ID NO. 22: KASQDVGTSVA

SEQ ID NO. 23: WTSTRHT

SEQ ID NO. 24: QQYSLYRS

Preferably, the antibody or antigen-binding fragment thereof is Sacituzumab TROP2) comprising at least the three CDR heavy chain sequences according to SEQ ID NO. 25, SEQ ID NO. 26 and SEQ ID NO. 27 and the three CDR light chain sequences according to SEQ ID NO. 28, SEQ ID NO. 29 and SEQ ID NO. 30.

Sacituzumab (TROP2) CDR heavy chain sequences

SEQ ID NO. 25: NYGMN

SEQ ID NO. 26: WINTYTGEPTYTDDFKG

SEQ ID NO. 27: GGFGSSYWYFDV

Sacituzumab (TROP2) CDR light chain sequences

SEQ ID NO. 28: KASQDVSIAVA

SEQ ID NO. 29: SASYRYT

SEQ ID NO. 30: QQHYITPLT

Preferably, the antibody or antigen-binding fragment thereof is Indusatumab (5F9, GLICY2C) comprising at least the three CDR heavy chain sequences according to SEQ ID NO. 31 , SEQ ID NO. 32 and SEQ ID NO. 33 and the three CDR light chain sequences according to SEQ ID NO. 34, SEQ ID NO. 35 and SEQ ID NO. 36.

Indusatumab (5F9, GLICY2C) CDR heavy chain sequences

SEQ ID NO. 31 : GYYWS

SEQ ID NO. 32: EINHRGNTNDNPSLKS

SEQ ID NO. 33: ERGYTYGNFDH

Indusatumab (5F9, GLICY2C) CDR light chain sequences

SEQ ID NO. 34: RASQSVSRNLA

SEQ ID NO. 35: GASTRAT

SEQ ID NO. 36: QQYKTWPRT Preferably, the antibody or antigen-binding fragment thereof is Tesolituzumab (cMet) comprising at least the three CDR heavy chain sequences according to SEQ ID NO. 37, SEQ ID NO. 38 and SEQ ID NO. 39 and the three CDR light chain sequences according to SEQ ID NO. 40, SEQ ID NO. 41 and SEQ ID NO. 42.

Tesolituzumab (cMet) CDR heavy chain sequences

SEQ ID NO. 37: AYTMH

SEQ ID NO. 38: WIKPNNGLANYAQKFQG

SEQ ID NO. 39: SEITTEFDY

Tesolituzumab (cMet) CDR light chain sequences

SEQ ID NO. 40: KSSESVDSYANSFLH

SEQ ID NO. 41 : RASTRES

SEQ ID NO. 42: QQSKEDPLT

Preferably, the antibody or antigen-binding fragment thereof is Farletuzumab (FoIRa) comprising at least the three CDR heavy chain sequences according to SEQ ID NO. 43, SEQ ID NO. 44 and SEQ ID NO. 45 and the three CDR light chain sequences according to SEQ ID NO. 46, SEQ ID NO. 47 and SEQ ID NO. 48.

Farletuzumab (FoIRa) CDR heavy chain sequences

SEQ ID NO. 43: GYGLS

SEQ ID NO. 44: MISSGGSYTYYADSVKG

SEQ ID NO. 45: HGDDPAWFAY

Farletuzumab (FoIRa) CDR light chain sequences

SEQ ID NO. 46: SVSSSISSNNLH

SEQ ID NO. 47: GTSNLAS

SEQ ID NO. 48: QQWSSYPYMYT

Preferably, the antibody or antigen-binding fragment thereof is Mirvetuximab (FoIRa) comprising at least the three CDR heavy chain sequences according to SEQ ID NO. 49, SEQ ID NO. 50 and SEQ ID NO. 51 and the three CDR light chain sequences according to SEQ ID NO. 52, SEQ ID NO. 53 and SEQ ID NO. 54.

Mirvetuximab (FoIRa) CDR heavy chain sequences SEQ ID NO. 49: GYFMN

SEQ ID NO. 50: RIHPYDGDTFYNQKFQG

SEQ ID NO. 51 : YDGSRAMDY

Mirvetuximab (FoIRa) CDR light chain sequences

SEQ ID NO. 52: KASQSVSFAGTSLMH

SEQ ID NO. 53: RASNLEA

SEQ ID NO. 54: QQSREYPYT

Preferably, the antibody or antigen-binding fragment thereof is Rovalpituzumab (DLL3) comprising at least the three CDR heavy chain sequences according to SEQ ID NO. 55, SEQ ID NO. 56 and SEQ ID NO. 57 and the three CDR light chain sequences according to SEQ ID NO. 58, SEQ ID NO. 59 and SEQ ID NO. 60.

Rovalpituzumab (DLL3) CDR heavy chain sequences

SEQ ID NO. 55: NYGMN

SEQ ID NO. 56: WINTYTGEPTYADDFKG

SEQ ID NO. 57: IGDSSPSDY

Rovalpituzumab (DLL3) CDR light chain sequences

SEQ ID NO. 58: KASQSVSNDVV

SEQ ID NO. 59: YASNRYT

SEQ ID NO. 60: QQDYTSPWT

Preferably, the antibody or antigen-binding fragment thereof is Enfortumab (Nectin-4) comprising at least the three CDR heavy chain sequences according to SEQ ID NO. 61 , SEQ ID NO. 62 and SEQ ID NO. 63 and the three CDR light chain sequences according to SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66.

Enfortumab (Nectin-4) CDR heavy chain sequences

SEQ ID NO. 61 : SYNMN

SEQ ID NO. 62: YISSSSSTIYYADSVKG

SEQ ID NO. 63: AYYYGMDV

Enfortumab (Nectin-4) CDR light chain sequences SEQ ID NO. 64: RASQGISGWLA

SEQ ID NO. 65: AASTLQS

SEQ ID NO. 66: QQANSFPPT

Preferably, the antibody or antigen-binding fragment thereof is Vandortuzumab (STEAP1) comprising at least the three CDR heavy chain sequences according to SEQ ID NO. 67, SEQ ID NO. 68 and SEQ ID NO. 69 and the three CDR light chain sequences according to SEQ ID NO. 70, SEQ ID NO. 71 and SEQ ID NO. 72.

Vandortuzumab (STEAP1) CDR heavy chain sequences

SEQ ID NO. 67: SDYAWN

SEQ ID NO. 68: YISNSGSTSYNPSLKS

SEQ ID NO. 69: ERNYDYDDYYYAMDY

Vandortuzumab (STEAP1) CDR light chain sequences

SEQ ID NO. 70: KSSQSLLYRSNQKNYLA

SEQ ID NO. 71 : WASTRES

SEQ ID NO. 72: QQYYNYPRT

With regard to the radionuclide-containing chelating moiety, no restrictions apply as long as the the targeting moiety and the radionuclide-containing chelating moiety can be linked to each other by a urea, thiourea or amide moiety. In the context of the present disclosure, the radionuclidecontaining chelating moiety preferably comprises HOPO or a derivative thereof, DFO or a derivative thereof, DFO* or a derivative thereof, DOTA or a derivative thereof, Macropa or a derivative thereof. In the context of the present disclosure, “HOPO” refers to 4-((4-(3-(Bis(2- (((1 ,2-dihydro-3-hydroxy-1-methyl-2-oxo-4-pyridinyl)carbonyl)amino)ethyl)amino)-2-((bis(2- (((1 ,2-dihydro-3-hydroxy-1-methyl-2-oxo-4- pyridinyl)carbonyl)amino)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutanoic acid, “DFO” refers to N1-hydroxy-N1-(5-(4-(hydroxy(5-(3-(4-isothiocyanatophenyl)thioureido)pentyl)amino)- 4-oxobutanamido)pentyl)-N4-(5-(N-hydroxyacetamido)pentyl)succinamide, “DFO*” refers to 5,11 ,16, 22-Tetraazahexacosanediamide, N¹-[5-(acetylhydroxyamino)pentyl]-N²⁶,5,16- trihydroxy-N²⁶-[5-[[[(4-isothiocyanatophenyl)amino]thioxomethyl]amino]pentyl]-4, 12, 15,23- tetraoxo, “DOTA” refers to 2,2',2",2"'-(1 ,4,7,10-Tetraazacyclododecane-1 ,4,7,10- tetrayl)tetraacetic acid, and “Macropa” refers to 6-((16-((6-carboxypyridin-2-yl)methyl)- 1 ,4,10,13-tetraoxa-7, 16-diazacyclooctadecan-7-yl)methyl)picolinic acid. Preferably, the radionuclide-containing chelating moiety comprises DOTA or a derivative thereof or Macropa or a derivative thereof. More preferably, the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

Depending on the nature of the radionuclide-containing chelating moiety and of the targeting moiety, structural modifications may be necessary in order to achieve a suitable attachment between the two moieties. Thus, for example, the radionuclide-containing chelating moiety can be attached to the targeting moiety in different ways and/or in different positions depending on the nature of the chelator. Similarly, the targeting moiety may comprise additional structural elements which modify and/or improve its properties without affecting its capability of acting as a targeting moiety. There are no limitations to said structural modifications as long as they provide a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety being linked to each other by a urea, thiourea or amide moiety.

Without being limiting as to the possibilities of attachment between the radionuclide-containing chelating moiety and the targeting moiety, when the radionuclide-containing chelating moiety comprises DOTA or a derivative thereof, the radionuclide-containing chelating moiety can be attached to the rest of the conjugate via one of the carboxylic acid groups or via one carbon atom of the chelating ring, as shown exemplarily below, where * denotes a suitable position where attachment between the chelating moiety and the targeting moiety is preferred and M denotes a suitable radionuclide.

Structural modifications may be necessary in order to achieve a suitable attachment between the radionuclide-containing chelating moiety and the targeting moiety. When the radionuclidecontaining chelating moiety comprises DOTA, any such structural modification is considered to be a derivative of DOTA.

Preferably, the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof. Without being limiting as to the possibilities of attachment between the radionuclidecontaining chelating moiety and the targeting moiety, when the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof, the radionuclide-containing chelating moiety can be attached to the rest of the conjugate via the carbon atom in para-position to the nitrogen atom in one of the pyridine rings as shown exemplarily below, where * denotes a suitable position where attachment between the chelating moiety and the targeting moiety is preferred and M denotes a suitable radionuclide.

, wherein X is a urea, thiourea or amide moiety and [A] is a targeting moiety as described throughout the present disclosure.

Structural modifications may be necessary in order to achieve a suitable attachment between the radionuclide-containing chelating moiety and the targeting moiety. Thus, for example, different groups may be attached to the carbon atom in para-position to the nitrogen atom in one of the pyridine rings of Macropa or a derivative thereof in order to provide for a suitable attachment to the targeting moiety. There are no limitations as to the nature, the chemical structure, the size and/or any other feature of the modifications that may be conducted as long as a suitable attachment by a urea, thiourea or amide moiety is achieved between the targeting moiety and the radionuclide-containing chelating moiety. When the radionuclide-containing chelating moiety comprises Macropa, any such structural modification is considered to be a derivative of Macropa. Structural modifications may also take place in other parts of the molecule, e.g. in the carbon atoms of the macrocyclic rind, in different positions of one or both pyridine rings, or in any other part as long as a suitable attachment between the radionuclidecontaining chelating moiety and the targeting moiety via a urea, thiourea or amide moiety is achieved. Without being limiting, one such modification is shown exemplarily below, where * denotes a suitable position where attachment between the chelating moiety and the targeting moiety is preferred and M denotes a suitable radionuclide.

, wherein

X is a urea, thiourea or amide moiety and [A] is a targeting moiety as described throughout the present disclosure.

Thus, for example, conjugates of the present disclosure comprising a targeting moiety and a radionuclide-containing chelating moiety, can be depicted according to the general Formula (I), wherein A is the targeting moiety, B is the radionuclide-containing chelating moiety and X is a urea, thiourea or amide moiety.

As described herein above, structural modifications may be necessary in order to achieve e.g. a suitable attachment between the radionuclide-containing chelating moiety and the targeting moiety and/or to modify and/or improve the molecule’s properties. This may require the incorporation of additional chemical content to the molecule’s structure, thus leading to conjugates of the present disclosure further comprising an additional linking moiety L.

With regard to the nature of the additional linking moiety L, there is no limitation as long as the targeting and radionuclide-comtaining moieties can be attached via a urea, thiourea or amide moiety.

Thus, if the additional linking moiety L is introduced between the targeting moiety and the urea, thiourea or amide moiety, conjugates of the present disclosure comprising a targeting moiety and a radionuclide-containing chelating moiety can be depicted according to the general Formula (la), wherein A is the targeting moiety, B is the radionuclide-containing chelating moiety, X is a urea, thiourea or amide moiety and L is an additional linking moiety.

Further, if the additional linking moiety L is introduced between the urea, thiourea or amide moiety and the radionuclide-containing chelating moiety, conjugates of the present disclosure comprising a targeting moiety and a radionuclide-containing chelating moiety can be depicted according to the general Formula (lb), wherein A is the targeting moiety, B is the radionuclide-containing chelating moiety, X is a urea, thiourea or amide moiety and L is an additional linking moiety.

Further, additional linking moieties L can be introduced between the urea, thiourea or amide moiety and the targeting moiety and the radionuclide-containing chelating moiety, respectively, thus leading to conjugates of the present disclosure comprising a targeting moiety and a radionuclide-containing chelating moiety which can be depicted according to the general Formula (Ic), wherein A is the targeting moiety, B is the radionuclide-containing chelating moiety, X is a urea, thiourea or amide moiety and L is an additional linking moiety.

In case additional linking moieties L are introduced between the urea, thiourea or amide moiety and the targeting moiety and the radionuclide-containing chelating moiety, respectively, these additional linking moieties L may be identical but can also differ from each other with regard to their size, chemical structure, physicochemical properties or any other feature and/or characteristic.

With regard to the radionuclide, no restrictions apply as long as it can be complexed by the chelating moiety. Preferably, the radionuclide is selected from actinium-225 (²²⁵Ac³⁺), radium- 223 (²²³Ra²⁺), bismuth-213 (²¹³Bi³⁺), lead-212 (²¹²Pb²⁺ and/or ²¹²Pb⁴⁺), terbium-149 (¹⁴⁹Tb³⁺), fermium-255 (²⁵⁵Fm³⁺), thorium-227 (²²⁷Th⁴⁺), thorium-226 (²²⁶Th⁴⁺), astatine-211 (²¹¹At⁺), astatine- 217 (²¹⁷At⁺) and uranium-230. Preferably, the radionuclide is selected from actinium- 225 (²²⁵Ac³⁺), radium-223 (²²³Ra²⁺), thorium-227 (²²⁷Th⁴⁺) and thorium-226 (²²⁶Th⁴⁺). Preferably, the radionuclide is selected from actinium-225 (²²⁵Ac³⁺) and thorium-227 (²²⁷Th⁴⁺). More preferably, the radionuclide is actinium-225 (²²⁵Ac³⁺/225Ac).

With regard to the radionuclide-containing chelating moiety, it is preferred that the chelating moiety is Macropa or a derivative thereof and the radionuclide is actinium-225 (²²⁵Ac³⁺). It is also preferred that the chelating moiety is Macropa or a derivative thereof and the radionuclide is radium-223 (²²³Ra²⁺).

The compositions of the present disclosure comprise a conjugate in which the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a urea, thiourea or amide moiety. Preferably, the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a thiourea or amide moiety. More preferably, the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a thiourea moiety.

With regard to the amount of methionine, no restrictions apply as long as as a composition suitable for pharmaceutical use is obtained. Preferably, the amount of methionine is chosen so that a composition suitable for pharmaceutical use with sufficient stability is obtained. In the context of the present disclosure, the pharmaceutical composition preferably comprises methionine in an amount of from 10 to 500mM. More preferably, the pharmaceutical composition comprises methionine in an amount of from 10 to 100mM. More preferably, the pharmaceutical composition comprises methionine in an amount of from 10 to 75mM. More preferably, the pharmaceutical composition comprises methionine in an amount of from 30 to 60mM. More preferably, the pharmaceutical composition comprises methionine in an amount of from 40 to 60mM.

With regard to the amount of cysteamine, no restrictions apply as long as a composition suitable for pharmaceutical use is obtained. Preferably, the amount of cysteamine is chosen so that a composition suitable for pharmaceutical use with sufficient stability is obtained. In the context of the present disclosure, the pharmaceutical composition preferably comprises cysteamine in an amount of from 10 to 500mM. More preferably, the pharmaceutical composition comprises cysteamine in an amount of from 10 to 100mM. More preferably, the pharmaceutical composition comprises cysteamine in an amount of from 10 to 75mM. More preferably, the pharmaceutical composition comprises cysteamine in an amount of from 30 to 60mM. More preferably, the pharmaceutical composition comprises cysteamine in an amount of from 20 to 60mM. More preferably, the pharmaceutical composition comprises cysteamine in an amount of from 20 to 50mM. More preferably, the pharmaceutical composition comprises cysteamine in an amount of from 20 to 40mM. In the context of the present disclosure, any pharmaceutical composition comprising a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a urea, thiourea or amide moiety can benefit from the addition of methionine.

A preferred conjugate of the present disclosure is a conjugate of formula (II) wherein M is a suitable radionuclide. Preferably, M is actinium-225 (²²⁵Ac). In the context of the present disclosure, the compound of formula (II) is also referred to as “PSMA-SMOL”. The term “PSMA-SMOL-TAC” or “PSMA-TAC SMOL” refers to the 225Ac conjugate of the compound of formula (II).

Further preferred conjugates of the present disclosure are conjugates of formula (III) and of formula (III’) wherein X is a urea, thiourea or amide moiety, [A] is a targeting moiety preferably comprising an antibody, an antibody fragment, a binding peptide, a binding polypeptide, a binding protein, an enzyme, a nucleobase-containing moiety or a lectin and M is a suitable radionuclide. Preferably, the targeting moiety [A] comprises an antibody, an antibody fragment, a binding peptide or a binding polypeptide. More preferably, the targeting moiety [A] comprises an antibody, a binding peptide or a binding polypeptide. More preferably, the targeting moiety [A] comprises an antibody, an antibody fragment or a binding peptide. Most preferably, the targeting moiety [A] comprises an antibody or an antibody fragment. In the compounds of formula (III) and of formula (III’), M is a suitable radionuclide. Preferably, M is actinium-225 (²²⁵Ac/225Ac).

Further preferred conjugates of the present disclosure are conjugates of formula (Illa) and of formula (I lib) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1 and M is a suitable radionuclide. Preferably, M is actinium-225 (²²⁵Ac/225Ac).

Further preferred conjugates of the present disclosure are conjugates of formula (Illa) and of formula (I lib) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody selected from Belimumab, Mogamulizumab, Blinatumomab, Ibritumomab, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab, Moxetuinomab, Brentuximab, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Cemiplimab, Nivolumab, Pembrolizumab, Siltuximab, Olaratumab, Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Vandortuzumab, Atezolizumab, Avelumab, Durvalumab, Capiomab, Flotuzuinab, Denosumab, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxoinab, Ftaracizumab, or a modified version thereof or an antigen-binding fragment thereof and M is a suitable radionuclide.

Further preferred conjugates of the present disclosure are conjugates of formula (Illa) and of formula (I lib) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody selected from Trastuzumab, Trastuzumab emtansine, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab and Vandortuzumab or a modified version thereof or an antigen-binding fragment thereof and M is a suitable radionuclide. Preferably, M is actinium-225 (²²⁵Ac/225Ac). Further preferred conjugates of the present disclosure are conjugates of formula (Illa) and of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1 and M is 225Ac.

Further preferred conjugates of the present disclosure are conjugates of formula (Illa) and of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody selected from Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab and Vandortuzumab or a modified version thereof or an antigen-binding fragment thereof and M is 225Ac.

A preferred conjugate of the present disclosure is a conjugate of formula (111 b) wherein X is a urea, thiourea or amide moiety, [Ab] is the antibody Pelgifatamab or a modified version thereof or an antigen-binding fragment thereof and M is 225Ac.

A preferred conjugate of the present disclosure is a conjugate of formula (111 b) wherein X is a urea, thiourea or amide moiety, [Ab] is the antibody Codrituzumab or a modified version thereof or an antigen-binding fragment thereof and M is 225Ac.

In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(ii) methionine or cysteamine in an amount of from 10 to 100 mM, wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 10 to 100 mM, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof. In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(ii) methionine or cysteamine in an amount of from 10 to 100 mM, wherein the targeting moiety comprises an antibody, an antibody fragment, a binding peptide, a binding polypeptide, a binding protein, an enzyme, a nucleobase-containing moiety, or a lectin.

(ii) methionine or cysteamine in an amount of from 10 to 100 mM, wherein the targeting moiety comprises an antibody, an antibody fragment, a binding peptide, a binding polypeptide, a binding protein, an enzyme, a nucleobase-containing moiety, or a lectin, and wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 10 to 75 mM, wherein the targeting moiety comprises an antibody, an antibody fragment, a binding peptide or a binding polypeptide, wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof. In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(ii) methionine or cysteamine in an amount of from 10 to 100 mM, wherein the targeting moiety comprises an antibody, an antibody fragment, a binding peptide, a binding polypeptide, a binding protein, an enzyme, a nucleobase-containing moiety, or a lectin, and wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 10 to 75 mM, wherein the targeting moiety comprises an antibody, an antibody fragment, a binding peptide or a binding polypeptide, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 30 to 60 mM, wherein the targeting moiety comprises an antibody, an antibody fragment or a binding peptide, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof. In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody, an antibody fragment or a binding peptide, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 30 to 60 mM, wherein the targeting moiety comprises an antibody, an antibody fragment or a binding peptide, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody, an antibody fragment or a binding peptide, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof. In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(ii) methionine or cysteamine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody, an antibody fragment or a binding peptide, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody or an antibody fragment, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody or an antibody fragment, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(i) a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a urea, thiourea or amide moiety, and (ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody or an antibody fragment, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody or a binding peptide, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody or a binding peptide, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody or an antigen-binding fragment thereof, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody or a binding peptide, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody or an antigen-binding fragment thereof, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 10 to 75 mM, wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof. In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(ii) methionine or cysteamine in an amount of from 30 to 60 mM, wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 10 to 75 mM, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 30 to 60 mM, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 40 to 60 mM, wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 10 to 75 mM, wherein the targeting moiety comprises an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAPI . wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof. In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(ii) methionine or cysteamine in an amount of from 10 to 75 mM, wherein the targeting moiety comprises a binding peptide or a binding polypeptide capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1. wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 10 to 75 mM, wherein the targeting moiety comprises an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAPI . wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 10 to 75 mM, wherein the targeting moiety comprises a binding peptide or a binding polypeptide capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1. wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAPI . wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises a binding peptide or a binding polypeptide capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1. wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAPI . wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises a binding peptide or a binding polypeptide capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1. wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAPI . wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

In a further embodiment, the present disclosure covers a pharmaceutical composition comprising (i) a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a urea, thiourea or amide moiety, and

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises a binding peptide or a binding polypeptide capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1. wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(i) a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a thiourea moiety, and

(ii) methionine or cysteamine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody selected from selected from Belimumab, Mogamulizumab, Blinatumomab, Ibritumomab, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab, Moxetuinomab, Brentuximab, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Cemiplimab, Nivolumab, Pembrolizumab, Siltuximab, Olaratumab, Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Vandortuzumab, Atezolizumab, Avelumab, Durvalumab, Capiomab, Flotuzuinab, Denosumab, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxoinab, Ftaracizumab, or a modified version thereof or an antigen-binding fragment thereof.

(ii) methionine or cysteamine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody selected from selected from Belimumab, Mogamulizumab, Blinatumomab, Ibritumomab, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab, Moxetuinomab, Brentuximab, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Cemiplimab, Nivolumab, Pembrolizumab, Siltuximab, Olaratumab, Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Vandortuzumab, Atezolizumab, Avelumab, Durvalumab, Capiomab, Flotuzuinab, Denosumab, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxoinab, Ftaracizumab, or a modified version thereof or an antigen-binding fragment thereof, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody selected from selected from Belimumab, Mogamulizumab, Blinatumomab, Ibritumomab, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab, Moxetuinomab, Brentuximab, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Cemiplimab, Nivolumab, Pembrolizumab, Siltuximab, Olaratumab, Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Vandortuzumab, Atezolizumab, Avelumab, Durvalumab, Capiomab, Flotuzuinab, Denosumab, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxoinab, Ftaracizumab, or a modified version thereof or an antigen-binding fragment thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody selected from selected from Belimumab, Mogamulizumab, Blinatumomab, Ibritumomab, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab, Moxetuinomab, Brentuximab, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Cemiplimab, Nivolumab, Pembrolizumab, Siltuximab, Olaratumab, Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Vandortuzumab, Atezolizumab, Avelumab, Durvalumab, Capiomab, Flotuzuinab, Denosumab, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxoinab, Ftaracizumab, or a modified version thereof or an antigen-binding fragment thereof, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody selected from selected from Belimumab, Mogamulizumab, Blinatumomab, Ibritumomab, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab, Moxetuinomab, Brentuximab, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Cemiplimab, Nivolumab, Pembrolizumab, Siltuximab, Olaratumab, Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Vandortuzumab, Atezolizumab, Avelumab, Durvalumab, Capiomab, Flotuzuinab, Denosumab, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxoinab, Ftaracizumab, or a modified version thereof or an antigen-binding fragment thereof, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

In a further embodiment, the present disclosure covers a pharmaceutical composition comprising (i) a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a thiourea moiety, and

(ii) methionine or cysteamine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody selected from Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab and Vandortuzumab, or a modified version thereof or an antigen-binding fragment thereof.

(ii) methionine or cysteamine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody selected from Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab and Vandortuzumab, or a modified version thereof or an antigen-binding fragment thereof, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine or cysteamine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody selected from Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab and Vandortuzumab, or a modified version thereof or an antigen-binding fragment thereof, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof. In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(i) a conjugate of formula (II) (PSMA-TAC SMOL)

(II), wherein M is a suitable radionuclide, and

(ii) methionine or cysteamine in an amount of from 10 to 100 mM, preferably of from 30 to 70 mM, more preferably of from 40 to 60 mM.

(i) a conjugate of formula (II) (PSMA-TAC SMOL) wherein M is a suitable radionuclide, preferably wherein M is 225Ac, and (ii) methionine or cysteamine in an amount of from 10 to 100 mM, preferably of from 30 to 70 mM, more preferably of from 20 to 60 mM, more preferably of from 40 to 60 mM.

(i) a conjugate of formula (II) (PSMA-TAC SMOL)

(II), wherein M is 225Ac, and (ii) methionine or cysteamine in an amount of from 10 to 100 mM, preferably of from 30 to 70 mM, more preferably of from 20 to 60 mM, more preferably of from 40 to 60 mM. In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody or an antigenbinding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1, M is a suitable radionuclide, and

(i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody or an antigenbinding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1, M is a suitable radionuclide, preferably wherein M is 225Ac, and

(ii) methionine or cysteamine in an amount of from 10 to 100 mM, preferably of from 30 to 70 mM, more preferably of from 20 to 60 mM, more preferably of from 40 to 60 mM.

(i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody or an antigenbinding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1 , M is 225Ac, and

(ii) methionine or cysteamine in an amount of from 10 to 100 mM, preferably of from 30 to 70 mM, more preferably of from 20 to 60 mM, more preferably of from 40 to 60 mM. In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody selected from Codrituzumab, Belimumab, Mogamulizumab, Blinatumomab, Ibritumomab, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab, Moxetuinomab, Brentuximab, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Cemiplimab, Nivolumab, Pembrolizumab, Siltuximab, Olaratumab, Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Vandortuzumab, Codrituzumab, Atezolizumab, Avelumab, Durvalumab, Capiomab, Flotuzuinab, Denosumab, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxoinab, Ftaracizumab, or a modified version thereof or an antigen-binding fragment thereof, or a modified version thereof or an antigen-binding fragment thereof, M is a suitable radionuclide, and

(i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody selected from from Trastuzumab,, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Codrituzumab and Vandortuzumab or a modified version thereof or an antigenbinding fragment thereof, M is a suitable radionuclide, and

(i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody selected from Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab,

Codrituzumab and Vandortuzumab or a modified version thereof or an antigenbinding fragment thereof, M is a suitable radionuclide, preferably wherein M is 225Ac, and

In a further embodiment, the present disclosure covers a pharmaceutical composition comprising (i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody selected from

Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Codrituzumab and Vandortuzumab or a modified version thereof or an antigenbinding fragment thereof, M is 225Ac, and

(i) a conjugate of formula (III) and/or of formula (III’) wherein X is a urea, thiourea or amide moiety, [A] is a targeting moiety preferably comprising an antibody, an antibody fragment, a binding peptide, a binding polypeptide, a binding protein, an enzyme, a nucleobase-containing moiety or a lectin and M is a suitable radionuclide and

(i) a conjugate of formula (III) and/or of formula (III’) wherein X is a urea, thiourea or amide moiety, [A] is a targeting moiety preferably comprising an antibody, an antibody fragment, a binding peptide, a binding polypeptide, a binding protein, an enzyme, a nucleobase-containing moiety or a lectin and M is a suitable radionuclide, preferably wherein M is 225Ac, and

(i) a conjugate of formula (III) and/or of formula (III’) wherein X is a urea, thiourea or amide moiety, [A] is a targeting moiety preferably comprising an antibody, an antibody fragment, a binding peptide, a binding polypeptide, a binding protein, an enzyme, a nucleobase-containing moiety or a lectin, M is 225Ac, and

(i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody selected from Codrituzumab, Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab and Vandortuzumab or a modified version thereof or an antigen-binding fragment thereof, M is 225Ac, and

(ii) methionine or cysteamine in an amount of from 10 to 100 mM, preferably of from 30 to 70 mM, more preferably of from 40 to 60 mM. In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(ii) methionine in an amount of from 10 to 100 mM, wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof.

(ii) methionine in an amount of from 10 to 100 mM, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine in an amount of from 10 to 100 mM, wherein the targeting moiety comprises an antibody, an antibody fragment, a binding peptide, a binding polypeptide, a binding protein, an enzyme, a nucleobase-containing moiety, or a lectin.

(ii) methionine in an amount of from 10 to 100 mM, wherein the targeting moiety comprises an antibody, an antibody fragment, a binding peptide, a binding polypeptide, a binding protein, an enzyme, a nucleobase-containing moiety, or a lectin, and wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof.

(ii) methionine in an amount of from 10 to 75 mM, wherein the targeting moiety comprises an antibody, an antibody fragment, a binding peptide or a binding polypeptide, wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof.

(ii) methionine in an amount of from 10 to 75 mM, wherein the targeting moiety comprises an antibody, an antibody fragment, a binding peptide or a binding polypeptide, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine in an amount of from 30 to 60 mM, wherein the targeting moiety comprises an antibody, an antibody fragment or a binding peptide, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody, an antibody fragment or a binding peptide, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody, an antibody fragment or a binding peptide, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody or a binding peptide, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine in an amount of from 10 to 75 mM, wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof.

(i) a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a urea, thiourea or amide moiety, and (ii) methionine in an amount of from 30 to 60 mM, wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof.

(ii) methionine in an amount of from 30 to 60 mM, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine in an amount of from 40 to 60 mM, wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof.

(ii) methionine in an amount of from 40 to 60 mM, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine in an amount of from 10 to 75 mM, wherein the targeting moiety comprises an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAPI . wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine in an amount of from 10 to 75 mM, wherein the targeting moiety comprises a binding peptide or a binding polypeptide capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1. wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAPI . wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof. In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(ii) methionine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises a binding peptide or a binding polypeptide capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1. wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine in an amount of from 10 to 75 mM, wherein the targeting moiety comprises an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAPI . wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine in an amount of from 10 to 75 mM, wherein the targeting moiety comprises a binding peptide or a binding polypeptide capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1. wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAPI . wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises a binding peptide or a binding polypeptide capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1. wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) methionine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody selected from selected from Belimumab, Mogamulizumab, Blinatumomab, Ibritumomab, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab, Moxetuinomab, Brentuximab vedoiin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Cemiplimab, Nivolumab, Pembrolizumab, Siltuximab, Olaratumab, Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Vandortuzumab, Atezolizumab, Avelumab, Durvalumab, Capiomab, Flotuzuinab, Denosumab, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxoinab, Ftaracizumab, or a modified version thereof or an antigen-binding fragment thereof.

(ii) methionine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody selected from selected from Belimumab, Mogamulizumab, Blinatumomab, Ibritumomab, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab, Moxetuinomab, Brentuximab, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Cemiplimab, Nivolumab, Pembrolizumab, Siltuximab, Olaratumab, Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Vandortuzumab, Atezolizumab, Avelumab, Durvalumab, Capiomab, Flotuzuinab, Denosumab, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxoinab, Ftaracizumab, or a modified version thereof or an antigen-binding fragment thereof, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(i) a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a thiourea moiety, and (ii) methionine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody selected from Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab and Vandortuzumab, or a modified version thereof or an antigen-binding fragment thereof.

(ii) methionine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody selected from Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab and Vandortuzumab, or a modified version thereof or an antigen-binding fragment thereof, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) methionine in an amount of from 40 to 60 mM, wherein the targeting moiety comprises an antibody selected from Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab and Vandortuzumab, or a modified version thereof or an antigen-binding fragment thereof, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

In a further embodiment, the present disclosure covers a pharmaceutical composition comprising (i) a conjugate of formula (II) (PSMA-TAC SMOL)

(H), wherein M is a suitable radionuclide, preferably wherein M is 225Ac, and

(ii) methionine in an amount of from 10 to 100 mM, preferably of from 30 to 70 mM, more preferably of from 40 to 60 mM.

(i) a conjugate of formula (II) (PSMA-TAC SMOL)

(II), wherein M is 225Ac, and

(ii) methionine in an amount of from 10 to 100 mM, preferably of from 30 to 70 mM, more preferably of from 40 to 60 mM. In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

In a further embodiment, the present disclosure covers a pharmaceutical composition comprising (i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody or an antigenbinding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAPI , M is 225Ac, and

(i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody selected from Codrituzumab, Belimumab, Mogamulizumab, Blinatumomab, Ibritumomab, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab, Moxetuinomab, Brentuximab, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Cemiplimab, Nivolumab, Pembrolizumab, Siltuximab, Olaratumab, Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Vandortuzumab, Codrituzumab, Atezolizumab, Avelumab, Durvalumab, Capiomab, Flotuzuinab, Denosumab, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxoinab, Ftaracizumab, or a modified version thereof or an antigen-binding fragment thereof, or a modified version thereof or an antigen-binding fragment thereof, M is a suitable radionuclide, preferably wherein M is 225Ac, and

(i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody selected from Even more preferably, the antibody or antibody fragment is preferably selected from Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab,

Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Codrituzumab and Vandortuzumab or a modified version thereof or an antigenbinding fragment thereof, M is a suitable radionuclide, preferably wherein M is 225Ac, and

(ii) cysteamine in an amount of from 10 to 100 mM, wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof.

(ii) cysteamine in an amount of from 10 to 100 mM, wherein the targeting moiety comprises an antibody, an antibody fragment, a binding peptide, a binding polypeptide, a binding protein, an enzyme, a nucleobase-containing moiety, or a lectin.

(ii) cysteamine in an amount of from 30 to 60 mM, wherein the targeting moiety comprises an antibody, an antibody fragment or a binding peptide, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody, an antibody fragment or a binding peptide, wherein the radionuclide-containing chelating moiety comprises DOTA or Macropa or a derivative thereof.

(ii) cysteamine in an amount of from 30 to 60 mM, wherein the targeting moiety comprises an antibody, an antibody fragment or a binding peptide, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) cysteamine in an amount of from 20 to 60 mM, wherein the targeting moiety comprises an antibody, an antibody fragment or a binding peptide, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

(ii) cysteamine in an amount of from 10 to 75 mM, wherein the radionuclide-containing chelating moiety comprises DOTA, Macropa or a derivative thereof.

(i) a conjugate of formula (II) (PSMA-TAC SMOL)

wherein M is a suitable radionuclide, and

(ii) cysteamine in an amount of from 10 to 100 mM, preferably of from 20 to 70 mM, more preferably of from 20 to 60 mM.

(i) a conjugate of formula (II) (PSMA-TAC SMOL) (II), wherein M is 225Ac, and

(ii) cysteamine in an amount of from 10 to 100 mM, preferably of from 20 to 70 mM, more preferably of from 20 to 40 mM. In a further embodiment, the present disclosure covers a pharmaceutical composition comprising

(i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody or an antigenbinding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1 , M is a suitable radionuclide, preferably wherein M is 225Ac, and (ii) cysteamine in an amount of from 10 to 100 mM, preferably of from 20 to 70 mM, more preferably of from 20 to 60 mM, more preferably of from 20 to 40 mM.

In a further embodiment, the present disclosure covers a pharmaceutical composition comprising (i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody selected from Codrituzumab, Belimumab, Mogamulizumab, Blinatumomab, Ibritumomab, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab, Moxetuinomab, Brentuximab, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Cemiplimab, Nivolumab, Pembrolizumab, Siltuximab, Olaratumab, Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Vandortuzumab, Codrituzumab, Atezolizumab, Avelumab, Durvalumab, Capiomab, Flotuzuinab, Denosumab, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxoinab, Ftaracizumab, or a modified version thereof or an antigen-binding fragment thereof, or a modified version thereof or an antigen-binding fragment thereof, M is a suitable radionuclide, preferably wherein M is 225Ac, and

(ii) cysteamine in an amount of from 10 to 100 mM, preferably of from 30 to 70 mM, more preferably of from 20 to 60 mM, more preferably of from 20 to 40 mM.

(i) a conjugate of formula (Illa) and/or of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody selected from Even more preferably, the antibody or antibody fragment is preferably selected from Trastuzumab, Pelgifatamab, Labetuzumab, Sacituzumab, Indusatumab, Tesolituzumab, Farletuzumab, Mirvetuximab, Rovalpituzumab, Enfortumab, Codrituzumab and Vandortuzumab or a modified version thereof or an antigenbinding fragment thereof, M is a suitable radionuclide, preferably wherein M is 225Ac, and (ii) cysteamine in an amount of from 10 to 100 mM, preferably of from 30 to 70 mM, more preferably of from 20 to 60 mM, more preferably of from 20 to 40 mM.

(ii) cysteamine in an amount of from 10 to 100 mM, preferably of from 30 to 70 mM, more preferably of from 40 to 60 mM. In accordance with another aspect, the present disclosure covers methods for the preparation of the compositions of the present disclosure, said methods comprising the steps described in the Experimental Section herein.

The pharmaceutical compositions of the present disclosure can be used in particular in therapy and prevention, i.e. prophylaxis, of disorders, in particular of hyperproliferative disorders, more particularly in hyperproliferative disorders such as cancer.

The term “treating” or “treatment” as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, particularly a hyperproliferative disorder, more particularly a hyperproliferative disorder such as cancer.

In accordance with a further aspect, the present disclosure covers the use of the pharmaceutical compositions of the present disclosure for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, more particularly in hyperproliferative disorders such as cancer.

In accordance with a further aspect, the present disclosure covers the pharmaceutical compositions of the present disclosure for use in the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, more particularly in hyperproliferative disorders such as cancer.

In accordance with a further aspect, the present disclosure covers a method of treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, more particularly in hyperproliferative disorders such as cancer, using an effective amount of a pharmaceutical composition of the present disclosure, as described supra.

In accordance with a further aspect, the present disclosure covers the use of the pharmaceutical compositions of the present disclosure for the preparation of a medicament for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, more particularly in hyperproliferative disorders such as cancer.

In the context of the present disclosure, the term “pharmaceutical compositions” refers to any composition comprising radionuclide-containing conjugates comprising urea, thiourea or amide linking moieties which are suitable to comprise methionine and/or cysteamine. Preferably, the pharmaceutical compositions according to the present disclosure are in liquid form, i.e., liquid pharmaceutical compositions. More preferably, the pharmaceutical compositions according to the present disclosure are aqueous liquid pharmaceutical compositions. Thus, the pharmaceutical compositions of the present disclosure may comprise further components, such as pharmaceutically suitable excipients. Any excipient may be used as long as it is suitable for the provision of the pharmaceutical compositions of the present disclosure. Preferably, if present, any further component such as pharmaceutically suitable excipients may be considered in view of the preferred forms of the pharmaceutical compositions according to the present disclosure, which are preferably liquid pharmaceutical compositions and more preferably aqueous liquid pharmaceutical compositions.

The pharmaceutical compositions of the present disclosure may comprise further components, such as pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia,

• fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di- Cafos®)),

• ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),

• bases for suppositories (for example polyethylene glycols, cacao butter, hard fat),

• solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins),

• surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®),

• buffers, acids and bases (for example histidine, phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),

• isotonicity agents (for example glucose, sodium chloride, sucrose),

• adsorbents (for example highly-disperse silicas),

• cryo- and lyoprotectors (for examples sucrose, trehalose, mannitol, glycine)

• viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl-cellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine),

• disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol®)), • flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)),

• coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropyl-methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)),

• capsule materials (for example gelatine, hydroxypropylmethylcellulose),

• synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),

• plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),

• penetration enhancers,

• stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),

• preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

• colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),

• flavourings, sweeteners, flavour- and/or odour-masking agents.

In addition to a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety the pharmaceutical compositions of the present disclosure may comprise further pharmaceutically active components and/or ingredients. In accordance with a further aspect, the present disclosure covers pharmaceutical combinations, in particular medicaments, comprising at least a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a urea, thiourea or amide moiety, and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of diseases, in particular of hyperproliferative disorders, more particularly of hyperproliferative disorders such as cancer. It is understood that the pharmaceutical combinations, particularly medicaments, comprising at least a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a urea, thiourea or amide moiety, and at least one or more further active ingredients also comprise methionine or cysteamine as do the pharmaceutical compositions described throughout this document. Thus, the same considerations relating to the use and/or addition of methionine or cysteamine as described for the pharmaceutical compositions throughout the present document also apply to pharmaceutical combinations, particularly, medicaments, which further comprise at least one or more further active ingredients. Thus, the present disclosure covers pharmaceutical combinations, in particular medicaments, comprising at least a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a urea, thiourea or amide moiety, methionine or cysteamine, and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of diseases, in particular of hyperproliferative disorders, more particularly of hyperproliferative disorders such as cancer.

Particularly, the present disclosure covers a pharmaceutical combination, which comprises:

• at least one conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a urea, thiourea or amide moiety, and

• one or more further active ingredients, in particular for the treatment and/or prophylaxis of diseases, in particular of hyperproliferative disorders, more particularly of hyperproliferative disorders such as cancer.

• at least one conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a urea, thiourea or amide moiety, methionine or cysteamine, and

The further pharmaceutical agent is selected from a non-steroidal antiandrogen, a steroidal antiandrogen, an androgen synthesis inhibitor, an antigonadotropin, a PARP inhibitor, an ATR inhibitor, an ATM inhibitor, a DNA-PK inhibitor, an AKT inhibitor, a Pi3K inhibitor, a PSMA- targeting beta emitter, an immune checkpoint inhibitor, an alpha emitter, a vaccine and a chemotherapeutic agent.

Preferably, the further pharmaceutical agent is selected from a non-steroidal antiandrogen, a steroidal antiandrogen, an androgen synthesis inhibitor, an antigonadotropin, a PARP inhibitor, an AKT inhibitor, a Pi3K inhibitor, a PSMA-targeting beta emitter, an immune checkpoint inhibitor, an alpha emitter, a vaccine and a chemotherapeutic agent. More preferably, the further pharmaceutical agent is selected from a non-steroidal antiandrogen, a steroidal antiandrogen, an androgen synthesis inhibitor, an antigonadotropin, a PARP inhibitor, a PSMA-targeting beta emitter, an alpha emitter, a vaccine and a chemotherapeutic agent.

More preferably, the further pharmaceutical agent is selected from a non-steroidal antiandrogen, a steroidal antiandrogen, an androgen synthesis inhibitor, an antigonadotropin and a PARP inhibitor.

Even more preferably, the further pharmaceutical agent is selected from a non-steroidal antiandrogen, a steroidal antiandrogen, an androgen synthesis inhibitor, and an antigonadotropin.

If the further pharmaceutical agent is a non-steroidal antiandrogen, it is preferably selected from darolutamide, bicalutamide, enzalutamide, apalutamide, flutamide, nilutamide and topilutamide. More preferably, the non-steroidal antiandrogen is selected from darolutamide and enzalutamide, most preferably the non-steroidal antiandrogen is darolutamide

If the further pharmaceutical agent is a steroidal antiandrogen, it is preferably selected from Cyproterone acetate, Allylestrenol, Chlormadinone acetate, Delmadinone acetate, Gestonorone caproate, Hydroxyprogesterone caproate, Medroxyprogesterone acetate, Megestrol acetate, Osaterone acetate, Oxendolone and Spironolactone. More preferably, the steroidal antiandrogen is Cyproterone acetate.

If the further pharmaceutical agent is an androgen synthesis inhibitor, it is preferably selected from ketoconazole, abiraterone, aminoglutethimide, goserelin and seviteronel. More preferably, the androgen synthesis inhibitor is arbiraterone or goserelin.

If the further pharmaceutical agent is an antigonadotropin, it is preferably selected from Abarelix, Danazol, Gestrinone, Paroxypropione, Cetrorelix, Degarelix, Elagolix, Ganirelix, Linzagolix and Relugolix. More preferably, the antigonadotropin is Degarelix or Relugolix.

If the further pharmaceutical agent is a PARP inhibitor, it is preferably selected from Olaparib, Rucaparib, Veliparib, Niraparib, Talazoparib, Pamiparib, CEP 9722, E7016 and Iniparib. More preferably, the PARP inhibitor is Olaparib or Rucaparib.

If the further pharmaceutical agent is an ATR inhibitor, it is preferably selected from Berzosertib, BAY1895344, AZD6738, M6620, AZ20 and VE 821. More preferably, the PARP inhibitor is Berzosertib or BAY1895344.

If the further pharmaceutical agent is an ATM inhibitor, it is preferably selected from AZD1390, KU-55933, KU-60019, KU-59403, CP-466722, AZ31/AZ32 and AZD0156.

If the further pharmaceutical agent is a DNA-PK inhibitor, it is preferably selected from ZD7648, Nedisertib, VX-984, CC-115, Samotolisib and BAY-8400. More preferably, the DNA-PK inhibitor is Nedisertib or BAY-8400. If the further pharmaceutical agent is an AKT inhibitor, it is preferably selected from Ipatasertib, afuresertib, miransertib, capivasertib, uprosertib and MK2206. More preferably, the AKT inhibitor is Ipatasertib.

If the further pharmaceutical agent is a Pi3K inhibitor, it is preferably selected from Copanlisib, Buparlisib, Duvelisib, Idelalisib, Paxalisib, Zandelisib, Inavolisib, Duvelisib, Alpelisib and Umbralisib. More preferably, the Pi3K inhibitor is Copanlisib.

If the further pharmaceutical agent is a PSMA-targeting beta emitter, it is preferably (177Lu)- vipivotide tetraxetan, 177Lu-PSMA-l and PNT2002.

If the further pharmaceutical agent is an immune checkpoint inhibitor, it is preferably selected from Atezolizumab, Durvalumab, Avelumab, Nivolumab, Pembrolizumab and Ipilimumab.

If the further pharmaceutical agent is an alpha emitter, it is preferably selected from 223Ra, J591-225AC and PSMA-617-225AC.

If the further pharmaceutical agent is a vaccine, it is preferably Sipoleucel T.

If the further pharmaceutical agent is a chemotherapeutic agent, it is preferably selected from Paclitaxel, Docetaxel, Ixabepilone, Vinorelbine, Nocodazole, Vincristine, Colchicine and Eribulin. More preferably, the chemotherapeutic agent is Paclitaxel or Docetaxel.

The term “combination” in the present disclosure is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts.

A “fixed combination” in the present disclosure is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as at least a conjugate comprising a targeting moiety and a radionuclide-containing chelating moiety, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a urea, thiourea or amide moiety, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.

A non-fixed combination or “kit-of-parts” in the present disclosure is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of- parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

The pharmaceutical compositions of the present disclosure can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical compositions where the combination causes no unacceptable adverse effects. The present disclosure also covers such pharmaceutical combinations. For example, the pharmaceutical compositions of the present disclosure can be combined with other known indication agents.

The amount of the administered active ingredient can vary widely according to such considerations as the particular compound and dosage unit employed, the mode and time of administration, the period of treatment, the age, sex, and general condition of the patient treated, the nature and extent of the condition treated, the rate of drug metabolism and excretion, the potential drug combinations and drug-drug interactions, and the like.

DESCRIPTION OF THE FIGURES

Figure 1 shows the chemical structure of the compound of formula (II), i.e., “PSMA-SMOL” (nonconjugated to a radionuclide).

Figure 2 shows the % of radiolabelled conjugate (RCP) for Th-227-HOPO-NHS Trastuzumab (iTLC) with and without methionine at Oh and after 96h.

Figure 3 shows the % of radiolabelled conjugate (RCP) for Th-227-HOPO-NCS-Trastuzumab (iTLC) with and without methionine at Oh and after 96h. iTLC at t=0 shows 98% radiolabeling for both samples with and without methionine. A decrease of 48% was observed after 96h without methionine while a decrease of only 8% was observed with methionine present.

Figure 4 shows the amount of free chelator (iTLC) for Ac-225-DOTA-NCS-GPC3 with and without methionine. An increase in RFC of 9% was observed without methionine while no change in RFC was observed with methionine present.

Figure 5 shows the amount of free chelator (iTLC) for Ac-225-Macropa-NCS-GPC3 with and without methionine after 1 h, 96h, 144h and 192h storage.

Figure 6 shows the average RFC (%) values (n = 3 RFC, iTLC) for Ac-225-macropa-NCS- Pelgifatamab samples at Oh, 48h, 72h and 96h after radiolabeling.

Figure 7 shows the binding of Ac-225-macropa-NCS-Pelgifatamab to PSMA-coated magnetic beads at Oh and after 96h in radiolabelled samples in the absence or presence of 50 mM methionine.

Figure 8 the binding of the binding of Ac-225-macropa-NCS-Pelgifatamab to GPC3-coated magnetic beads at Oh and after 96h, 144h and 192h in radiolabelled samples in the absence or presence of 50 and 100 mM methionine. Figure 9 shows the binding of Ac-225-DOTA-NCS-GPC3 to GPC3-coated magnetic beads at Oh and after 96h in radiolabelled samples in the absence or presence of 50 mM methionine.

Figure 10 shows the binding of Th-227-HOPO-NCS-Trastuzumab to HER2-coated magnetic beads at Oh and after 96h in radiolabelled samples in the absence or presence of 50 mM methionine.

Figure 11 shows the binding of Th-227-HOPO-NHS-Trastuzumab to HER2-coated magnetic beads at Oh and after 96h in radiolabelled samples in the absence or presence of 50 mM methionine.

Figure 12 shows the cell cytotoxicity of (a) Ac225_macropa-NCS-GPC3, (b) Ac225_macropa- NCS-GPC3 + 50 mM Methionine, (c) Ac225_macropa-NCS-GPC3 + 100 mM Methionine and (d) Ac225_macropa-NCS-lsotype against the GPC3-expressing Hepatocellular Carcinoma cell line Hep3B2.

Figure 13 shows the cell cytotoxicity of (a) Ac225_macropa-NCS-GPC3, (b) Ac225_macropa- NCS-GPC3 + 50 mM Methionine, (c) Ac225_macropa-NCS-GPC3 + 100 mM Methionine and (d) Ac225_macropa-NCS-lsotype against the GPC3-expressing Hepatocellular Carcinoma cell line HepG2.

Figure 14 shows the RCP (determined by SE-HPLC) for Zr-89-DFO*-NCS-GPC3 without and with 50mM methionine. RCP was quantified by SE-HPLC.

Figure 15 shows the monomeric purity for Ac-225-macropa-Pelgifatamab with 50mM and without methionine. The monomeric purity decreased 9% over 96h while with 50mM methionine present the decrease was reduced to 4%.

Figure 16 shows the monomeric purity for Ac-225-macropa-NCS-GPC3 with 50mM and without methionine. The monomeric purity decreased 12% over 96h while with 50mM methionine present the decrease was reduced to 6%.

Figure 17 shows the monomeric purity for Th-227-HOPO-NCS-Trastuzumab with 50mM and without methionine. The monomeric purity decreased 8% over 96h while with 50mM methionine present the decrease was reduced to 5%.

Figure 18 shows the monomeric purity for Ac-225-DOTA-NCS-GPC3 with and without methionine. The monomeric purity decreased 26% over 96h while with 50mM methionine present the decrease was reduced to 15%.

Figure 19 shows the monomeric purity for Th-227-HOPO-NHS-Trastuzumab with and without methionine. The monomeric purity decreased 24% over 96h while with methionine present the decrease was reduced to 19%.

Figure 20 shows the radiopurity for Ac-225-PSMA-SMOL with and without methionine. The radiopurity of the 225Ac-PSMA-SMOL decreases over 72h by 20% without the presence of methionine in the formulation and by 6% with 10mM methionine present in the formulation. Increasing the methionine concentration to 100mM is shown to also retard the decrease in radiopurity over 72h to 6%.

Figure 21 shows the mean RCP for Ac-225-PSMA-SMOL with and without methionine after 96h.

Figure 22 shows the mean UV purity for Ac-225-PSMA-SMOL with and without methionine after 96h.

Figure 23 shows the RCP for Ac-225-PSMA-SMOL as a function of the Cysteamine concentration after 96h.

Figure 24 shows the mean UV purity for Ac-225-PSMA-SMOL as a function of the Cysteamine concentration after 96h.

Figure 25 shows the IRF for compositions comprising 225Ac-Sacituzumab-Macropa and 225Ac- Farletuzumab-Macropa with and without methionine or cysteamine.

EXPERIMENTAL SECTION

Abbreviations

Table 1. List of Abbreviations

The following table lists the abbreviations used herein.

225Ac actinium-225

Ac-225 actinium-225

ACC antibody-chelator conjugate

ACN acetonitrile

BCA Bicinchoninic acid

BRFF-HPC1 Serum free medium

CAR chelator-to-antibody ratio

DCTA 1 ,2-diaminocyclohexanetetraacetic acid

DMA N,N-dimethylacetamide

DMSO dimethyl sulfoxide

DOTA 1 ,4,7, 10-tetraazacyclododecane-1 ,4,7, 10-tetraacetic acid

ESI electrospray ionization EtOH ethanol

FBS fetal bovine serum

FPLC fast protein liquid chromatography

GPC3 Glypican 3

HCI hydrochloric acid

HPGe high purity germanium

HPLC high performance liquid chromatography iTLC instant thin layer chromatography

IRF immunoreactive fraction mAb monoclonal antibody min minutes

MS mass spectrometry

NaCI sodium chloride nm nanometer nmol nanomol

Pelgifatamab prostate-specific membrane antigen lgG1 antibody

PBS phosphate buffered saline

PSMA prostate-specific membrane antigen

RAC radioactive concentration

RCP radiochemical purity

RFC radiolabelled-free chelator

SEC size exclusion chromatography

TAC targeted actinium conjugate (Ac-225 labelled ACC)

TFA trifluoroacetic acid

LIPLC ultra performance liquid chromatography

UV ultraviolet

References

Strickley, R., Lambert W., A review of Formulations of Commercially Available Antibodies,

Jorunal of Pharmacuetical Sciences, 110 (7), 2021 , pp. 2590-2608. Vermeulen K., et al., Design and Challenges of Radiopharaceuticals, Seminars in Nuclear Medicine, 49 (5), 2019, pp. 339-356.

Wu , Z., Drug stability testing and formulation strategies, Pharmaceutical Development and Technology, 23 (10), 2018, p. 941.

Conjugation and purification

Macropa-NCS-GPC3:

6-[[16-[(6-carboxy-2-pyridyl)methyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadec-7-yl]methyl]-4- [2-(4-isothiocyanatophenyl)ethoxy]pyridine-2-carboxylic acid was dissolved in DMA to 10 mg/ml. Anti-GPC3 antibody was dissolved in PBS to 10 mg/mL and the pH was adjusted to 9 with 1M carbonate buffer. Chelator and antibody were mixed and incubated on a thermomixer shaking at 350 rpm at RT for two hours. Product was purified by FPLC (column: HiLoad 16/600 Superdex 200 pg column; running buffer: 100 mM acetate/100 mM NaCI 1 :1 , pH 5; flow: 1 mL/min; detection: UV 214/254 nm). Concentration and monomeric purity were determined by SEC-LIV CAR was determined by SEC-MS using positive electrospray ionization and the following equation: CAR=[(A*An)/A]0, A=lntensity of all signals of the maximum entropy envelope, An=signals of the maximum entropy envelope containing chelators.

DOTA-NCS-GPC3: p-SCN-Bn-DOTA (Macrocyclics, B-205) and anti-GPC3 antibody were dissolved in PBS to 10 mg/mL. The pH of the antibody was adjusted to 9 with 1M carbonate buffer. p-SCN-Bn-DOTA was added to the antibody and the mixture was incubated on a thermomixer shaking at 550 rpm at RT overnight. The conjugate was purified by FPLC (column: HiLoad 16/600 Superdex 200 pg column; running buffer: 20 mM sodium acetate, pH 5; flow: 1 mL/min; detection: UV 280 nm). The concentration and monomeric purity of the combined DOTA-antibody fraction were measured by SEC-UV. CAR was determined by SEC-MS using positive electrospray ionization and the following equation: CAR=[(A*An)/A]0, A=lntensity of all signals of the maximum entropy envelope, An=signals of the maximum entropy envelope containing chelators.

DFO*-NCS-GPC3:

5,11 ,16,22-T etraazahexacosanediamide, N 1 -[5-(acetylhydroxyamino)pentyl]-N26,5, 16- trihydroxy-N26-[5-[[[(4-isothiocyanatophenyl)amino]thioxomethyl]amino]pentyl]-4, 12, 15,23- tetraoxo- (p-Phe-NCS-DFO*, ABX advanced chemical compounds, 7272. XXXX) dissolved in DMA to 10 mg/ml. Anti-GPC3 antibody was dissolved in PBS to 10 mg/mL. The pH of the antibody was adjusted to 9 with 1M carbonate buffer. p-Phe-NCS-DFO* was added to the antibody and the mixture was incubated on a thermomixer shaking at 1 hour at 37°C. The conjugate was purified by PD-10 column according to manufactures instructions (Cytiva, 17085101). The monomeric purity of the DFO*-GPC3 conjugate was measured by SEC-LIV. CAR was determined by SEC-MS using positive electrospray ionization and the following equation: CAR=[(A*An)/A]0, A=lntensity of all signals of the maximum entropy envelope, An=signals of the maximum entropy envelope containing chelators.

HOPO-NCS-Trastuzumab:

NCS-HOPO chelator was dissolved in DMA to 10 mg/ml. Trastuzumab was dissolved to 10 mg/ml in PBS and the pH was adjusted to 9 with 1M carbonate buffer. Chelator and trastuzumab were mixed and incubated on a thermomixer shaking at 350 rpm at RT for one hour. Product was purified by FPLC (column: HiLoad 16/600 Superdex 200 pg column; running buffer: 30 mM citrate buffer, pH 5; flow: 1 mL/min; detection: UV 214/254 nm). Concentration, monomeric purity and CAR were determined by SEC-LIV.

HOPO-NHS-Trastuzumab:

HOPO-chelatorwas dissolved in 1 :1 MES/DMA to 10 mg/ml. Dissolved NHC in 0.1 M MES buffer to 10 mg/ml. Dissolved EDC in 0.1 M MES buffer to 50 mg/ml. The components were mixed by first adding the EDC to the chelator followed by NHS. Incubate for 35 min in the dark at 22 °C, 700 rpm 10 sec intervals. Activated chelator was added to trastuzumab and incubated for 30 min in the dark at 22 °C, 700 rpm 10 sec intervals. 12 % 0.3 M citric acid was added to quench the reaction. Product was purified by FPLC (column: HiLoad 16/600 Superdex 200 pg column; running buffer: 30 mM citrate buffer, pH 5; flow: 1 mL/min; detection: UV 214/254 nm). Concentration, monomeric purity and CAR were determined by SEC-UV.

Sacituzumab-Macropa and Farletuzumab-Macropa

The conjugates of formula (lllb) (Sacituzumab-Macropa and Farletuzumab-Macropa), i.e., conjugates comprising the chelator macropa and the antibodies Sacituzumab and Farletuzumab capable of binding to TROP2 and FoIRa, respectively, were prepared according to the following procedure: 6-[[16-[(6-carboxy-2-pyridyl)methyl]-1 ,4,10,13-tetraoxa-7,16-diazacyclooctadec-7- yl]methyl]-4-[2-(4-isothiocyanatophenyl)ethoxy]pyridine-2-carboxylic acid was dissolved in DMA to 10 mg/ml. Sacituzumab or Farletuzumab antibody were dissolved in PBS to 10 mg/mL and the pH was adjusted to 9 with 1M carbonate buffer. Chelator and antibody were mixed and incubated on a thermomixer shaking at 350 rpm at RT for one hour. Product was purified by FPLC (column: HiLoad 10/300 Superdex 200 pg column; running buffer: 6 mM citrate buffer containing 10 mM histidine/glycine, 50 mM methionine and 100 mM NaCI (pH 6) or 100 mM acetate buffer (pH 5) or 30mM citrate buffer, 0.1 mg/ml PS80 and 1 :1 water/saline containing 30mM Cysteamine (pH 7); flow: 0.75 mL/min; detection: UV 280 nm). Concentration and monomeric purity were determined by SEC-UV. CAR was determined by SEC-MS using positive electrospray ionization and the following equation: CAR=[(A*An)/A]0, A=lntensity of all signals of the maximum entropy envelope, An=signals of the maximum entropy envelope containing chelators.

Radiolabelling

Ac-225-Macropa-NCS-GPC3:

Ac-225 was added to Macropa-NCS-GPC3 in citrate buffer (30 mM citrate, pH 5.5) containing 50 mM methionine at a specific activity of 2 MBq/mg and a radioactive concentration of 1-2.5 kBq/pL. The mixture was incubated for one hour at room temperature followed by determination of RCP by iTLC.

Ac-225-DOTA-NCS-GPC3:

Ac-225 was added to DOTA-NCS-GPC3 in citrate buffer (30 mM citrate, pH 5.5) containing 50 mM methionine at a specific activity of 2 MBq/mg and a radioactive concentration of 1-2.5 kBq/pL. The mixture was incubated for one hour at 60 °C followed by determination of RCP by iTLC.

Zr-89-DFO*-GPC3:

Zirconium-89 in 1M oxalic acid (10 MBq in 12 uL) was added to DFO*-NCS-GPC3 in HEPES 1 M, pH 7.3, and further diluted into HEPES pH 7.3, to a final volume of 97 uL containing 50 mM methionine with a specific activity of 20 MBq/mg and a RAC of 103 MBq/mL. After incubation for 30 minutes at 37 °C, the sample was diluted to a RAC of 23 MBq/mL with formulation buffer (10 mM L-Histidine, 130 mM Glycine, 5% (m/v) Sucrose in water for injection) containing 50 mM methionine.

Ac-225-macropa-NCS-PSMA SMOL (PSMA-SMOL-TAC):

PSMA-SMOL (a PSMA targeting small molecule consisting of a pharmacophore linked to a Macropa chelator via an NCS linker) was radiolabelled with Ac-225 in a formulation buffer containing OmM, 10mM or 100 mM methionine in respective replicates, at a molecular activity of 300 kBq/nmol and a radioactive concentration of 2 kBq/pL. The reaction was incubated for one hour at room temperature before analysis at relevant time points.

Ac-225-Sacituzumab-Macropa and Ac225-Farletuzumab-Macropa

Radiolabeling of the conjugates of formula (I lib) (Ac-225-Sacituzumab-Macropa and Ac-225- Farletuzumab-Macropa), i.e., conjugates comprising the chelator macropa and the antibodies Sacituzumab and Farletuzumab capable of binding to TROP2 and FoIRa, respectively and labelled with 225Ac, was carried out according to the following procedure: Ac-225 was added to Macropa-Sacituzumab or Macropa-Farletuzumab in acetate buffer ( pH 5) or 6 mM citrate, 10 mM histidine/glycine containing 50 mM methionine or 30mM citrate, 0.1mg/ml PS80 and 1 :1 water/saline containing 30mM Cysteamine at a specific activity of 500 KBq/nmol and a radioactive concentration of 2 kBq/pL. The mixture was incubated for one hour at room temperature followed by determination of radiolabeling efficiency by iTLC.

Analytical methods iTLC (citrate)

An iTLC was preformed to measure radiolabeling of the TAC. In brief, iTLC. SG. plate was cut to obtain 11 cm x 1 cm strips. Application point (1 cm), cut point (4 cm) and end of run point (10 cm) was marked with a marked and 2 ul of TAC was applied on n=3 strips per sample. The strips were developed in 3 mL mobile phase in LSC Vials. When the liquid front had reached the marked end point, they were removed from the vial and placed on an aluminum foil to dry. The strips were cut in two at 4 cm: the shorter “application” half (A) and the longer “front” half (F). Each part was carefully folded and placed at the bottom of scintillation vials. For thorium-227, the samples were read off immediately, while for actinium-225 a 6h delay is needed to obtain secular equilibrium in the sample. The application part was counted for 60 sec and front part counted for 120 sec in the AutoGEM. The measured activity at application and front was used to calculate the % RCP in each replicate at each given time point. iTLC (RFC)

A free chelator iTLC was preformed to measure the amount of free chelator in the conjugate solution over time. In brief, an iTLC. SG. plate was cut to obtain 12 cm x 1 cm strips. Application point, cut point and end of run point was marked at 1 cm, 4 cm and 10 cm, respectively. 2 pL of TAC sample was applied on n = 3 iTLC strips for elution with a freshly made 1 : 1 1 M ammonium acetate /100% metanol mobile phase The strips were developed in 3 mL mobile phase in LSC Vials. When the liquid front had reached the marked end point, they were removed from the vial and placed on an aluminum foil to dry. The strips were cut in two at 4 cm: the shorter “application” half (A) and the longer “front” half (F). Each part was carefully folded and placed at the bottom of scintillation vials. For thorium-227, the samples were read off immediately, while for actinium- 225 a 6h delay is needed to obtain secular equilibrium in the sample. The application part was counted for 60 sec and front part counted for 120 sec in the AutoGEM. The measured activity at application and front was used to calculate the % RCP in each replicate at each given time point. iTLC (Ac-225-Sacituzumab-Macropa and Ac225-Farletuzumab-Macropa)

The radiolabelling efficiency of the conjugates was measured by instant thin layer chromatography using citrate buffer in saline for elution, three replicates for each sample. Unlabelled Ac-225 elutes in the solvent front while the radiolabelled compounds do not move from the application section. The measurement of radioactivity was done with a Digital GammaRay Spectrometer (DSPEC-50, Ortec). The activities were measured at least 6 hours after radiolabelling to allow daughter nuclides to be in equilibrium with Ac-225. The radiolabelling efficiency of the samples is defined as [(radioactivity of application section)/(total radioactivity on strip)] x 100.

Immunoreactive fraction assay

Targeted Actinium Conjugates (TAC), Targeted Thorium Conjugates (TTC) and Targeted Zirconium Conjugates (TZC)

Shortly after completion of the radiolabeling and 96 hours later (samples stored at room temperature), the binding of each sample to antigen-coated M-270-carboxy Dynabeads was determined. In short, 3-600 pg beads were placed in 2 mL Eppendorf tubes in 50 pL buffer (PBS/3% BSA). The radiolabeled compounds were diluted to 5 Bq/pL in buffer and added to each bead-containing tube. The samples were run in triplicate. The binding lasted for 60-90 min while shaking the tubes on a Thermomixer (Eppendorf) at 750 rpm at room temperature. After completion of the binding step, 40 pL of buffer was added to each tube and a magnet (DynaMag- 2) was used to separate the beads from half of the supernatant. The radio activities in the supernatant and in the beads of each sample were measured using a Digital Gamma-Ray Spectrometer. With Ac-225, the activities were measured after at least 6 hours, to allow daughter nuclides to be in equilibrium. For Th-227 the activity could be measured immediately. Total binding was defined as [(activity in beads - activity in supernatant)/ (total activity)] x 100.

Ac-225-Sacituzumab-Macropa and Ac225-Farletuzumab-Macropa

Shortly after completion of the radiolabelling of Macropa-Sacituzumab and Macropa- Farletuzumab, the binding of each sample to its respective antigen-coated M270-carboxy Dynabeads were determined. In short, 100 pg beads were placed in 2 mL Eppendorf tubes in 50 pL buffer (PBS/3% BSA). The samples were run in triplicate. The radiolabelled compounds were diluted to 5 Bq/pL in buffer and added to each bead-containing tube. The binding lasted for 60 min while shaking at 750 rpm at room temperature. After completion of the binding step, 40 pL of buffer was added to each tube and a magnet (DynaMag-2) was used to separate the beads from half of the supernatant. The radio activities in the supernatant and in the beads of each sample were measured using a Digital Gamma-Ray Spectrometer. The activities were measured after at least 6 hours, to allow daughter nuclides to be in equilibrium with Ac-225. Total binding was defined as [(activity in beads - activity in supernatant)/(total activity)] x 100.

SEC-HPLC

Purity of the TACs, TTCs and TZCs were determined by SEC-HPLC. The method separates higher aggregates, dimer and fragments from the monomer. The separation was done using a Acquity LIPLC Protein BEH SEC, 1.7 pm, 200A, 4.6 x 300 mm column operated at 30 °C. The mobile phase was 200 mM Ammonium acetate and 300 mM NaCI containing 10% 2-propanol and 0.1 mM DCTA (pH 7) for the TACs, 170 mM Ammonium acetate, 30 mM acetic acid and 300 mM NaCI containing 5% DMSO and 1 mM DTPA (pH5.5) for the TTCs and 150 mM NaCI, 10 mM EDTA in Dulbecco PBS, pH 6.8 containing 10% 2-propanol for the TZCs. The flowrate was 0.3 mL/min, and the TACs/TTCs were detected using a radioactivity detector. The analyses were performed on an Agilent 1200 series or a Vanquish HPLC. Fractionation was performed using a Thermo fraction collector based on retention times of the peaks in the radio chromatograms. The fractions were counted on a high-resolution germanium detector.

Ac-225-Sacituzumab-Macropa and Ac225-Farletuzumab-Macropa

Purity and stability of Ac-225-Sacituzumab-Macropa and Ac225-Farletuzumab-Macropa were determined by SEC-LIV and SEC-radio and followed over the course of 120 hours. The method separates higher aggregate, dimer and fragments from the ACC monomer. The separation was done using a Acquity LIPLC Protein BEH SEC, 1 .7 pm, 200A, 4.6 x 300 mm column operated at 30 °C. The mobile phase was 170 mM Ammonium acetate and 300 mM NaCI containing 10% 2-propanol and 0.1 mM DCTA. The flowrate was 0.3 mL/min, and the ACCs were detected at UV 280 nm. The analysis was performed on an Agilent 1200 series HPLC with 25 pL injections. For radiochemical purity (RCP), the column eluate was detected by a gamma radioactivity detector. The eluate was collected as fractions by an Agilent G1364F fraction collector. The fractions were collected based on the retention time of the aggregate, monomer and fragments. Fractions were allowed to reach secular equilibrium for the Fr-221 daughter of Ac-225 (1 hour). Fr-221 was quantified in each fraction as a proxy for Ac-225, as these isotopes were in secular equilibrium. The total counts of the Ac-225 in each fraction were thus quantified. The total Ac- 225 in the fraction representing the monomer peak of the chromatogram was then divided by the total Ac-225 quantified in all fractions of the chromatogram and multiplied by 100 to attain a %RCP value for the 225Ac-TAC drug product in the respective experimental radioprotectant buffer conditions. RP-HPLC PSMA-SMOL Molecule Targeted Actinium Conjugate (PSMA- SMOL-TAC)

Purity of the PSMA-SMOL-TAC was determined by RP-HPLC. The method separates the target radiochemical entity from radio-impurities to determine the radiopurity. The separation was done using a BioZen Peptide XB-C18, 1.7 pm, 2.1 x 150 mm column operated at 50 °C. The aqueous mobile phase (A) was 20 mM TRIS containing 1mM EDTA (pH 7), and the organic mobile phase (B) was 100%(v/v) Methanol. The flow rate was 0.4 mL/min, with a gradient of 40% B to 60% B from 0 to 20 minutes, and static 60% B from 20 to 25 minutes. The total run time was 25 minutes. The PSMA-SMOL-TAC was detected using a radioactivity detector. The analyses were performed on an Agilent 1200 series HPLC.

Cell cytotoxicity In-vitro cytotoxicity of Ac-225-macropa-NCS-GPC3 ± 50 mM Methionine was measured in Human Hepatocellular Carcinoma cell lines expressing different levels of GPC3. Hep3B2 and HepG2 cells were seeded at an appropriate cell density in the cell media MEM + 10% FCS. One day after seeding, Ac-225-macropa-NCS-GPC3 at a specific activity of 2 MBq/mg and 5 kBq/ml were titrated in parallel with a relevant negative isotype control which was radiolabeled in the same conditions. Ac-225-macropa-NCS-GPC3 was added at Oh, after 96h, 144h and 192h. Cells were treated for 6 days and subsequentially cell viability was determined using Hoechst and PI staining and analyze on Operetta CLS High Content Analysis System (Perkin Elmer)

Stability study with PSMA-SMOL-TAC

Preparation of 225Ac-PSMA-SMOL-TAC compositions with methionine and cysteamine

The lyophilisate of PSMA-SMOL-TAC was reconstituted with sterile water for injection (SWFI) at 0.2 mg/ml concentration. A 900 pl aliquot of the reconsituted PSMA-SMOL-TAC was added to 17.1 ml of the relevant Formulation Buffer (30mM Citrate, 0.1mg/ml PS80 and 0.45% NaCI) containing either 75 mM L-Methionine or 1 mM I 5mM I 10mM I 20mM I 50mM I 75mM Cysteamine Hydrochloride. An aliquot of approximately 63pl 0.37MBq/pl Actinium-225 in 0.05 M HCI (volume varies with stock decay) was added to achieve a target final radioactive concentration (RAC) of 1.3 MBq/ml with a 10pg/ml PSMA-SMOL-TAC concentration. The reaction mixture was placed on a heated shaker (25 °C, 250 rpm) for 60 minutes. A reaction sample was subsequently assessed for the radiochemical purity (RCP) of the 225Ac-PSMA- SMOL-TAC by reverse phase high pressure liquid chromatography (RP-HPLC) with fractionation after 96 hours incubation at ambient room temperature as part of an assessment of shelf life to elucidate the optimum choice of radioprotectant.

Reverse Phase High Pressure Liquid Chromatography (RP-HPLC) with Fractionation

Table 2 - RP-HPLC parameters for the determination of the RCP values of 225Ac-PSMA-SMOL- TAC compositions with methionine and/or cysteamine on an Agilent Infinity II 1260 equipped with a fractionation sample collector.

A 10OpI sample of the 225Ac-PSMA-SMOL-TAC in the respective experimental buffer conditions were injected onto an Agilent Infinity II 1260 equipped with a fractionation sample collector. The sample was run with conditions described in Table 2 on an Agilent Infinity II 1260 HPLC machine after the completion of the 96-hour incubation, alongside relevant controls. Column eluate was detected by a UV detector measuring at 270nm and a gamma radioactivity detector. The eluate was collected as fractions by an Agilent G1364F fraction collector. The fractions were collected as 10-minute bulk fractions, expect for the 225Ac-PSMA-SMOL-TAC peak, which was collected as 0.17ml fractions triggered by an up slope of 0.4 mV/s in the expected elution window of 15 to 20 minutes. A subsequent switch in slope to baseline of 0.01 mV/s returned the machine to 10- minute bulk fractionation until the end of the 35-minute run time.

Fractions were allowed to reach secular equilibrium for the Fr-221 daughter of Ac-225 - a time not less than 2 hours (as described in: Kelly et al., “A suitable time point for quantifying the radiochemical purity of 225Ac-labeled radiopharmaceuticals”, doi: 10.1186/s41181-021-00151- y). Fr-221 was quantified in each fraction as a proxy for Ac-225, as these isotopes were in secular equilibrium. The total counts of the Ac-225 in each fraction were thus quantified. The total Ac- 225 in the fractions representing the 225Ac-PSMA-SMOL-TAC peak of the chromatogram were then divided by the total Ac-225 quantified in all fractions of the chromatogram and multiplied by 100 to attain a %RCP value for the 225Ac-PSMA-SMOL-TAC drug product in the respective experimental radioprotectant buffer conditions after the 96-hour incubation period.

Stability of pharmaceutical compositions comprising 225Ac-Sacituzumab-Macropa and 225Ac-Farletuzumab-Macropa

Table 3 shows the radiolabeling efficiency of pharmaceutical compositions comprising 225Ac- Sacituzumab-Macropa and 225Ac-Farletuzumab-Macropa with and without methionine or cysteamine as determined by iTLC at different times (t = Oh, 24h, 120h), showing that any degradation of the conjugates does not arise from decomplexation of 225Ac from the chelator.

Table 3. Radiolabeling efficiency of pharmaceutical compositions comprising 225Ac- Sacituzumab-Macropa and 225Ac-Farletuzumab-Macropa with and without methionine or cysteamine as determined by iTLC at different times (t = Oh, 24h, 120h).

Table 4 and Figure 25 show the stability of pharmaceutical compositions comprising 225Ac- Sacituzumab-Macropa and 225Ac-Farletuzumab-Macropa with and without methionine or cysteamine as determined by the measurement of the radiochemical purity, immunoreactive fraction and stability of the different compositions at different times (t = Oh, 24h, 120h).

Table 4. RCP and stability of pharmaceutical compositions comprising 225Ac-Sacituzumab-

Macropa and 225Ac-Farletuzumab-Macropa with and without methionine or cysteamine at different times (t = Oh, 24h, 120h).

Claims

1. A pharmaceutical composition comprising

(ii) methionine or cysteamine in an amount of from 10 to 100 mM, preferably of from 10 to 75mM.

2. The pharmaceutical composition according to claim 1 , wherein the radionuclidecontaining chelating moiety comprises DOTA, Macropa or a derivative thereof.

3. The pharmaceutical composition according to any of claims 1 or 2, wherein the radionuclide-containing chelating moiety comprises Macropa or a derivative thereof.

4. The pharmaceutical composition according to any of claims 1 to 3, comprising methionine in an amount of from 10 to 75mM, preferably of from 30 to 60mM, more preferably of from 40 to 60m M.

5. The pharmaceutical composition according to any of claims 1 to 3, comprising cysteamine in an amount of from 20 to 60mM, preferably of from 20 to 50mM, more preferably of from 20 to 40mM.

6. The pharmaceutical composition according to any of claims 1 to 5, wherein the targeting moiety comprises an antibody, an antibody fragment, a binding peptide or a binding polypeptide, preferably wherein the targeting moiety comprises an antibody, an antibody fragment or a binding peptide, more preferably wherein the targeting moiety comprises an antibody or an antigen-binding fragment thereof.

7. The pharmaceutical composition according to any of claims 1 to 6, wherein the targeting moiety is capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAPI .

8. The pharmaceutical composition according to any of claims 1 to 7, wherein the targeting moiety comprises an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GUCY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1.

9. The pharmaceutical composition according to any of claims 1 to 8, wherein the radionuclide is an alpha-emitting radionuclide, preferably wherein the radionuclide is actinium-225 (225Ac).

10. The pharmaceutical composition according to any of claims 1 to 9, wherein the radionuclide is actinium-225 (225Ac).

11. The pharmaceutical composition according to any of claims 1 to 10, wherein the targeting moiety and the radionuclide-containing chelating moiety are linked to each other by a thiourea moiety.

12. The pharmaceutical composition according to any of claims 1 to 7, wherein the conjugate is a compound of formula (III) or a compound of formula (III’) wherein X is a urea, thiourea or amide moiety, [A] is a targeting moiety preferably comprising an antibody, an antibody fragment, a binding peptide or a binding polypeptide, more preferably wherein the targeting moiety comprises an antibody or an antigenbinding fragment thereof and M is a suitable radionuclide.

13. The pharmaceutical composition according to any of claims 1 to 8, wherein the conjugate is a compound of formula (Illa) or a compound of formula (lllb) wherein X is a urea, thiourea or amide moiety, [Ab] is an antibody or an antigen-binding fragment thereof capable of binding to PSMA, HER2, GPC3, CEACAM5, TROP2, GLICY2C, cMet, FoIRa, DLL3, Nectin-4 or STEAP1 and M is a suitable radionuclide.

14. The pharmaceutical composition according to claim 13, wherein [Ab] is Pelgifatamab.

15. The pharmaceutical composition according to any of claims 12 to 14, wherein X is a thiourea moiety.

16. The pharmaceutical composition according to any of claims 1 to 7, wherein the conjugate is a compound of formula (II)

(II), and wherein M is a suitable radionuclide.

17. The pharmaceutical composition according to any of claims 12 to 16, wherein M is 225Ac.

18. The pharmaceutical composition according to any of claims 1 to 17, which is a liquid pharmaceutical composition, preferably an aqueous liquid pharmaceutical composition.

19. The pharmaceutical composition according to any of claims 1 to 18 for use in the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, more particularly in hyperproliferative disorders such as cancer.

20. Use of a pharmaceutical composition according to any of claims 1 to 18 for the preparation of a medicament for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, more particularly in hyperproliferative disorders such as cancer.

21. A method of treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, more particularly of hyperproliferative disorders such as cancer, said method comprising administering an effective amount of a pharmaceutical composition according to any of claims 1 to 18 to a patient in need thereof.

22. A pharmaceutical combination comprising a pharmaceutical composition according to any of claims 1 to 18 and one or more further active ingredients.