Bispecific molecule formulation

Abstract

The present invention relates to a pharmaceutical composition comprising a bispecific antigen binding protein and 1 to 20 mM methionine, 50 to 1000 mM trehalose, 1 to 100 mM citric acid and 0.001 to 0.1 % (w / v) poloxamer 188. The pharmaceutical composition may be used in a medicine. Further provided are an injection device, a vial and a kit comprising the pharmaceutical composition and a method of preparing the pharmaceutical composition.

Description

[0001] New PCT Patent Application

[0002] Applicant: Immatics Biotechnologies GmbH Immatics Ref.: P243PC00

[0003] Bispecific Molecule Formulation

[0004] The present invention relates to a pharmaceutical composition comprising a bispecific antigen binding protein and 1 to 20 mM methionine, 50 to 1000 mM trehalose, 1 to 100 mM citric acid and 0.001 to 0.1 % (w / v) poloxamer 188. The pharmaceutical composition may be used in a medicine. Further provided are an injection device, a vial and a kit comprising the pharmaceutical composition and a method of preparing the pharmaceutical composition.

[0005] The development of pharmaceutical formulations for protein-based therapeutics represents a pivotal frontier in modern medicine. Proteins serve as the building blocks of life, orchestrating a multitude of physiological processes within the human body. Leveraging their inherent biological activity, researchers have engineered protein-based therapeutics to intervene in disease pathways at the molecular level, offering promising solutions for conditions ranging from cancer and autoimmune disorders to metabolic diseases and infections.

[0006] Bispecific proteins represent an emerging innovative class of protein-based therapeutics designed to simultaneously target two different epitopes or proteins, thereby offering enhanced therapeutic efficacy and versatility compared to traditional monospecific drugs. Bispecific proteins hold immense promise for treating a wide array of diseases, including cancer, autoimmune disorders, and infectious diseases.

[0007] An example for bispecific molecules that hold tremendous potential to treat e.g. cancer is the so called T cell Engaging Receptor (TCER®) format developed by the applicant of the present invention. TCERs® are off-the-shelf biologies that leverage the body's immune system by redirecting and activating T cells towards cancer cells presenting specific tumor antigens. These novel biologies are engineered to allow T cells in the body to become activated and attack the tumor, regardless of the T cells' intrinsic specificity. A TCER® contains a T cellrecruiting antibody domain coupled to a pHLA-binding TCR domain. These domains are attached to a Fc domain.

[0008] One of the foremost challenges in formulating protein therapeutics lies in maintaining their structural integrity and activity throughout their journey from production to administration into the patient's body. The inherent complexity of proteins poses challenges in their formulation, handling, and delivery. Proteins are generally delicate molecules susceptible to denaturation, aggregation, and degradation under various environmental stresses, including temperature fluctuations, pH changes, and mechanical forces. Ensuring the stability of these proteins during storage, transportation, and administration is therefore imperative to preserve their therapeutic efficacy and safety.

[0009] Bispecific proteins present an additional distinctive set of hurdles with respect to their formulation. One of the primary challenges stems from the intricate molecular architecture of bispecific proteins, which often involves the fusion of two distinct binding domains or the engineering of complex protein scaffolds. Ensuring the structural integrity and proper folding of bispecific proteins throughout the formulation process is essential for maintaining their biological activity and therapeutic efficacy. Due to the unique pharmacology of bispecific proteins, technology developed for formulating monospecific proteins cannot be expected to be readily transferable to bispecific proteins.

[0010] Thus, while bispecific proteins hold tremendous potential for revolutionizing the treatment landscape across various disease areas, their formulation represents a formidable challenge. In addition, different bispecific proteins differ considerably in terms of their properties such as stability. Therefore, for each bispecific protein a specific, individual formulation must be found that achieves the desired properties (such as stability). Consequently, the quest for optimized formulations tailored to these intricate biomolecules is paramount for ensuring their safety, efficacy, and ultimately, their clinical success.

[0011] For example, promising bispecific proteins that are directed against the tumor antigen KVLEHVVRV (SEQ ID NO: 25) have been described in the art (WO 2021 / 023658). However, optimized formulations for these KVLEHVVRV (SEQ ID NO: 25) targeting protein-based therapeutics have not been described.

[0012] Accordingly, there is a need for means and methods to provide formulations that convey stability to such KVLEHVVRV (SEQ ID NO: 25) targeting TCERs®.

[0013] Thus, the technical problem underlying the present invention is the provision formulations / pharmaceutical compositions that convey stability to such bispecific molecules, in particular KVLEHVVRV (SEQ ID NO: 25) targeting TCERs® (e.g. MAG-003 TCER®). The technical problem is solved and the above mentioned needs are addressed by the provision of the embodiments characterized in the claims and as provided herein below.

[0014] Accordingly, in a first aspect, the invention provides a pharmaceutical composition comprising an antigen binding protein comprising one antigen binding site A, wherein said antigen binding site A comprises a TCR alpha variable domain (Va) comprising a complementarity determining region (CDR) CDRal having the amino acid sequence of SEQ ID NO: 16, a CDRa2 having the amino acid sequence of SEQ ID NO: 17, and a CDRa3 having the amino acid sequence of SEQ ID NO: 18, and a TCR beta variable domain (Vp) comprising a CDR 1 having the amino acid sequence of SEQ ID NO: 12, a CDR 2 having the amino acid sequence of SEQ ID NO: 13, and a CDR 3 having the amino acid sequence of SEQ ID NO: 14, and comprising 1 to 20 mM methionine, 50 to 1000 mM trehalose, 1 to 100 mM citric acid and 0.001 to 0.1 % (w / v) poloxamer 188, and having a pH of about 6.3 to 7.0, preferably about 6.5. One or more of the CDRs may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0015] In a preferred embodiment, the invention relates to a pharmaceutical composition according to the first aspect, wherein the antigen binding protein comprises or consists of

[0016] (i) a first polypeptide chain comprising or consisting of an amino acid sequence according to SEQ ID NO: 26 or an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26, and

[0017] (ii) a second polypeptide chain comprising or consisting of an amino acid sequence according to SEQ ID NO: 2 or an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, wherein the composition has a pH of about 6.5 and comprises about 4.5 mM methionine, about 292 mM trehalose, about 20 mM citric acid and about 0.02 % (w / v) poloxamer 188.

[0018] In a second aspect, the invention provides an injection device comprising the pharmaceutical composition of the first aspect.

[0019] In a third aspect, the invention provides a kit comprising one or more vials containing the pharmaceutical composition of the first aspect.

[0020] In a fourth aspect, the invention provides a method of making an aqueous pharmaceutical composition, the method comprising providing: (i) an antigen binding protein as defined in the first aspect, (ii) methionine, (iii) trehalose, (iv) citric acid, (v) Poloxamer 188, and (vi) sterile water, mixing or combining (i) to (vi) in sufficient amounts, and adjusting the pH to around 6.3 to 7.0. In a fifth aspect, the invention provides the pharmaceutical composition of the first aspect for use in medicine.

[0021] In a sixth aspect, the invention provides a method of treating a proliferative disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of the first aspect.

[0022] As illustrated in the appended Example 1 it has been found that the inventive formulation described herein conveys excellent stability to the tested TCER® (i.e. MAG-003 TCER®). The TCER® was incubated at elevated temperatures either in the formulation of the prior art or the formulation of the present invention. The amount of monomeric protein as well as high-molecular weight species (HMWS) was determined at certain timepoints. Figure 1 in combination with Table 4 shows that the decrease of monomeric protein was slower in the formulation of the present invention compared to the formulation of the prior art. Conversely, the increase of HMWS was faster in the formulation of the prior art. Accordingly, the appended Example demonstrates increased stability of the antigen binding protein in the formulation of the present invention. The stability of the formulation was independent of the concentration of the TCER® molecule (Example 2, Figure 2). Thus, the present invention provides a formulation / pharmaceutical composition that conveys excellent stability to the bispecific molecule, i.e. the MAG-003 TCER®.

[0023] The MAGE-A tumor antigen of the amino acid sequence 'KVLEHVVRV' (SEQ ID NO: 25), also known as MAG-003 peptide, is an HLA-A*02:01-restricted cytotoxic T lymphocyte (CTL) epitope of MAGE-A4 (amino acids 286-294) and MAGE-A8 (amino acids 288-296) (Jia ZC et al. Clin Dev. Immunol. 2010, 567594). MAGE-A4 and MAGE-A8 are both proteins and members of the MAGE-A gene family. The functions of MAGE-A8 and -A4 are not known, though they may play a role in embryonal development and aspects of tumor transformation / progression. Multiple alternatively spliced variants have been identified for these proteins. The MAGE-A antigen of SEQ ID NO: 25 belongs to cancer / testis (CT) antigens that are expressed in tumors but not in normal tissues except testis and placenta. Expression of the MAGE-A4 protein and mRNA, for example, has been linked to the development and prognosis of various cancers. MAGE-A derived peptides in particular the MAGE-A4 and / or MAGE-A8 derived peptide 'KVLEHVVRV', which are presented by molecules of the major histocompatibility complex (MHC), may be bound by TCRs and are thus a target for T cell based immunotherapy.

[0024] WO 2017 / 158103 discloses TCRs, more particularly native TCRs, such as the native TCR R7P1D5, that bind to a complex of a MAGE-A antigenic peptide having the amino acid sequence of KVLEHVVRV (SEQ ID NO: 25; MAG-003) and an HLA class I molecule, and their use in the diagnosis, treatment and prevention of cancerous diseases.

[0025] Native T cell receptors (TCRs) specifically binding to MHC presented cancer antigens are often of lower affinity (KD= 1-300 pM) when compared to TCRs specifically binding to MHC presented viral antigens. Part of the explanation for this phenomenon seems to be that T cells that develop in the thymus are negatively selected (tolerance induction) on self-peptide-MHC ligands, such that T cells with too high affinity to such self-peptide-MHCs are deleted. This low affinity may be one possible explanation for tumor immune escape (Aleksic et al., Eur J Immunol. 2012 Dec; 42(12) :3174-9) . Therefore, it is desirable to design TCR variants that bind with higher affinity to cancer antigens for use as antigen recognizing constructs in an adoptive cell therapy (ACT), or as recognition module of a soluble approach, i.e. using bispecific molecules (Hickman et al., J Biomol Screen. 2016 Sep; 21(8) :769-85).

[0026] Accordingly, antigen-binding proteins were developed specifically binding to their target with higher affinity, thus allowing to target even a tumor cell or cell lines with reduced expression of the target antigenic peptide, while a high safety profile is maintained due to a low or reduced cross-reactivity with off-target peptides (also referred to as "similar peptides"). In this respect bispecific formats were developed referred to asT cell engaging receptor (TCER; in the following also referred to as "TCER® molecules" or "TCER®"), which comprises one part that specifically binds to a surface molecule on a T cell and another part that specifically binds to a MHC-peptide complex.

[0027] Specifically, in WO2021 / 023658 a TCER® was developed comprising CDR variants derived from the above mentioned parental TCR R7P1D5. The first polypeptide chain of said TCER® is disclosed as SEQ ID NO: 136 and the second polypeptide chain of said TCER® is disclosed as SEQ ID NO: 137 in WQ2021 / 023658. SEQ ID NO: 136 of WQ2021 / 023658 corresponds to SEQ ID NO: 1 in the present application and SEQ ID NO: 137 of WQ2021 / 023658 corresponds to SEQ ID NO: 2 in the present application. Said TCER® is referred to herein also as MAG-003 TCER®. The T-cell recruiting part of said TCER® is in particular described in WQ2021 / 023657 (as BMA031 (V36)). SEQ ID NO: 42 (VL) of WQ2021 / 023657 corresponds to SEQ ID NO: 3 in the present application and SEQ ID NO: 43 (VH) of WQ2021 / 023657 corresponds to SEQ ID NO: 7 in the present application.

[0028] Also in WO2021 / 023658 it is demonstrated that said TCER® effectively binds and kills target cancer cells while maintaining a high safety profile due to low cross-reactivity to similar peptides. Furthermore, a significant in vivo tumor growth inhibition of said TCER® is demonstrated in WO2021 / 023658 in a therapeutic mouse model.

[0029] However, given the innovative nature of TCER® molecules suitable buffers / formulations / compositions for said molecules have not been determined. For example, in WO2021 / 023658 the MAG-003 TCER® is stored in phosphate-buffered saline (see Example 5 of WO2021 / 023658). The present inventors determined formulations that convey excellent stability to TCER® molecules, in particular the MAG-003 TCER®. As mentioned above the present inventors demonstrated in the appended Example that the MAG-003 TCER® is more stable in inventive formulations compared to the formulation of the prior art (i.e. phosphate-buffered saline (PBS) as used in WO2021 / 023658).

[0030] In the following the invention is described in more detail.

[0031] In particular, the invention relates to the following items.

[0032] 1. A pharmaceutical composition comprising an antigen binding protein comprising one antigen binding site A, wherein said antigen binding site A comprises a TCR alpha variable domain (Va) comprising a complementarity determining region (CDR) CDRal having the amino acid sequence of SEQ ID NO: 16, a CDRa2 having the amino acid sequence of SEQ ID NO: 17, and a CDRa3 having the amino acid sequence of SEQ ID NO: 18, and a TCR beta variable domain (Vp) comprising a CDR 1 having the amino acid sequence of SEQ ID NO: 12, a CDR 2 having the amino acid sequence of SEQ ID NO: 13, and a CDR 3 having the amino acid sequence of SEQ ID NO: 14, wherein one or more of the CDRs may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution, wherein the pharmaceutical composition comprises i) 1 to 20 mM methionine, ii) 50 to 1000 mM trehalose, iii) 1 to 100 mM citric acid, and iv) 0.001 to 0.1 % (w / v) poloxamer 188, and wherein the pharmaceutical composition has a pH of about 6.3 to 7.0, preferably about 6.5. The pharmaceutical composition according to item 1, wherein the antigen binding site A comprises or consists of a T cell receptor (TCR) or a tumor antigen (TA) / MHC binding fragment thereof. The pharmaceutical composition according to item 1 or 2, wherein the antigen binding site A comprises

[0033] (i) a Vacomprising or consisting of an amino acid sequence according to SEQ ID NO: 15, or a variant thereof, which comprises the CDRal, CDRa2, and CDRa3 according to SEQ ID NO: 16, 17, and 18, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 15, and

[0034] (ii) a Vp comprising or consisting of an amino acid sequence according to SEQ ID NO: 11, or a variant thereof, which comprises the CDR|31, CDR|32, and CDR|33 according to SEQ ID NO: 12, 13, and 14, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 11. The pharmaceutical composition according to any of items 1 to 3, wherein the antigen binding protein is a bispecific antigen binding protein and comprises a further antigen binding site B. The pharmaceutical composition according to item 4, wherein the antigen binding site B specifically binds to an T cell receptor (TCR) / CD3 complex. The pharmaceutical composition according to item 4 or 5, wherein the antigen binding site B comprises or consists of an antibody or an antigen binding fragment thereof. The pharmaceutical composition according to any of items 4 to 6, wherein the antigen binding site B comprises (i) a VHcomprising a CDRH1 having the amino acid sequence of SEQ ID NO: 8, a CDRH2 having the amino acid sequence of SEQ ID NO: 9, and a CDRH3 having the amino acid sequence of SEQ ID NO: 10, and

[0035] (ii) a VLcomprising a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 5, and a CDRL3 having the amino acid sequence of SEQ ID NO: 6, wherein one or more of the CDRs may comprise one, two orthree amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution. The pharmaceutical composition according to any of items 4 to 7, wherein the antigen binding site B comprises

[0036] (i) a VHcomprising or consisting of the amino acid sequence of SEQ ID NO: 7 or a variant thereof, which comprises the CDRH1, CDRH2 and CDRH3 according to SEQ ID NO: 8, 9 and 10, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 7, and

[0037] (ii) a VLcomprising or consisting of the amino acid sequence of SEQ ID NO: 27 or a variant thereof, which comprises the CDRL1, CDRL2, and CDRL3 according to SEQ ID NO: 4, 5 and 6, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 27, respectively. The pharmaceutical composition according to any of items 1 to 8, wherein the antigenbinding protein comprises or consists of a first polypeptide chain comprising a structure represented by the formula:

[0038] VL-L1-VP; and a second polypeptide chain comprising a structure represented by the formula: Va-L2-VH; wherein LI and L2 are linkers. The pharmaceutical composition according to any of items 1 to 9, wherein the antigenbinding protein comprises or consists of a first polypeptide chain comprising a structure represented by the formula: VL-L1-VP-L3-FC1; and a second polypeptide chain comprising a structure represented by the formula: Va-L2-VH-L4-FC2; wherein LI, L2, L3 and L4 are linkers and may be present or absent, and FC1 and FC2 are Fc-domains and may be the same or different. The pharmaceutical composition according to item 10, wherein

[0039] FC1 comprises or consists of the amino acid sequence according to SEQ ID NO: 19 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 19; and / or

[0040] FC2 comprises or consists of the amino acid sequence according to SEQ ID NO: 20 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 20. The pharmaceutical composition according to any of items 1 to 11, wherein the antigen binding protein comprises or consists of

[0041] (i) a first polypeptide chain comprising or consisting of an amino acid sequence according to SEQ ID NO: 26 or an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26, preferably comprising the CDRL1, CDRL2, CDRL3, CDR 1, CDR 2, and CDR 3 according to SEQ ID NOs: 4, 5, 6, 12, 13, and 14, respectively, and

[0042] (ii) a second polypeptide chain comprising or consisting of an amino acid sequence according to SEQ ID NO: 2 or an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, preferably comprising the CDRal, CDRa2, CDRa3, CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 16, 17, 18, 8, 9, and 10, respectively. The pharmaceutical composition according to any of items 1 to 12, wherein the antigen binding protein comprises a modification of the N-terminal and / or C-terminal amino acid(s), preferably wherein an N-terminal glutamine is substituted by a pyro-glutamate. The pharmaceutical composition according to any one of items 1 to 13, comprising 4.5 mM methionine. The pharmaceutical composition according any one of items 1 to 14, comprising 292 mM trehalose. The pharmaceutical composition according to any one of items 1 to 15, comprising 20 mM citric acid. The pharmaceutical composition according to any one of items 1 to 16, comprising 0.02 % (w / v) poloxamer 188. The pharmaceutical composition according to any one of items 1 to 17, wherein the pharmaceutical composition has a pH of 6.5 and comprises4.5 mM methionine, 292 mM trehalose, 20 mM citric acid, and 0.02 % (w / v) poloxamer 188. The pharmaceutical composition according to any one of items 1 to 18, wherein the pharmaceutical composition is a solution, preferably an aqueous solution. The pharmaceutical composition according to any one of items 1 to 19, wherein the concentration of the antigen binding protein is from 0.1 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 12.5 mg / mL, about 0.1 mg / mL to about 15 mg / mL, about 0.1 mg / mL to about 20 mg / mL, about 0.1 mg / mL to about 25 mg / mL, about 0.1 mg / mL to about 30 mg / mL, about 0.1 mg / mL to about 35 mg / mL, about 0.1 mg / mL to about 40 mg / mL, about 0.1 mg / mL to about 45 mg / mL, about 0.1 mg / mL to about 50 mg / mL, about 0.2 mg / mL to about 8 mg / mL, about 0.25 mg / mL to about 7.5 mg / mL, about 0.5 mg / mL to about 5 mg / mL, about 0.75 mg / mL to about 1.25 mg / mL, about 1 mg / mL, about 1 mg / mL to about 100 mg / mL, about 2 mg / mL to about 80 mg / mL, about 2.5 mg / mL to about 75 mg / mL, about 5 mg / mL to about 50 mg / mL, about 7.5 mg / mL to about 12.5 mg / mL, or about 10 mg / mL, in particular, about 1 mg / mL to about 90 mg / mL, about 1 mg / mL to about 80 mg / mL, about 1 mg / mL to about 70 mg / mL, about 1 mg / mL to about 60 mg / mL, about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 40 mg / mL, about 1 mg / mL to about 35 mg / mL, about 1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 25 mg / mL, about 1 mg / mL to about 20 mg / mL, about 1 mg / mL to about 19 mg / mL, about 1 mg / mL to about 18 mg / mL, about 1 mg / mL to about 17 mg / mL, about 1 mg / mL to about 16 mg / mL, about 1 mg / mL to about 15 mg / mL, about 1 mg / mL to about 14 mg / mL, about 1 mg / mL to about 13 mg / mL, about 1 mg / mL to about 12 mg / mL, about 1 mg / mL to about 11 mg / mL, or about 1 mg / mL to about 10 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, about 1 mg / mL to about 20 mg / mL, or about 1 mg / mL to about 30 mg / mL, wherein the concentration is selected from the group consisting of about 1.0 mg / mL, 1.5 mg / mL, 2.0 mg / mL, 2.5 mg / mL, 3.0 mg / mL,

[0043] 3.5 mg / mL, 4.0 mg / mL, 4.5 mg / mL, 5.0 mg / mL, 5.5 mg / mL, 6.0 mg / mL, 6.5 mg / mL, 7.0 mg / mL, 7.5 mg / mL, 8.0 mg / mL, 8.5 mg / mL, 9.0 mg / mL, 9.5 mg / mL, 10.0 mg / mL, 10.5 mg / mL, 11.0 mg / mL, 11.5 mg / mL, 12.0 mg / mL, 12.5 mg / mL, 13.0 mg / mL, 13.5 mg / mL, 14.0 mg / mL, 14.5 mg / mL, 15.0 mg / mL, 15.5 mg / mL, 16.0 mg / mL, 16.5 mg / mL, 17.0 mg / mL, 17.5 mg / mL, 18.0 mg / mL, 18.5 mg / mL, 19.0 mg / mL, 19.5 mg / mL, 20.0 mg / mL,

[0044] 20.5 mg / mL, 21.0 mg / mL, 21.5 mg / mL, 22.0 mg / mL, 22.5 mg / mL, 23.0 mg / mL, 23.5 mg / mL, 24.0 mg / mL, 24.5 mg / mL, 25.0 mg / mL, 25.5 mg / mL, 26.0 mg / mL, 26.5 mg / mL, 27.0 mg / mL, 27.5 mg / mL, 28.0 mg / mL, 28.5 mg / mL, 29.0 mg / mL, 29.5 mg / mL, or about 30.0 mg / mL. The pharmaceutical composition according to any one of items 1 to 20, wherein the concentration of the antigen binding protein is selected from the group consisting of about 1.0 mg / mL, about 1.5 mg / mL, about 2.0 mg / mL, about 2.5 mg / mL, about 3.0 mg / mL, about 3.5 mg / mL, about 4.0 mg / mL, about 4.5 mg / mL, about 5.0 mg / mL, about

[0045] 5.5 mg / mL, about 6.0 mg / mL, about 6.5 mg / mL, about 7.0 mg / mL, about 7.5 mg / mL, about 8.0 mg / mL, about 8.5 mg / mL, about 9.0 mg / mL, about 9.5 mg / mL, about 10.0 mg / mL, about 10.5 mg / mL, about 11.0 mg / mL, about 11.5 mg / mL, about 12.0 mg / mL, about 12.5 mg / mL, about 13.0 mg / mL, about 13.5 mg / mL, about 14.0 mg / mL, about

[0046] 14.5 mg / mL, about 15.0 mg / mL, about 15.5 mg / mL, about 16.0 mg / mL, about 16.5 mg / mL, about 17.0 mg / mL, about 17.5 mg / mL, about 18.0 mg / mL, about 18.5 mg / mL, about 19.0 mg / mL, about 19.5 mg / mL, about 20.0 mg / mL, about 20.5 mg / mL, about 21.0 mg / mL, about 21.5 mg / mL, about 22.0 mg / mL, about 22.5 mg / mL, about 23.0 mg / mL, about 23.5 mg / mL, about 24.0 mg / mL, about 24.5 mg / mL, about 25.0 mg / mL, about 25.5 mg / mL, about 26.0 mg / mL, about 26.5 mg / mL, about 27.0 mg / mL, about about 27.5 mg / mL, about 28.0 mg / mL, about 28.5 mg / mL, about 29.0 mg / mL, about 29.5 mg / mL, or about 30.0 mg / mL. An injection device comprising the pharmaceutical composition of any one of items 1 to 21, preferably wherein the injection device is a prefilled syringe. A kit comprising one or more vials containing the pharmaceutical composition of any one of items 1 to 21, preferably wherein the kit further comprises an injection device for administration of the pharmaceutical composition to a subject in need thereof. A method of making an aqueous pharmaceutical composition, the method comprising providing:

[0047] (i) an antigen binding protein as defined in items 1 to 13,

[0048] (ii) methionine,

[0049] (iii) trehalose,

[0050] (iv) citric acid;

[0051] (v) poloxamer 188, and

[0052] (vi) sterile water, mixing or combining (i) to (vi) in sufficient amounts, and adjusting the pH to around 6.3 to 7.0. A pharmaceutical composition of any one of items 1 to 21 for use in medicine. A method of treating a proliferative disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to any one of items 1 to 21. The term "Antigen Binding Protein" herein refers to a polypeptide or a complex of two or more polypeptides comprising an antigen binding site that is able to specifically bind to an antigen, in particular an antigenic peptide in a complex with MHC. The antigen binding protein may be a soluble, multivalent and multispecific (e.g., bivalent and bispecific) antigen binding protein comprising two polypeptide chains. The antigen binding protein may comprises a first TCR variable domain, which may be a TCR alpha variable domain (Va) and a second TCR variable domain, which may be a TCR beta variable domain (Vp). The antigen binding protein may further comprise two further variable domains, preferably an antibody heavy chain variable domain (VH) and an antibody light chain variable domain (VL), and optionally a constant domain. Such an antigen-binding protein thus comprises two different antigen binding sites. Antigen binding site A is formed by the TCR alpha and beta variable domains and antigen binding site B is formed by the antibody heavy and light chain variable domains. Such a multispecific (e.g., bispecific) antigen-binding protein is able to specifically bind to two different antigens simultaneously, as it is known from, for example bispecific antibodies. In such a bispecific antigen binding protein, the variable domains may be arranged in various orientations. Techniques to produce such bispecific antigen binding proteins are known to the skilled in the art.

[0053] The pharmaceutical composition of the present invention comprises an antigen binding protein comprising TCR-derived variable domains. A native TCR is a heterodimeric cell surface protein of the immunoglobulin super-family, which is associated with invariant proteins of the CD3 complex involved in mediating signal transduction. "Native" as used for example in the wording "native TCR" may refer to a wildtype TCR. Native heterodimeric TCRs exist in a|3 and y6 forms, which are structurally similar but have distinct locations and probably functions. Native, full-length a|3 heterodimeric TCRs consist of an a-chain and a p-chain. The skilled person is well aware how the TCR chains are assembled by recombination of the corresponding genomic regions. The a-chain comprises a variable region (V region) encoded by a TRAV gene, a joining region (J region) encoded by a TRAJ gene, and a constant region (C region) encoded by a TRAC gene. The p-chain comprises a variable region (V region) encoded by a TRBV gene, a joining region (J region) encoded by a TRBJ gene and a constant region (C region) encoded by a TRBC gene, and usually a short diversity region (D region) encoded by a TRBD gene between the V and J regions, although this D region is often considered as part of the J region (Lefranc, (2001), Curr Protoc Immunol Appendix 1: Appendix 10). The genes encoding different a-chain and 0-chain variable, joining and constant regions are referred to in IMGT nomenclature by unique numbers (Folch and Lefranc, (2000), Exp Clin Immunogenet 17(1): 42-54; Scaviner and Lefranc, (2000), Exp Clin Immunogenet 17(2): 83-96; LeFranc and LeFranc, (2001), "T cell Receptor Factsbook", Academic Press). Further information on TCR genes can be found in the international ImMunoGeneTics information system®, Lefranc M-P et al., (Nucleic Acids Res. 2015 Jan;43(Database issue):D413-22; and http: / / www.imgt.org / ).

[0054] On protein level, TCR a-, 0-, y- and 6-chains comprise two immunoglobulin domains, the variable domain and the constant domain. The variable domain corresponds to the V(D)J region. The constant domain corresponds to the C region. The constant domain is the membrane-proximal domain and may also include the transmembrane (TM) domain and a short cytoplasmic tail. Each of the constant and variable domains include an intra-chain disulfide bond. The variable domains (Vaand Vpin a TCRs and VYand V5in y6 TCRs) contain highly polymorphic loops comprising the complementarity determining regions (CDRs).

[0055] Each TCR variable domain comprises three "TCR complementarity determining regions (CDRs)" embedded in a framework sequence, one being the hypervariable region named CDR3. The CDRs comprised in an a-chain TCR variable domain may also be referred to as CDRal, CDRa2, and CDRa3 or CDRal, CDRa2, and CDRa3. The CDRs comprised in a P-chain TCR variable domain may also be referred to as CDRbl, CDRb2, and CDRb3 or CDR01, CDR02, and, CDR03. The sequences encoding CDRal and CDRa2 are comprised in TRAV, the sequences encoding CDRa3 are comprised in TRAV and TRAJ, the sequences encoding CDRbl and CDRb2 are comprised in TRBV, and the sequences encoding CDRb3 are comprised in TRBV, TRBD and TRBJ. In TCRs, the CDR1 and CDR3 amino acid residues make contact with the antigenic peptide, while the CDR2 amino acid residues mainly contact the HLA molecule (Stadinski et al., J Immunol. 2014, 192(12): 6071-6082; Cole et al., J Biol Chem. 2014, 289(2) :628-38).

[0056] "TCR framework regions" (FRs) refer to amino acid sequences interposed between the CDRs, i.e. to those portions of the variable domains that are to some extent conserved among different TCRs. The a-, 0-, y- and 6-chain variable domains each have four FRs, herein designated FRl-a, FR2-a, FR3-a, FR4-a (for an a- or y-chain), and FRl-b, FR2-b, FR3-b, FR4-b (for a 0- or 6-chain), respectively. Accordingly, an a-chain or y-chain variable domain may be described as (FRl-a)-(CDRal)-(FR2-a)-(CDRa2)-(FR3-a)-(CDRa3)-(FR4-a) and a 0- or 6-chain variable domain may be described as (FRl-b)-(CDRbl)-(FR2-b)-(CDRb2)-( FR3-b)-(CD Rb3 )-( FR4- b). In the context of the present invention, the CDR / FR sequences in an a-, p, y- or 6-chain variable domain is determined based on IMGT definition (Lefranc et al., Dev. Comp. Immunol., 2003, 27(l):55-77; www.imgt.org). Accordingly, CDR / FR amino acid positions when related to TCR or TCR-derived domains are indicated according to said IMGT definition. Preferably, the IMGT position of the CDR / FR amino acid positions of the variable domain Vais given in analogy to the IMGT numbering of TRAV24*01 and / or the IMGT position of the CDR / FR amino acid positions of the variable domain Vpis given in analogy to the IMGT numbering of TRBV12- 3*01.

[0057] A "domain" may be any region of a protein, generally defined on the basis of sequence homologies and often referring to a specific structural or functional entity.

[0058] An "immunoglobulin (Ig) domain" refers to a protein domain that consists of a 2-layer sandwich of 7-9 antiparallel p-strands arranged in two p-sheets with a Greek key topology. Proteins containing Ig domains are subsumed into the immunoglobulin superfamily, including e.g. antibodies, T-cell receptors (TCRs) and cell adhesion molecules. Examples of Ig domains are the variable and constant domains of antibodies and TCRs.

[0059] The term "variable domain" as used herein includes TCR variable domains and antibody variable domains.

[0060] A "TCR variable domain" in the context of the present invention refers to a variable domain of a TCR.

[0061] Vain the context of the present invention refers to a variable domain of a TCR a-chain. Vp in the context of the present invention refers to a variable domain of a TCR p-chain. An "antibody variable domain" in the context of the present invention refers to a variable domain of an antibody.

[0062] VLin the context of the present invention refers to a variable domain of an antibody light chain.

[0063] VHin the context of the present invention refers to a variable domain of an antibody heavy chain.

[0064] CLin the context of the present invention refers to a constant domain of an antibody light chain.

[0065] CHI, CH2 and CH3in the context of the present invention refer to constant domains of an antibody heavy chain, in particular an IgG heavy chain. The term "antigen binding site" as used herein includes TCR antigen binding sites and antibody antigen binding sites. An antigen binding site comprises six CDRs. For an antibody, the antigen binding site may comprise three heavy chain CDRs (CDRH1, CDRH2 and CDRH3) and three light chain CDRs (CDRL1, CDRL2 and CDRL3). For a TCR, the antigen binding site may comprise three alpha chain CDRs (CDRal, CDRa2 and CDRa3) and three beta chain CDRs (CDRP1, CDRP2 and CDR 3).

[0066] The term "antigen" or "target antigen" as used herein refers to a molecule or a portion of a molecule or complex that is capable of being specifically bound by an antigen binding site, wherein said antigen binding site is present in an antigen binding protein.

[0067] The term "epitope", also known as antigenic determinant, is the part of an antigen that is recognized by the immune system. As used herein, the term epitope comprises the terms "structural epitope" and "functional epitope". The "structural epitope" are those amino acids of the antigen, e.g. peptide-MHC complex, that are covered by the antigen binding protein when bound to the antigen. Typically, all amino acids of the antigen are considered covered that are within 5 A of any atom of an amino acid of the antigen binding protein. The structural epitope of an antigen may be determined by art known methods including X-ray crystallography or NMR analysis. The structural epitope of an antibody typically comprises 20 to 30 amino acids. The "functional epitope" as herein defined is a subset of those amino acids forming the structural epitope and comprises the amino acids of the antigen that are critical for formation of the interface with an antigen binding protein or functional fragment thereof, either by directly forming non-covalent interactions such as H-bonds, salt bridges, aromatic stacking or hydrophobic interactions or by indirectly stabilizing the binding conformation of the antigen and is, for instance, determined by mutational scanning. The functional epitope may be also referred to as "binding motif". Typically, the functional epitope of an antigen bound by an antibody comprises between 4 and 6 amino acids. Typically, the functional epitope of a peptide-MHC complex comprises between 2 to 6 or 7 amino acids of the peptide and 2 to 7 amino acids of the MHC molecule. Since MHC I presented peptides typically have a length between 8 to 10 amino acids only a subset of amino acids of each given peptide is part of the functional epitope of a peptide-MHC complex. The epitope, in particular the functional epitope bound by the antigen binding protein comprises or consists of the amino acids of the antigen that are required for formation of the binding interface. "Antigenic peptide in a complex with an MHC protein", herein refers to an antigenic peptide that is non-covalently bound to an MHC molecule. In particular, the antigenic peptide is located to a "peptide-binding groove" formed by the MHC molecule. An antigenic peptide in a complex with an MHC protein is herein also referred to as "peptide-MHC complex" or "pMHC complex". A complex of an MHC molecule and an antigenic peptide that is a tumor antigen (TA) is herein also referred to as "(TA) / MHC". In the context of the present invention, the TA is the MAGE-A antigenic peptide according to SEQ ID NO: 25 (KVLEHVVRV). This antigenic peptide is also called MAG-003 in the context of this invention.

[0068] The "Major Histocompatibility Complex" (MHC) is a set of cell surface proteins essential for the acquired immune system to recognize foreign molecules in vertebrates, which in turn determines histocompatibility. The main function of MHC molecules is to bind to antigens derived from pathogens and display them on the cell surface for recognition by the appropriate T cells. The human MHC is also called the HLA (human leukocyte antigen) complex (or just HLA). Thus, MHC is preferably HLA. The MHC gene family is divided into three subgroups: class I, class II, and class III. Complexes of peptide and MHC class I molecules (MHC I) are usually recognized by CD8-positive T cells (CD8+ T cells) bearing the appropriate T cell receptor (TCR), whereas complexes of peptide and MHC class II molecules (MHC II) are usually recognized by CD4-positive helper-T cells (CD4+ T cells) bearing the appropriate TCR. CD4 and CD8 usually function as co-receptors of a TCR in binding to MHC I and MHC II, respectively. In some exceptional cases, complexes of peptide and MHC I are recognized by CD8-negative (in particular CD8-negative, CD4-positive) T cells (Soto et al., 2013, Cancer Immunol Immunother. 2013 Feb; 62(2): 359-369). Since the responses of CD8-positive and CD4-positive T cells contribute jointly and synergistically to the anti-tumor effect, the identification and characterization of tumor-associated antigens and corresponding T cell receptors is important in the development of cancer immunotherapies such as vaccines and cell therapies. It is preferred that the MHC protein belongs to MHC class I. The MHC class I HLA protein in the context of the present disclosure may be an HLA-A, HLA-B or HLA-C protein, preferably HLA-A protein. The HLA-A gene is located on the short arm of chromosome 6 and encodes the larger, a-chain, constituent of HLA-A. Variation of HLA-A a-chain is key to HLA function. This variation promotes genetic diversity in the population. Since each HLA has a different affinity for peptides of certain structures, greater variety of HLAs means greater variety of antigens to be 'presented' on the cell surface. It is most preferred that the MHC protein is of the serotype HLA-A*02. The skilled person is well aware that HLA-A*02 can be further subdivided. A preferred serotype is HLA-A*02:01. In the MHC class I dependent immune reaction, peptides not only have to be able to bind to certain MHC class I molecules expressed by tumor cells, they subsequently also have to be recognized by T cells bearing specific T cell receptors (TCR). As mentioned above, it is especially envisaged that the antigen-binding proteins for the herein described formulations are multispecific, e.g. bispecific antigen-binding proteins.

[0069] The term "bispecific" in connection with the herein described antigen-binding proteins refers to antigen-binding proteins with at least two valences and binding specificities for at least two different antigens and, thus, comprise at least two antigen binding sites. The term "valence" refers to the number of binding sites of an antigen-binding protein, e.g. a bivalent antigen binding protein relates to an antigen binding protein that has two binding sites. It should be noted, that, the term valence refers to the number of binding sites, wherein those binding sites may bind to the same or different targets, i.e. a bivalent antigen binding protein may be monospecific, i.e. binding one target, or bispecific, i.e. binding two different targets. Targets may be antigens, such as (target) peptides.

[0070] In the context of the present invention it is preferred that at least one antigen-binding site is derived from a TCR, more particularly, that at least one antigen binding site comprises the TCR derived CDRs as described herein.

[0071] In the context of "bispecific" it is preferred herein that at least one specificity of the antigen binding sites is derived from a TCR, more particularly, that at least one antigen binding site comprises the TCR derived CDRs as described herein. Accordingly, "bispecific" in the context of the present invention may refer to an antigen-binding protein which combines at least one antigen binding site comprising TCR derived CDRs, and at least one further antigen binding site, wherein said at least one further antigen binding site, is preferably derived from an antibody and thus comprises antibody CDRs. As mentioned before, a preferred format is the TCER® format. When it is referred to a bispecific molecule it is, however, possible that e.g. the Fc part of said molecule has an additional binding partner e.g. FcRn.

[0072] Thus, the invention relates to a bispecific antigen binding protein comprising:

[0073] An antigen binding site A, which is formed by a TCR Vaand a TCR Vpdomain, and specifically binds to a complex of a MAGE-A antigenic peptide having the amino acid sequence of KVLEHVVRV (SEQ ID NO: 25; MAG-003) that is in a complex with an HLA class I molecule; and An antigen binding site B, which is formed by an antibody VHand an antibody VLdomain, and specifically binds to an T cell receptor (TCR) / CD3 complex, preferably to an a / |3 T cell receptor (TCR) / CD3 complex.

[0074] Optionally, said antigen binding protein may further bind to FcRn via its Fc part.

[0075] The term "format" herein refers to antigen-binding protein comprising a specific number and type of domains that are present in said antigen-binding protein and the spatial organization thereof, in particular variable and optionally constant domains. Important characteristics of such antigen binding protein formats are the number of polypeptide chains (single chain, double chain or multiple chains), the type and length of linkers connecting different domains, the number of variable domains (and thus the number of valences), the number of different variable domains (and thus the number of specificities for different antigens, e.g. bispecific, multispecific), and the order and orientation of variable domains (e.g. cross-over, parallel).

[0076] "At least one" herein refers to one or more of the specified objects such as 1, 2, 3, 4, 5 or 6 or more of the specified objects. For example, at least one binding site herein refers to 1, 2, 3, 4, 5 or 6 or more binding sites.

[0077] The terms "a / p TCR" or a" y / 6 TCR" refer to a TCR comprising an a-chain and a p-chain as described above, or a y-chain and a 6-chain, respectively. Such a TCR may also be described as "full length TCR" or "conventional TCR". An a / |3 TCR or a y / 6 TCR may be a native TCR or may be an engineered TCR that retains the structure of a native TCR, i.e. an engineered TCR comprising minor modifications in the variable and / or constant domains, such as a humanized TCR.

[0078] "Single chain TCR (scTCR)" as used herein denotes a TCR in which the variable domains of the TCR are located on a single polypeptide. Typically, the variable domains in scTCRs are separated by a linker, wherein said linker typically comprises 10 to 30 amino acids, such as 25 amino acids.

[0079] A "chimeric protein" herein refers to a protein comprising sequences from multiple species. A "chimeric TCR" herein refers to a TCR comprising sequences from multiple species. Preferably, a chimeric TCR may comprise an a-chain comprising at least one domain from a human and one domain from mouse. More preferably, a chimeric TCR may comprise an a- chain comprising a variable domain of a human a-chain and, for example, a constant domain of a murine TCR a-chain. A native "antibody" comprises two heavy and two light chains, wherein the heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chain, lambda (A.) and kappa (K). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Each chain contains distinct domains (also referred to as regions). The light chain includes two domains, a variable domain (VL) and a constant domain (CL). The heavy chain includes four or five domains depending on the antibody isotype; a variable domain (VH) and three or four constant domains (CHi, CH2 and CH3, and optionally CH, collectively referred to as CH). The variable domains of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen. The constant domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fcreceptors (FCR).

[0080] The specificity of the antibody resides in the structural complementarity between the antibody binding site and the antigenic determinant. Antibody binding sites are made up of residues that are primarily from the "antibody complementarity determining regions" (CDRs) or hypervariable regions. Occasionally, residues from non-hypervariable or framework regions (FR) may influence the overall domain structure and hence the binding site. CDRs refer to amino acid sequences that together define the binding affinity and specificity of an antibody binding site. The light (L) and heavy (H) chains of an antibody each have three CDRs, designated CDR1-L, CDR2-L, CDR3-L and CDR1-H, CDR2-H, CDR3-H, respectively or CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, respectively. "Antibody framework regions" (FRs) refer to amino acid sequences interposed between CDRs, i.e. to those portions of antibody light and heavy chain variable regions that are relatively conserved among different antibodies in a single species. The light and heavy chains of an antibody each have four FRs, designated FR1-L, FR2-L, FR3-L, FR4-L, and FR1-H, FR2-H, FR3-H, FR4-H, respectively. Accordingly, the light chain variable domain may be described as (FR1-L)-(CDR1-L)-(FR2-L)-(CDR2-L)-(FR3-L)-(CDR3- L)-(FR4-L) and the heavy chain variable domain may be described as (FR1-H)-(CDR1-H)-(FR2- H)-(CDR2-H)-(FR3-H)-(CDR3-H)-(FR4-H). As used herein, a "human framework region" is a framework region that is substantially identical (about 85%, or more, in particular 90%, 95%, 97%, 99% or 100%) to the framework region of a naturally occurring human antibody. CDR / FR definition in an antibody light or heavy chain variable domain may be determined based on IMGT definition (Lefranc et al., Dev. Comp. Immunol., 2003, 27(l):55-77; www.imgt.org). In context of the present application it is preferred that CDR / FR definition in an immunoglobulin light or heavy chain are determined according to Kabat numbering (Kabat et al., 1992, Sequences of Proteins of Immunological Interest). Accordingly, amino acid sequences of the CDR1, CDR2, and CDR3 of a given variable chain of an antibody or antibody fragment are indicated according to said Kabat definition.

[0081] Knowing the amino acid sequence of the CDRs of an antibody, a TCR or an antigen binding protein of the invention, one skilled in the art can easily determine the framework regions, such as the TCR framework regions or antibody framework regions. In cases where the CDRs are not indicated, the skilled in the art can first determine the CDR amino acid sequences based on the IMGT definition for TCRs or the Kabat or IMGT definition for antibodies and then determine the amino acid sequences of the framework regions.

[0082] In the context of the present application, a sequence that is "at least 85% identical to a reference sequence" is a sequence having, over its entire length, 85%, or more, in particular 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the entire length of a reference sequence. Proteins consisting of an amino acid sequence "At least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% Identical" to a reference sequence may comprise mutations such as deletions, insertions and / or substitutions compared to the reference sequence. In case of substitutions, the protein consisting of an amino acid sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a reference sequence may correspond to a homologous sequence derived from another species than the reference sequence.

[0083] In the context of the present application, the "percentage of identity" can be calculated using a global pairwise alignment (i.e. the two sequences are compared over their entire length). Methods for comparing the identity of two or more sequences are well known in the art. For example, the "needle" program, which uses the Needleman-Wunsch global alignment algorithm (Needleman and Wunsch, J. Mol. Biol., 1970, 48:443-453) to find the optimum alignment (including gaps) of two sequences when considering their entire length, may be used. The needle program is for example available on the ebi.ac.uk World Wide Web site and is further described in the following publication (EMBOSS: The European Molecular Biology Open Software Suite (2000) Rice, P. Longden, I. and Bleasby, A. Trends in Genetics 16, (6) pp. 276—277). The percentage of identity between two polypeptides, in accordance with the invention, may be calculated using the EMBOSS: needle (global) program with a "Gap Open" parameter equal to 10.0, a "Gap Extend" parameter equal to 0.5, and a Blosum62 matrix.

[0084] "Amino acid mutations" may be deletions, insertions or substitutions.

[0085] "Amino acid substitutions" may be conservative or non-conservative. Conservative substitutions refer to substitutions in which one amino acid is substituted for another amino acid with similar structural and / or chemical properties.

[0086] A conservative amino acid substitution may include the substitution of an amino acid by another amino acid of the same class, for example, (1) nonpolar: Ala, Vai, Leu, He, Pro, Met, Phe, Trp; (2) uncharged polar: Gly, Ser, Thr, Cys, Tyr, Asn, Gin; (3) acidic: Asp, Glu; and (4) basic: Lys, Arg, His. Other conservative amino acid substitutions may also be made as follows: (1) aromatic: Phe, Tyr, His; (2) proton donor: Asn, Gin, Lys, Arg, His, Trp; and (3) proton acceptor: Glu, Asp, Thr, Ser, Tyr, Asn, Gin (see, for example, U.S. Patent No. 10,106,805, the contents of which are incorporated by reference in their entirety).

[0087] Conservative substitutions may be made in accordance with Table 1. Methods for predicting tolerance to protein modification may be found in, for example, Guo et al., Proc. Natl. Acad. Sci., USA, 2004, 101(25):9205-9210, the contents of which are incorporated by reference in their entirety.

[0088] Table 1: Conservative Amino Acid substitutions

[0089] Conservative Amino Acid Substitutions

[0090] Amino Acid Substitutions (others are known in the art)

[0091] Ala Ser, Gly, Cys

[0092] Arg Lys, Gin, His

[0093] Asn Gin, His, Glu, Asp

[0094] Asp Glu, Asn, Gin

[0095] Cys Ser, Met, Thr

[0096] Gin Asn, Lys, Glu, Asp, Arg

[0097] Glu Asp, Asn, Gin

[0098] Gly Pro, Ala, Ser

[0099] His Asn, Gin, Lys

[0100] He Leu, Vai, Met, Ala

[0101] Leu He, Vai, Met, Ala

[0102] Lys Arg, Gin, His

[0103] Met Leu, lie, Vai, Ala, Phe

[0104] Phe Met, Leu, Tyr, Trp, His

[0105] Ser Thr, Cys, Ala

[0106] Thr Ser, Vai, Ala

[0107] Trp Tyr, Phe

[0108] Tyr Trp, Phe, His

[0109] Vai lie, Leu, Met, Ala, Thr The skilled person is aware that the antigen binding protein of the present invention may be glycosylated, amidated, carboxylated, phosphorylated, esterified, N-acylated, cyclized via, e.g., a disulfide bridge, or converted into an acid addition salt and / or optionally dimerized or polymerized, or conjugated.

[0110] The antigen binding protein of the present disclosure can be synthetic, recombinant, isolated, engineered and / or purified.

[0111] An "engineered" antigen binding protein, in particular an engineered TCR in the context of the present invention refers to a protein that has been modified by biotechnological methods, in particular by introducing amino acid mutations into the native protein sequence. Such biotechnological methods are well known to the skilled in the art.

[0112] By "purified" is meant, when referring to a polypeptide, e.g. to the antigen binding protein of the invention or a nucleotide sequence, e.g. encoding antigen binding proteins or functional fragment thereof described herein, that the indicated molecule is present in the substantial absence of other biological macromolecules of the same type. The term "purified" as used herein in particular means that at least 75%, 85%, 95%, or 98% by weight, of biological macromolecules of the same type are present. The term "purified" as used herein may further indicate that the antigen binding protein is free from DNA, RNA, proteins, polypeptides or cells that would interfere with its therapeutic, diagnostic, prophylactic, research or other use.

[0113] The term "isolated" means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not "isolated," but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is "isolated". An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell. An isolated antigen binding protein is substantially free of other antigen binding proteins having different antigenic specificities. Moreover, an isolated antigen binding protein may be substantially free of other cellular material and / or chemicals.

[0114] A "recombinant" molecule is one that has been prepared, expressed, created, or isolated by recombinant means. Recombinant molecules may not exist in nature.

[0115] The term "gene" means a DNA sequence that codes for, or corresponds to, a particular sequence of amino acids which comprises all or part of one or more proteins or enzymes, and may or may not include regulatory DNA sequences, such as promoter sequences, which determine for example the conditions under which the gene is expressed. Some genes, which are not structural genes, may be transcribed from DNA to RNA, but are not translated into an amino acid sequence. Other genes may function as regulators of structural genes or as regulators of DNA transcription. In particular, the term gene may be intended for the genomic sequence encoding a protein, i.e. a sequence comprising regulator, promoter, intron and exon sequences.

[0116] "Affinity" is defined, in the context of the present invention by the equilibrium binding between the antigen binding protein and its antigen. Affinity is usually expressed as equilibrium dissociation constant (KD).

[0117] "KD" is the equilibrium dissociation constant, a ratio of koff / kon, between the antigen binding protein and its antigen. KDand affinity are inversely related. The KDvalue relates to the concentration of the antigen binding protein and the lower the KDvalue, the higher the affinity of the antigen binding protein. The KDvalue can be experimentally assessed by a variety of known methods, such as measuring association and dissociation rates with surface plasmon resonance (SPR) or bio-layer interferometry (BLI). As is known to the skilled in the art, the experimental conditions used for those experiments, such as buffer used, concentration of the protein, can strongly influence the results.

[0118] "Half maximal effective concentration" also called "EC50", typically refers to the concentration of a molecule, which induces a response halfway between the baseline and maximum after a specified exposure time. The lower the EC50value, the higher the functional avidity of the molecule. EC50values can be experimentally assessed by a variety of known methods, for example cytokine release assays, in which the activation of effector cells is determined via measuring the release of cytokines from effector cells or ELISA- or flow cytometry-based killing assays, in which the activation of effector cells is determined via the killing of target (cancer) cells.

[0119] The term "specificity" in the context of the present invention denotes the capacity of an antigen binding protein to discriminate its target peptide from peptides having a different amino acid sequence, e.g. similar peptides as defined below. An antigen binding protein is considered specific for a target peptide if binding to the target peptide occurs with a significantly higher affinity and / or higher functional avidity than the binding to similar peptides. Specificity may also refer to the selectivity of a molecular interaction, particularly the ability of a molecule (such as a protein) to discriminate between different ligands or binding partners. Thus, in the context of proteins, specificity may relate to the ability of a protein to bind selectively to its cognate ligand or binding partner, despite the high concentration of other molecules present in the corresponding environment. It is evident for the skilled person that in context of the present invention specificity may mean the ability of an antigen-binding protein to discriminate between different antigens and to bind selectively to its target antigen.

[0120] In the context of the present specification, the term "about" when referring to a specific value is meant to indicate that the value may deviate by ± 10%, ± 9%, ± 8%, ± 7%,± 6%,± 5%,± 4%,± 3%,± 2% or ± 1%.

[0121] Throughout the instant application, the term "and / or" is a grammatical conjunction that is to be interpreted as encompassing that one or more of the cases it connects may occur. For example, the wording "such native sequence proteins can be prepared using standard recombinant and / or synthetic methods" indicates that native sequence proteins can be prepared using standard recombinant and synthetic methods or native sequence proteins can be prepared using standard recombinant methods or native sequence proteins can be prepared using synthetic methods.

[0122] Furthermore, throughout the instant application, the term "comprising" is to be interpreted as encompassing all specifically mentioned features as well optional, additional, unspecified ones. As used herein, the use of the term "comprising" also discloses the embodiment wherein no features other than the specifically mentioned features are present (i.e. "consisting of"). The term "consisting of" means that no further component (or likewise features, integers, steps and the like) can be present.

[0123] The term "consisting essentially of" or grammatical variants thereof when used herein are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof but only if the additional features, integers, steps, components or groups thereof do not materially alter the basic and novel characteristics of the claimed product, composition, device or method and the like.

[0124] Thus, the term "consisting essentially of" means that specific further components (or likewise features, integers, steps and the like) can be present, namely those not materially affecting the essential characteristics of the product, composition, device or method. In other words, the term "consisting essentially of" (which can be interchangeably used herein with the term "comprising substantially"), allows the presence of other components in the product, composition, device or method in addition to the mandatory components (or likewise features, integers, steps and the like), provided that the essential characteristics of the product, composition, device or method are not materially affected by the presence of other components.

[0125] Furthermore, the indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0126] As mentioned above, the present inventors determined formulations that convey excellent stability to TCER® molecules, in particular the MAG-003 TCER®. Accordingly, the invention relates to a pharmaceutical composition, wherein the pharmaceutical composition comprises i) 1 to 20 mM methionine, ii) 50 to 1000 mM trehalose, iii) 1 to 100 mM citric acid, and iv) 0.001 to 0.1 % (w / v) poloxamer 188, and wherein the pharmaceutical composition has a pH of about 6.3 to 7.0, preferably about 6.5.

[0127] In a preferred embodiment, the pharmaceutical composition has a pH of 6.5 and comprises 4.5 mM methionine, 292 mM trehalose, 20 mM 20 mM citric acid and 0.02 % (w / v) poloxamer 188. The corresponding buffer is referred to as WP3_01 in the appended example.

[0128] As mentioned above, it is envisaged that the described pharmaceutical compositions / formulations are used e.g. to store therapeutic proteins, in particular TCERs®. Accordingly, it is evident for the skilled person that the pharmaceutical composition also comprises a TCER®, in particular a TCER® binding to MAG-003. Suitable TCERs® that are envisaged to be comprised in the pharmaceutical compositions are described throughout this application.

[0129] The invention provides a pharmaceutical composition comprising an antigen binding protein comprising one antigen binding site A, wherein said antigen binding site A comprises a TCR alpha variable domain comprising a complementarity determining region (CDR) CDRal having the amino acid sequence of SEQ ID NO: 16, a CDRa2 having the amino acid sequence of SEQ ID NO: 17, and a CDRa3 having the amino acid sequence of SEQ ID NO: 18, and a TCR beta variable domain comprising a CDR1 having the amino acid sequence of SEQ ID NO: 12, a CDR2 having the amino acid sequence of SEQ ID NO: 13, and a CDR3 having the amino acid sequence of SEQ ID NO: 14, and comprising 1 to 20 mM methionine, 50 to 1000 mM trehalose, 1 to 100 mM citric acid and 0.001 to 0.1 % (w / v) poloxamer 188, and having a pH of about 6.3 to 7.0, preferably around 6.5. One or more of the CDRs may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution. Exemplary conservative amino acid substitutions are shown above in table 1. Preferably, the amino acid mutations (if present) are mutations of the first and / or last amino acids of a CDR.

[0130] The antigen binding protein comprised in the pharmaceutical composition of the invention specifically binds to a MAGE-A antigenic peptide consisting of the amino acid sequence 'KVLEHVVRV' (SEQ ID NO: 25). The peptide, which is also referred to as MAG-003 peptide, is derived from MAGE-A4 (amino acids 286-294) or MAGE-A8 (amino acids 288-296) (Jia ZC et al. Clin Dev. Immunol. 2010, 567594). MAGE-A4 and MAGE-A8 are members of the MAGE-A gene family. They belong to the group of cancer / testis (CT) antigens, which are expressed in tumors but not in normal tissues except testis and placenta. The MAGE-A antigenic peptide is presented on the surface of cancer cells by molecules of the major histocompatibility complex (MHC), preferably MHC I. More particularly, the MAGE-A antigenic peptide is presented on the cell surface in complex with a HLA protein, preferably HLA-A, more preferably HLA-A*02. The MAGE-A peptide of SEQ ID NO: 25 is presented on cancer cells by molecules of the major histocompatibility complex (MHC). It may be bound by TCRs and is thus a target for tumor immunotherapy.

[0131] The term "pharmaceutical composition" as used herein refers to a composition capable of inducing a desired therapeutic effect when properly administered to a subject. The subject may also be referred to as patient. The terms "pharmaceutical composition", "composition", "pharmaceutical formulation" and "formulation" may be used synonymously herein.

[0132] Such a pharmaceutical composition comprises a therapeutically effective amount of an antigen binding protein, in admixture with pharmaceutically acceptable formulation agents selected for suitability with the mode of administration. 1 The pharmaceutical composition may be sterile. The pharmaceutical composition may include a pharmaceutically acceptable carrier.

[0133] "Pharmaceutically" or "pharmaceutically acceptable" refers to compositions and their components that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate.

[0134] A "pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. A pharmaceutically acceptable carrier may include solvents, bulking agents, stabilizing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like which are physiologically compatible. The carrier may be an aqueous carrier. The aqueous carrier may be capable of imparting improved properties when combined with an antigen binding protein described herein, for example, improved solubility, efficacy, and / or improved immunotherapy.

[0135] Further examples of pharmaceutically acceptable carriers or diluents useful in the present invention include stabilizers such as SPGA, carbohydrates , proteins, protein containing agents such as bovine serum or skimmed milk and buffers.

[0136] The dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and gender of the patient, etc. This pharmaceutical composition may be provided in unit dosage form, will generally be provided in a sealed container and may be provided as part of a kit. Such a kit would normally (although not necessarily) include instructions for use. It may include a plurality of said unit dosage forms.

[0137] Preferably, the pharmaceutical composition is formulated for administration by injection, e.g., intravenous injection.

[0138] Empirical considerations, such as the biological half-life, generally will contribute to the determination of the dosage. Frequency of administration may be determined and adjusted over the course of therapy and is based on reducing the number of cancer cells, maintaining the reduction of cancer cells, reducing the proliferation of cancer cells, or killing the cancer cells. Alternatively, sustained continuous release formulations of the antigen binding protein may be appropriate. Various formulations and devices for achieving sustained release are known in the art.

[0139] In particular, the pharmaceutical compositions may contain vehicles, which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions, or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. To prepare pharmaceutical compositions, an effective amount of the described antigen binding protein may be dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The formulation is preferably sterile and fluid to the extent that easy syringeability and injectability exists. It should be stable under the conditions of manufacture and storage. Under ordinary conditions of storage and use, these preparations preferably contain a preservative to prevent the growth of microorganisms.

[0140] Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered as injectable solutions described above.

[0141] The doses used for the administration can be adapted as a function of various parameters, and in particular as a function of the relevant pathology, or alternatively of the desired duration of treatment.

[0142] The pharmaceutical composition may be provided in substantially pure form, for example at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% pure.

[0143] The antigen binding site A may comprise or consist of a T cell receptor (TCR) or TA / MHC binding fragment(s) thereof. The expression "TA / MHC" in the context of the present specification refers to a complex of an MHC molecule and a tumor antigen (TA). The TA may be a MAGE-A antigenic peptide, more particularly the MAGE-A antigenic peptide according to SEQ ID NO: 25 (KVLEHVVRV) in a complex with a MHC protein, such as an HLA protein, for instance HLA-A*02.

[0144] The antigen binding site A may comprise a TCR alpha chain variable domain (Va) and a TCR beta chain variable domain (Vp).

[0145] The antigen binding site A may comprise a Vacomprising or consisting of an amino acid sequence according to SEQ ID NO: 15, or a variant thereof, which preferably comprises the CDRal, CDRa2, and CDRa3 according to SEQ ID NO: 16, 17 and 18, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 15, and a Vpcomprising or consisting of an amino acid sequence according to SEQ ID NO: 11, or a variant thereof, which preferably comprises the CDR 1, CDR 2, and CDR 3 according to SEQ ID NO: 12, 13 and 14, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 11.

[0146] It is preferred that the antigen binding protein is a bispecific antigen binding protein and comprises a further antigen binding site B. Preferably, the antigen binding site B specifically binds to an a / |3 T cell receptor (TCR) / CD3 complex.

[0147] The antigen binding site B preferably comprises or consists of an antibody or an antigen binding fragment thereof. Preferably, the antigen binding site B comprises a light chain variable domain (VL) and a heavy chain variable domain (VH).

[0148] The antigen binding site B may comprise a VHcomprising a CDRH1 having the amino acid sequence of SEQ ID NO: 8, a CDRH2 having the amino acid sequence of SEQ ID NO: 9, and a CDRH3 having the amino acid sequence of SEQ ID NO: 10, and a VLcomprising a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 5, and a CDRL3 having the amino acid sequence of SEQ ID NO: 6, wherein one or more of the CDRs may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0149] It is evident for the skilled person that under certain conditions a glutamine amino acid residue may be converted into pyro-glutamate. In particular, N-terminal glutamine may be converted into pyro-glutamate. Accordingly, it is evident for the skilled person that the present application also encompasses the described antigen binding proteins with pyroglutamate at the N-terminus instead of glutamine. In other words, when an antigen binding protein as described herein has a glutamine residue at the N-terminus also the corresponding amino acid sequence with pyro-glutamate instead of glutamine at the N-terminus is encompassed.

[0150] For example, when in the described antigen binding protein the VL having the amino acid sequence according to SEQ ID NO: 3 is at the N-terminus said VL may comprise or consist of the amino acid sequence according to SEQ ID NO: 24 (with pyro-glutamate at the N- terminus). Accordingly, the antigen-binding proteins for use according to the invention may comprise a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 24. The antigen binding proteins for use according to the invention may also comprise a VL comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 24. The antigen binding proteins for use according to the invention may comprise a VL comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 24 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 4, 5, and 6, respectively. For simplicity it is mostly referred to SEQ ID NO: 27 (encompassing glutamin and pyro-glutamate at the N-terminus) herein in context of the preferred VL. It is evident for the skilled person that SEQ ID NO: 27 and "SEQ ID NO: 3 or SEQ ID NO: 24" may be used interchangeably herein. In other words, when it is referred to SEQ ID NO: 27 it may also be referred to as "SEQ ID NO: 3 and SEQ ID NO: 24" or "SEQ ID NO: 3 or SEQ ID NO: 24". It is evident for the skilled person that the herein described antigenbinding proteins may be a mixture of molecules with pyro-glutamate at the N-terminus and molecules with glutamine at the N-terminus.

[0151] Accordingly, when it is referred herein to an antigen binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 27 it is evident for the skilled person that it may be referred to a composition comprising an antigen binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 3 and optionally comprising an antigen-binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 24. Similarly, when it is referred herein to an antigen binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 27 it is evident for the skilled person that it may be referred to a composition comprising an antigen binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 24 and optionally comprising an antigen binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 3.

[0152] When it is referred herein to an antigen-binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 27 it is evident for the skilled person that it may be referred to a composition comprising an antigen-binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 3 and optionally comprising at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of an antigen-binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 24.

[0153] The VHmay comprise or consist of the amino acid sequence of SEQ ID NO: 7 or a variant thereof, which comprises the CDRH1, CDRH2 and CDRH3 according to SEQ ID NO: 8, 9 and 10, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 7, and the VLcomprises or consists of the amino acid sequence of SEQ ID NO: 27 or a variant thereof, which comprises the CDRL1, CDRL2, and CDRL3 according to SEQ ID NO: 4, 5 and 6, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 27.

[0154] The VHmay also comprise or consist of the amino acid sequence of SEQ ID NO: 7 or a variant thereof, which comprises the CDRH1, CDRH2 and CDRH3 according to SEQ ID NO: 8, 9 and 10, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 7, and the VLcomprises or consists of the amino acid sequence of SEQ ID NO: 27 or a variant thereof, which comprises the CDRL1, CDRL2, and CDRL3 according to SEQ ID NO: 4, 5 and 6, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 27.

[0155] The antigen-binding protein may comprise or consist of a first polypeptide chain comprising a structure represented by the formula:

[0156] VL-L1-VP; and a second polypeptide chain comprising a structure represented by the formula:

[0157] Va-L2-VH; wherein VL, Vp, Vaand VHcomprise or consist of the sequences as defined above, and LI and L2 are linkers.

[0158] The term "linker" as used herein refers to one or more amino acid residues inserted between domains or a domain and an agent to provide sufficient mobility for the domains or elements, for example the variable domains of bispecific antigen binding to fold correctly to form the antigen binding sites.

[0159] A linker may consist of 0 amino acid meaning that the linker is absent. A linker is inserted at the transition between variable domains or between variable domains and constant domains (or dimerization domains), respectively, at the amino acid sequence level. The transition between domains can be identified because the approximate size of the antibody domains as well as of the TCR domains is well understood. The precise location of a domain transition can be determined by locating peptide stretches that do not form secondary structural elements such as beta-sheets or alpha-helices as demonstrated by experimental data or as can be assumed by techniques of modelling or secondary structure prediction. A linker, as long as it is not specified otherwise in the respective context, can be from at least 1 to 30 amino acids in length. A linker can be 2-25, 2-20, or 3-18 amino acids long. A linker can also be a peptide of a length of no more than 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 amino acids. A linker can also be 5-25, 5-15, 4-11, 10-20, or 20-30 amino acids long. Furthermore, a linker can be about, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids long. A linker can also be less than 24, less than 20, less than 16, is less than 12, less than 10, for example from 5 to 24, 10 to 24 or 5-10 amino acid residues in length. Said linker may be equal to 1 or more amino acid residues in length, such as more than 1, more than 2, more than 5, more than 10, more than 20 amino acid residues in length, or more than 22 amino acid residues in length. Preferably, the linkers LI and L2 are a glycine / serine linkers, i.e. a linkers consisting of or essentially consisting of glycine and serine residues. In some embodiments, the linkers LI and L2 are comprise or consist of the amino acid sequence according to SEQ ID NO: 22 (GGGSGGGG).

[0160] The antigen-binding protein may comprise or consist of a first polypeptide chain comprising a structure represented by the formula:

[0161] VL-L1-VP-L3-FC1; and a second polypeptide chain comprising a structure represented by the formula: Va-L2-VH-L4-FC2; wherein VL, Vp, Vaand VHcomprise or consist of the sequences as defined above and LI, L2, L3 and L4 are linkers, wherein L3 and L4 may be present or absent. Preferably, LI and L2 are glycine / serine linkers, preferably comprising or consisting of the amino acid sequence according to SEQ ID NO: 22 and F3 and F4 are absent.

[0162] Accordingly, in a preferred embodiment the antigen-binding protein comprises or consists of a first polypeptide chain comprising a structure represented by the formula:

[0163] VL-L1-VP-FC1; and a second polypeptide chain comprising a structure represented by the formula: Va-L2-VH-FC2; wherein VL, Vp, Va, VH, LI, L2, FC1 and FC2 comprise or consist of the sequences as described herein. In a preferred embodiment the first polypeptide of the above formula comprises or consists of the amino acid sequence of SEQ ID NO: 26 and the second polypeptide of the above formula comprises or consists of the amino acid sequence of SEQ ID NO: 2. FC1 and FC2 are Fc-domains and may be the same or different, preferably different.

[0164] The Fc domain may comprises or further comprise the "RF" and / or "Knob-into-hole" mutation, preferably the "Knob-into-hole" mutation.

[0165] The "RF mutation" typically refers to the amino acid substitutions of the amino acids HY into RF in the CH3 domain of Fc domains, such as the amino acid substitution H435R and Y436F in CH3 domain as described by Jendeberg et al. (Jendeberg et al., 1997, J. Immunological Meth., 201: 25-34) and is described as advantageous for purification purposes as it abolishes binding to protein A. In case the bispecific antigen binding protein comprises two Fc domains, the RF mutation may be in one or both, preferably in one Fc domain.

[0166] The "Knob-into-Hole" technology refers to amino acid substitutions T366S, L368A and Y407V (Hole) and T366W (Knob) both in the CH3-CH3 interface to promote heteromultimer formation. Those knob-into-hole mutation can be further stabilized by the introduction of additional cysteine amino acid substitutions Y349C and S354C. The "Knob-into-Hole" technology together with the stabilizing cysteine amino acid substitutions has been described in patents US5731168 and US8216805. The Fc domain of one polypeptide of the described antigen-binding proteins for example FC1, may comprise the amino acid substitution T366W (Knob) in its CH3 domain and the Fc domain of the other polypeptide, for example FC2, may comprise the amino acid substitution T366S, L368A and Y407V (Hole) in its CH3 domain, or vice versa. The Fc domain of one of the polypeptides, for example FC1, may comprise or further comprise the amino acid substitution S354C in its CH3 domain and the Fc domain of the other polypeptide, for example FC2, may comprises or further comprise the amino acid substitution Y349C in its CH3 domain, or vice versa. Accordingly, the Fc domain of one of the polypeptides, for example FC1, may comprise the amino acid substitutions S354C and T366W (Knob) in its CH3 domain and the Fc domain of the other polypeptide, for example FC2, may comprises the amino acid substitution Y349C, T366S, L368A and Y407V (Hole) in its CH3 domain, or vice versa. The skilled person is readily capable to determine to which positions in the described antigen-binding proteins said positions correspond. In other words, the skilled person can readily determine where said amino acid substitutions are to be introduced in the described antigen-binding proteins.

[0167] The "Knob" mutation together with the cysteine amino acid substitution S354C is, for example, present in the Fc domain comprising or consisting of the amino acid sequence of SEQ ID NO: 19 and the "Hole" mutation together with the cysteine amino acid substitutions Y349C is present in the Fc domain comprising or consisting amino acid sequence of SEQ ID NO: 20.

[0168] This set of amino acid substitutions can be further extended by inclusion of the amino acid substitutions K409A on one polypeptide and F405K in the other polypeptide as described by Wei et al. (Wei et al., Oncotarget, 2017, 8(31):51037-51049). Accordingly, the Fc domain of one of the polypeptides, for example FC1, may comprise or further comprise the amino acid substitution K409A in its CH3 domain and the Fc domain of the other polypeptide, for example FC2, comprises or further the amino acid substitution F405K in its CH3 domain, or vice versa. In some cases artificially introduced cysteine bridges may improve the stability of the (bispecific) antigen-binding proteins, optimally without interfering with the binding characteristics of the (bispecific) antigen-binding proteins. Such cysteine bridges can further improve heterodimerization.

[0169] Further amino acid substitutions, such as charged pair substitutions, have been described in the art, for example in EP 2 970 484 to improve the heterodimerization of the resulting proteins.

[0170] Accordingly, the Fc domain of one of the polypeptides, for example FC1, may comprise or further comprise the charge pair substitutions E356K, E356R, D356R, or D356K and D399K or D399R, and the Fc domain of the other polypeptide, for example FC2, may comprise or further comprise the charge pair substitutions R409D, R409E, K409E, or K409D and N392D, N392E, K392E, or K392D, or vice versa.

[0171] The Fc domain on one or both, preferably both polypeptide chains of the antigenbinding protein may comprise one or more alterations that inhibit Fc gamma receptor (FcyR) binding. Such alterations can include L234A, L235A.

[0172] With the inclusion of Fc-parts consisting of Hinges, CH2 and CH3 domains, or parts thereof, into antigen-binding proteins, more particularly into bispecific antigen-binding proteins the problem of unspecific immobilization of these molecules, induced by Fc:Fc- gamma receptor (FcgR) interactions arose. FcgRs are composed of different cell surface molecules (FcgRI, FcgRIla, FcgRIlb, FcgRI 11) binding with differing affinities to epitopes displayed by Fc-parts of IgG-molecules. As such an unspecific (i.e. not induced by either of the two binding domains of a bispecific molecule) immobilization is unfavorable due to i) influence on pharmacokinetics of a molecule and ii) off-target activation of immune effector cells various Fc-variants and mutations to ablate FcgR-binding have been identified. In this context, Morgan et al. disclose the exchange of the residues 233-236 of human IgGl with the corresponding sequence derived from human lgG2, i.e. the residues 233P, 234V and 235A and wherein no amino acid is present at position 236, resulting in abolished FcgRI binding, abolished Clq binding and diminished FcgRIII binding (Morgan et al., Immunology, 1995, 86(2): 319-324). EP1075496 discloses antibodies and other Fc-containing molecules with variations in the Fc region (such as one or more of 233P, 234V, 235A and no residue or G in position 236 and 327G, 330S and 331S) wherein the recombinant antibody is capable of binding the target molecule without triggering significant complement dependent lysis, or cell mediated destruction of the target.

[0173] Accordingly, the Fc region may comprise or further comprise one or more of the amino acids or deletions selected from the group consisting of 233P, 234V, 235A, 236 (No residue) or G, 327G, 330S, 331S, preferably, the Fc region comprises or further comprises the amino acids 233P, 234V, 235A, 236 (No residue) or G and one or more amino acids selected from the group consisting of 327G, 330S, 331S, most preferably, the Fc region comprises or further comprises the amino acids or deletions 233P, 234V, 235A, 236 (No residue) and 331S.

[0174] The Fc domain may comprise or further comprise the amino acid substitution N297Q, N297G or N297A, preferably N297Q.

[0175] The amino acid substitution "N297Q", "N297G" or "N297A" refer to amino acid substitutions at position 297 that abrogate the native N-Glycosylation site within the Fc- domain. This amino acid substitution further prevents Fc-gamma-receptor interaction and decreases the variability of the final protein products, i.e. the bispecific antigen binding proteins of the present invention, due to sugar residues as described for example in Tao and Morrison (Tao and Morrison, J Immunol., 1989, 143(8):2595-601.).

[0176] In particular when no light chain is present, the Fc domain may comprise or further comprise the amino acid substitution C220S. The amino acid substitution "C220S" deletes the cysteine forming the Cm-CL disulfide-bridge.

[0177] The Fc domain may comprise or further comprise at least two additional cysteine residues, for example S354C and Y349C or L242C and K334C, wherein S354C is in the Fc- domain of one polypeptide, such as FC1, and Y349C is in the Fc domain of the other polypeptide, such as FC2, to form a heterodimer and / or wherein L242C and K334C are located in the same Fc-domain, either in the FC1 or FC2 of one or both polypeptides to form a intradomain C-C bridge. The skilled person is readily capable to determine whether the above described mutations / substitutions are present in the disclosed sequences. Accordingly, the skilled person knows that when it is referred herein to antigen-binding proteins via sequence identity to disclosed sequences said mutations / substitutions may need to be present in said antigenbinding proteins.

[0178] It is envisaged that FC1 comprises or consists of the amino acid sequence according to SEQ ID NO: 19 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 19; and / or FC2 comprises or consists of the amino acid sequence according to SEQ ID NO: 20 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 20.

[0179] Accordingly, it is envisaged that the antigen binding protein of the described composition comprises or consists of a first polypeptide chain comprising or consisting of an amino acid sequence according to SEQ ID NO: 1 or an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, and a second polypeptide chain comprising or consisting of an amino acid sequence according to SEQ ID NO: 2 or an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2.

[0180] Again it is evident for the skilled person that the glutamine residue in SEQ ID NO: 1 may be converted to pyro-glutamate. SEQ ID NO: 23 represents SEQ ID NO: 1 with a pyro-glutamate instead of a glutamine at the most N-terminal position.

[0181] Accordingly, the first polypeptide chain of the antigen-binding proteins may comprise or consist of the amino acid sequence according to SEQ ID NO: 23 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 23 and preferably comprising the CDRL1, CDRL2, CDRL3, CDR|31, CDR|32, and CDR|33 according to SEQ ID NOs: 4, 5, 6, 12, 13, and 14, respectively.

[0182] For simplicity it is mostly referred to SEQ ID NO: 26 (encompassing glutamin and pyroglutamate at the N-terminus) herein in context of the preferred first polypeptide chain. It is evident for the skilled person that SEQ ID NO: 26 and "SEQ ID NO: 1 or SEQ ID NO: 23" may be used interchangeably herein. In other words, when it is referred to SEQ ID NO: 26 it may also be referred to as "SEQ ID NO: 1 and SEQ ID NO: 23" or "SEQ ID NO: 1 or SEQ ID NO: 23". Again, it is evident for the skilled person that the herein described antigen-binding proteins may be a mixture of molecules with pyro-glutamate at the N-terminus and molecules with glutamine at the N-terminus. Accordingly, when it is referred herein to an antigen-binding protein comprising a polypeptide comprising or consisting of the amino acid sequence according to SEQ ID NO: 26 it is evident for the skilled person that it may be referred to a composition comprising an antigen-binding protein comprising a polypeptide comprising or consisting of the amino acid sequence according to SEQ ID NO: 1 and optionally comprising an antigenbinding protein comprising a polypeptide comprising or consisting of the amino acid sequence according to SEQ ID NO: 23. Similarly, when it is referred herein to an antigen-binding protein comprising a polypeptide comprising or consisting of the amino acid sequence according to SEQ ID NO: 26 it is evident for the skilled person that it may be referred to a composition comprising an antigen-binding protein comprising a polypeptide comprising or consisting of the amino acid sequence according to SEQ ID NO: 23 and optionally comprising an antigenbinding protein comprising a polypeptide comprising or consisting of the amino acid sequence according to SEQ ID NO: 1.

[0183] When it is referred herein to an antigen-binding protein comprising a polypeptide comprising or consisting of the amino acid sequence according to SEQ ID NO: 26 it is evident for the skilled person that it may be referred to a composition comprising an antigen-binding protein comprising a polypeptide comprising or consisting of the amino acid sequence according to SEQ ID NO: 1 and optionally comprising at least at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of an antigen-binding protein comprising a polypeptide comprising or consisting of the amino acid sequence according to SEQ ID NO: 23.

[0184] Accordingly, it is also envisaged that the antigen binding protein of the described composition comprises or consists of a first polypeptide chain comprising or consisting of an amino acid sequence according to SEQ ID NO: 23 or an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 23, and a second polypeptide chain comprising or consisting of an amino acid sequence according to SEQ ID NO: 2 or an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2.

[0185] Preferably, the antigen binding protein consists of a first polypeptide chain comprising or consisting of an amino acid sequence according to SEQ ID NO: 26 and a second polypeptide chain comprising or consisting of an amino acid sequence according to SEQ ID NO: 2. More preferably, the antigen binding protein consists of a first polypeptide chain consisting of an amino acid sequence according to SEQ ID NO: 26 and a second polypeptide chain consisting of an amino acid sequence according to SEQ ID NO: 2. This is the antigen binding protein for which stability was tested in the examples section and referred to as MAG-003 TCER®.

[0186] As mentioned, the antigen binding protein may comprise a modification of the N- terminal and / or C-terminal amino acid(s), preferably wherein the N-terminal glutamine is substituted by a pyro-glutamate.

[0187] As mentioned above, the inventors determined compositions / formulations that convey e.g. excellent stability to TCERs®. In the following the corresponding components are described. The pharmaceutical composition may comprise at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3 or 4.4 mM methionine. The pharmaceutical composition may comprise less than 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6 or 5 mM methionine. The pharmaceutical composition may comprise 11.5 to 15 mM, 2.5 to 12.5 mM, 3 to 10 mM, 3.5 to 7.5 mM, 3.5 to 6 mM, 3.75 to 5.5 mM, 4 to 5 mM or 4.25 to 4.75 mM methionine. It is preferred that the pharmaceutical composition comprises about 4.5 mM methionine. Thus, it is also preferred that the pharmaceutical composition comprises 4.5 mM methionine. It is evident for the skilled person that L-Methionine is preferred.

[0188] The pharmaceutical composition may further comprise at least 100, 125, 150, 175, 200, 225, 250 or 275 mM trehalose. Accordingly, it is envisaged that the pharmaceutical composition comprises less than 900, 800, 700, 600, 500, 450, 400 or 350 mM trehalose. Thus, the pharmaceutical composition may comprise 100 to 800 mM, 150 to 600 mM, 200 to 400 mM, 250 to 350 mM, 275 to 325 mM or 290 to 310 mM trehalose. Preferably, the pharmaceutical composition comprises 270 to 310 mM or 280 to 300 mM trehalose. It is preferred that the pharmaceutical composition comprises about 290 mM trehalose, about 292 mM trehalose or about 292.2 mM trehalose. Accordingly, it is also preferred that the pharmaceutical composition comprises 292 mM trehalose, more preferably 292.2 mM trehalose. Trehalose dihydrate may be used.

[0189] The pharmaceutical composition may further comprise at least 7.5, 10, 12.5, 15 or 17.5 mM citric acid. Accordingly, the pharmaceutical composition may comprise less than 90, 80, 70, 60, 50, 40 or 30 mM citric acid. Thus, the pharmaceutical composition may comprise 5 to 75 mM, 10 to 50 mM, 15 to 25 mM, 17.5 to 22.5 mM, 18 to 22 mM or 19 to 21 mM citric acid. It is preferred that the pharmaceutical composition comprises about 20 mM citric acid. Preferably, the pharmaceutical composition comprises 20 mM citric acid. Citric acid monohydrate may be used.

[0190] The pharmaceutical composition may further comprise at least 0.002 %, 0.005 %, 0.01 % or 0.015 % (w / v) poloxamer 188. Accordingly, the pharmaceutical composition may comprise less than 0.09 %, 0.08 %, 0.07 %, 0.06 %, 0.05 %, 0.04 %, 0.03 % or 0.025 % (w / v) poloxamer 188. Thus, the pharmaceutical composition may comprise 0.005 to 0.05 % (w / v), 0.01 to 0.03 % (w / v) or 0.015 to 0.025 % (w / v) poloxamer 188. It is preferred that the pharmaceutical composition comprises about 0.02 % (w / v) poloxamer 188. Preferably, the pharmaceutical composition comprises 0.02 % (w / v) poloxamer 188.

[0191] The pharmaceutical composition may have a pH of at least 6.4. Accordingly, the pharmaceutical composition may have a pH of less than 6.9, 6.8, 6.7 or 6.6. Thus, the pharmaceutical composition may have a pH of about 6.4 to 6.6.

[0192] Preferably, the pharmaceutical composition has a pH of about 6.5. Accordingly, it is also preferred that the pharmaceutical composition has a pH of 6.5.

[0193] In a preferred embodiment, the pharmaceutical composition has a pH of about 6.5 and comprises about 4.5 mM methionine, about 292 mM trehalose, about 20 mM citric acid and about 0.02 % (w / v) poloxamer 188. In another preferred embodiment, the pharmaceutical composition has a pH of 6.5 and comprises 4.5 mM methionine, 292.2 mM trehalose, 20 mM citric acid and 0.02 % (w / v) poloxamer 188.

[0194] The composition may be a solution, preferably an aqueous solution.

[0195] The inventors showed that the inventive formulation conveys excellent stability to an antigen binding protein as described herein.

[0196] The skilled person is readily capable to determine suitable concentrations of the antigen binding protein in the composition. The concentration of the antigen binding protein within the formulation according to the invention may be about 0.1 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 12.5 mg / mL, about 0.1 mg / mL to about 15 mg / mL, about 0.1 mg / mL to about 20 mg / mL, about 0.1 mg / mL to about 25 mg / mL, about 0.1 mg / mL to about 30 mg / mL, about 0.1 mg / mL to about 35 mg / mL, about 0.1 mg / mL to about 40 mg / mL, about 0.1 mg / mL to about 45 mg / mL, about 0.1 mg / mL to about 50 mg / mL, about 0.2 mg / mL to about 8 mg / mL, about 0.25 mg / mL to about 7.5 mg / mL, about 0.5 mg / mL to about 5 mg / mL, about 0.75 mg / mL to about 1.25 mg / mL or about 1 mg / mL. The concentration of the antigen binding protein within the formulation may also be about 1 mg / mL to about 100 mg / mL, about 2 mg / mL to about 80 mg / mL, about 2.5 mg / mL to about 75 mg / mL, about 5 mg / mL to about 50 mg / mL, about 7.5 mg / mL to about 12.5 mg / mL or about 10 mg / mL. In particular, the concentration of the antigen binding protein within the formulation may be about 1 mg / mL to about 100 mg / mL, about 1 mg / mL to about 90 mg / mL, about 1 mg / mL to about 80 mg / mL, about 1 mg / mL to about 70 mg / mL, about 1 mg / mL to about 60 mg / mL, about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 40 mg / mL, about 1 mg / mL to about 35 mg / mL, about 1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 25 mg / mL, about 1 mg / mL to about 20 mg / mL, about 1 mg / mL to about 19 mg / mL, about 1 mg / mL to about 18 mg / mL, about 1 mg / mL to about 17 mg / mL, about 1 mg / mL to about 16 mg / mL, about 1 mg / mL to about 15 mg / mL, about 1 mg / mL to about 14 mg / mL, about 1 mg / mL to about 13 mg / mL, about 1 mg / mL to about 12 mg / mL, about 1 mg / mL to about 11 mg / mL or about 1 mg / mL to about 10 mg / mL. Preferably, the concentration of the antigen binding protein within the formulation is about 1 mg / mL to about 10 mg / mL, about 1 mg / mL to about 20 mg / mL or about 1 mg / mL to about 30 mg / mL, e.g. about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, about 3 mg / mL, about 3.1 mg / mL, about 3.2 mg / mL, about 3.3 mg / mL, about 3.4 mg / mL, about 3.5 mg / mL, about 3.6 mg / mL, about 3.7 mg / mL, about 3.8 mg / mL, about 3.9 mg / mL, about 4 mg / mL, about 4.1 mg / mL, about 4.2 mg / mL, about 4.3 mg / mL, about 4.4 mg / mL, about 4.5 mg / mL, about 4.6 mg / mL, about 4.7 mg / mL, about 4.8 mg / mL, about 4.9 mg / mL, about 5 mg / mL, about 5.1 mg / mL, about 5.2 mg / mL, about 5.3 mg / mL, about 5.4 mg / mL, about 5.5 mg / mL, about 5.6 mg / mL, about 5.7 mg / mL, about 5.8 mg / mL, about 5.9 mg / mL, about 6 mg / mL, about 6.1 mg / mL, about 6.2 mg / mL, about 6.3 mg / mL, about 6.4 mg / mL, about 6.5 mg / mL, about 6.6 mg / mL, about 6.7 mg / mL, about 6.8 mg / mL, about 6.9 mg / mL, about 7 mg / mL, about 7.1 mg / mL, about 7.2 mg / mL, about 7.3 mg / mL, about 7.4 mg / mL, about 7.5 mg / mL, about 7.6 mg / mL, about 7.7 mg / mL, about 7.8 mg / mL, about 7.9 mg / mL, about 8 mg / mL, about 8.1 mg / mL, about 8.2 mg / mL, about 8.3 mg / mL, about 8.4 mg / mL, about 8.5 mg / mL, about 8.6 mg / mL, about 8.7 mg / mL, about 8.8 mg / mL, about 8.9 mg / mL, about 9 mg / mL, about 9.1 mg / mL, 9.2 mg / mL, about 9.3 mg / mL, about 9.4 mg / mL, about 9.5 mg / mL, about 9.6 mg / mL, about 9.7 mg / mL, about 9.8 mg / mL, about 9.9 mg / mL, about 10 mg / mL, about 10.1 mg / mL, about 10.2 mg / mL, about 10.3 mg / mL, about 10.4 mg / mL, about 10.5 mg / mL, about 10.6 mg / mL, about 10.7 mg / mL, about 10.8 mg / mL, about 10.9 mg / mL, about 11 mg / mL, about 11.1 mg / mL, about

[0197] 11.2 mg / mL, about 11.3 mg / mL, about 11.4 mg / mL, about 11.5 mg / mL, about 11.6 mg / mL, about 11.7 mg / mL, about 11.8 mg / mL, about 11.9 mg / mL, about 12 mg / mL, about 12.1 mg / mL, about 12.2 mg / mL, about 12.3 mg / mL, about 12.4 mg / mL, about 12.5 mg / ml, about

[0198] 12.6 mg / mL, about 12.7 mg / mL, about 12.8 mg / mL, about 12.9 mg / mL, about 13 mg / mL, about 13.1 mg / mL, about 13.2 mg / mL, about 13.3 mg / mL, about 13.4 mg / mL, about 13.5 mg / mL, about 13.6 mg / mL, about 13.7 mg / mL, about 13.8 mg / mL, about 13.9 mg / mL, about 14 mg / mL, about 14.1 mg / mL, about 14.2 mg / mL, about 14.3 mg / mL, about 14.4 mg / mL, about 14.5 mg / mL, about 14.6 mg / mL, about 14.7 mg / mL, about 14.8 mg / mL, about 14.9 mg / mL, about 15 mg / mL, about 15.1 mg / mL, about 15.2 mg / mL, about 15.3 mg / mL, about 15.4 mg / mL, about 15.5 mg / mL, about 15.6 mg / mL, about 15.7 mg / mL, about 15.8 mg / mL, about 15.9 mg / mL, about 16 mg / mL, about 16.1 mg / mL, about 16.2 mg / mL, about 16.3 mg / mL, about 16.4 mg / mL, about 16.5 mg / mL, about 16.6 mg / mL, about 16.7 mg / mL, about 16.8 mg / mL, about 16.9 mg / mL, about 17 mg / mL, about 17.1 mg / mL, about 17.2 mg / mL, about 17.3 mg / mL, about 17.4 mg / mL, about 17.5 mg / mL, about 17.6 mg / mL, about 17.7 mg / mL, about 17.8 mg / mL, about 17.9 mg / mL, about 18 mg / mL, about 18.1 mg / mL, about

[0199] 18.2 mg / mL, about 18.3 mg / mL, about 18.4 mg / mL, about 18.5 mg / mL, about 18.6 mg / mL, about 18.7 mg / mL, about 18.8 mg / mL, about 18.9 mg / mL, about 19 mg / mL, about 19.1 mg / mL, about 19.2 mg / mL, about 19.3 mg / mL, about 19.4 mg / mL, about 19.5 mg / mL, about

[0200] 19.6 mg / mL, about 19.7 mg / mL, about 19.8 mg / mL, about 19.9 mg / mL, about 20 mg / mL, about 20.5 mg / mL, about 21 mg / mL, about 21.5 mg / mL, about 22 mg / mL, about 22.5 mg / mL, about 23 mg / mL, about 23.5 mg / mL, about 24 mg / mL, about 24.5 mg / mL, about 25 mg / mL, about 25.5 mg / mL, about 26 mg / mL, about 26.5 mg / mL, about 27 mg / mL, about 27.5 mg / mL, about 28 mg / mL, about 28.5 mg / mL, about 29 mg / mL, about 29.5 mg / mL or about 30 mg / mL. The pharmaceutical composition may comprise or consist of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, 1 to 20 mM, 1.5 to 15 mM, 2.5 to 12.5 mM, 3 to 10 mM, 3.5 to 7.5 mM, 3.5 to 6 mM, 3.75 to 5.5 mM, 4 to 5 mM or 4.25 to 4.75 mM methionine, 200 to 400 mM trehalose, 15 to 25 mM citric acid and 0.005 to 0.05 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of 6.3 to 6.8.

[0201] The pharmaceutical composition may comprise or consist of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, 3.5 to 6 mM methionine, 50 to 1000 mM, 100 to 800 mM, 150 to 600 mM, 200 to 400 mM, 250 to 350 mM, 275 to 325 mM or 290 to 310 mM trehalose, 15 to 25 mM citric acid and 0.005 to 0.05 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of 6.3 to 6.8.

[0202] Furthermore, the pharmaceutical composition may comprise or consist of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, 3.5 to 6 mM methionine, 200 to 400 mM trehalose, 1 to 100 mM, 5 to 75 mM, 10 to 50 mM, 15 to 25 mM, 17.5 to 22.5 mM or 19 to 21 mM citric acid and 0.005 to 0.05 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of 6.3 to 6.8.

[0203] The pharmaceutical composition may also comprise or consist of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, 3.5 to 6 mM methionine, 200 to 400 mM trehalose, 15 to 25 mM citric acid and about 0.001 to 0.1 % (w / v), 0.005 to 0.05 % (w / v), 0.01 to 0.03 % (w / v) or 0.015 to 0.025 % poloxamer 188, wherein the pharmaceutical composition has a pH of 6.3 to 6.8.

[0204] It is also envisaged that the pharmaceutical composition comprises or consists of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, 3.5 to 6 mM methionine, 200 to 400 mM trehalose, 15 to 25 mM citric acid and 0.005 to 0.05 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of about 6.3 to 7.0, 6.3 to 6.9, 6.3 to 6.8, 6.4 to 6.7, or 6.4 to 6.6.

[0205] The pharmaceutical composition may comprises or consists of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, 1 to 20 mM, 1.5 to 15 mM, 2.5 to 12.5 mM, 3 to 10 mM, 3.5 to 7.5 mM, 3.5 to 6 mM, 3.75 to 5.5 mM, 4 to 5 mM or 4.25 to 4.75 mM methionine, 275 to 325 mM trehalose, 18 to 22 mM citric acid and 0.015 to 0.025 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of 6.4 to 6.7.

[0206] The pharmaceutical composition may comprise or consist of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, 4.25 to 4.75 mM methionine, 50 to 1000 mM, 100 to 800 mM, 150 to 600 mM, 200 to 400 mM, 250 to 350 mM, 275 to 325 mM or 290 to 310 mM trehalose, 18 to 22 mM citric acid and 0.015 to 0.025 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of 6.4 to 6.7.

[0207] The pharmaceutical composition may comprise or consist of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, 4.25 to 4.75 mM methionine, 275 to 325 mM trehalose, 1 to 100 mM, 5 to 75 mM, 10 to 50 mM, 15 to 25 mM, 17.5 to 22.5 mM, 18 to 22 mM or 19 to 21 mM citric acid and 0.015 to 0.025 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of 6.4 to 6.7.

[0208] The pharmaceutical composition may also comprise or consist of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, 4.25 to 4.75 mM methionine, 275 to 325 mM trehalose, 18 to 22 mM citric acid and about 0.001 to 0.1 % (w / v), 0.005 to 0.05 % (w / v), 0.01 to 0.03 % (w / v) or 0.015 to 0.025 % poloxamer 188, wherein the pharmaceutical composition has a pH of 6.4 to 6.7.

[0209] Furthermore, the pharmaceutical composition may comprise or consist of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, 4.25 to 4.75 mM methionine, 275 to 325 mM trehalose, 18 to 22 mM citric acid and 0.015 to 0.025 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of about 6.3 to 7.0, 6.3 to 6.9, 6.3 to 6.8, 6.4 to 6.7, or 6.4 to 6.6.

[0210] The pharmaceutical composition may comprise or consist of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, 1 to 20 mM, 1.5 to 15 mM, 2.5 to 12.5 mM, 3 to 10 mM, 3.5 to 7.5 mM, 3.5 to 6 mM, 3.75 to 5.5 mM, 4 to 5 mM or 4.25 to 4.75 mM methionine, about 292 mM trehalose, such as 292.2 mM trehalose, about 20 mM citric acid and about 0.02 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of about 6.5.

[0211] The pharmaceutical composition may comprise or consist of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, about 4.5 mM methionine, 50 to 1000 mM, 100 to 800 mM, 150 to 600 mM, 200 to 400 mM, 250 to 350 mM, 275 to 325 mM or 290 to 310 mM trehalose, about 20 mM citric acid and about 0.02 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of about 6.5.

[0212] In addition, the pharmaceutical composition may comprise or consist of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, about 4.5 mM methionine, about 292 mM trehalose, such as 292.2 mM trehalose, 1 to 100 mM, 5 to 75 mM, 10 to 50 mM, 15 to 25 mM, 17.5 to 22.5 mM, 18 to 22 mM or 19 to 21 mM citric acid and about 0.02 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of about 6.5.

[0213] The pharmaceutical composition may comprise or consist of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, about 4.5 mM methionine, about 292 mM trehalose, such as 292.2 mM trehalose, about 20 mM citric acid and about 0.001 to 0.1 % (w / v), 0.005 to 0.05 % (w / v), 0.01 to 0.03 % (w / v) or 0.015 to 0.025 % poloxamer 188, wherein the pharmaceutical composition has a pH of about 6.5. The pharmaceutical composition may also comprise or consist of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, about 4.5 mM methionine, about 292 mM trehalose, such as 292.2 mM trehalose, about 20 mM citric acid and about 0.02 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of about 6.3 to 7.0, 6.3 to 6.9, 6.3 to 6.8, 6.4 to 6.7, or 6.4 to 6.6.

[0214] In a preferred embodiment, the pharmaceutical composition comprises or consists of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, about 4.5 mM methionine, about 292 mM trehalose, such as 292.2 mM trehalose, about 20 mM citric acid and about 0.02 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of about 6.5.

[0215] In another preferred embodiment, the pharmaceutical composition comprises or consists of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2, about 4.5 mM methionine, about 292 mM trehalose, such as 292.2 mM trehalose, about 20 mM citric acid and about 0.02 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of about 6.5. In another preferred embodiment, the pharmaceutical composition comprises or consists of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, 4.5 mM methionine, 292 mM trehalose, 20 mM citric acid and 0.02 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of 6.5. In another preferred embodiment, the pharmaceutical composition comprises or consists of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2 or first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively, 4.5 mM methionine, 292.2 mM trehalose, 20 mM citric acid and 0.02 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of 6.5. In another preferred embodiment, the pharmaceutical composition consists of an antigen binding protein consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2, 4.5 mM methionine, 292.2 mM trehalose, 20 mM citric acid and 0.02 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of 6.5.

[0216] In particular embodiments the pharmaceutical composition comprises or consists of an antigen binding protein comprising or consisting of a first polypeptide chain according to SEQ ID NO: 26 and a second polypeptide chain according to SEQ ID NO: 2, about 4.5 mM methionine, about 292 mM trehalose, such as 292.2 mM trehalose, about 20 mM citric acid and about 0.02 % (w / v) poloxamer 188, wherein the pharmaceutical composition has a pH of about 6.5 and wherein the concentration of the antigen binding protein is from 0.1 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 12.5 mg / mL, about 0.1 mg / mL to about 15 mg / mL, about 0.1 mg / mL to about 20 mg / mL, about 0.1 mg / mL to about 25 mg / mL, about 0.1 mg / mL to about 30 mg / mL, about 0.1 mg / mL to about 35 mg / mL, about 0.1 mg / mL to about 40 mg / mL, about 0.1 mg / mL to about 45 mg / mL, about 0.1 mg / mL to about 50 mg / mL, about 0.2 mg / mL to about 8 mg / mL, about 0.25 mg / mL to about 7.5 mg / mL, about 0.5 mg / mL to about 5 mg / mL, about 0.75 mg / mL to about 1.25 mg / mL, about 1 mg / mL, about 1 mg / mL to about 100 mg / mL, about 2 mg / mL to about 80 mg / mL, about 2.5 mg / mL to about 75 mg / mL, about 5 mg / mL to about 50 mg / mL, about 7.5 mg / mL to about 12.5 mg / mL, or about 10 mg / mL, in particular, about 1 mg / mL to about 90 mg / mL, about 1 mg / mL to about 80 mg / mL, about 1 mg / mL to about 70 mg / mL, about 1 mg / mL to about 60 mg / mL, about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 40 mg / mL, about 1 mg / mL to about 35 mg / mL, about 1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 25 mg / mL, about 1 mg / mL to about 20 mg / mL, about 1 mg / mL to about 19 mg / mL, about 1 mg / mL to about 18 mg / mL, about 1 mg / mL to about 17 mg / mL, about 1 mg / mL to about 16 mg / mL, about 1 mg / mL to about 15 mg / mL, about 1 mg / mL to about 14 mg / mL, about 1 mg / mL to about 13 mg / mL, about 1 mg / mL to about 12 mg / mL, about 1 mg / mL to about 11 mg / mL, or about 1 mg / mL to about 10 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, about 1 mg / mL to about 20 mg / mL, or about 1 mg / mL to about 30 mg / mL, wherein the concentration is selected from the group consisting of about 1.0 mg / mL, 1.5 mg / mL, 2.0 mg / mL, 2.5 mg / mL, 3.0 mg / mL, 3.5 mg / mL, 4.0 mg / mL, 4.5 mg / mL, 5.0 mg / mL, 5.5 mg / mL, 6.0 mg / mL, 6.5 mg / mL, 7.0 mg / mL, 7.5 mg / mL, 8.0 mg / mL, 8.5 mg / mL, 9.0 mg / mL, 9.5 mg / mL, 10.0 mg / mL, 10.5 mg / mL, 11.0 mg / mL, 11.5 mg / mL, 12.0 mg / mL, 12.5 mg / mL, 13.0 mg / mL, 13.5 mg / mL, 14.0 mg / mL, 14.5 mg / mL, 15.0 mg / mL, 15.5 mg / mL, 16.0 mg / mL, 16.5 mg / mL, 17.0 mg / mL, 17.5 mg / mL, 18.0 mg / mL, 18.5 mg / mL, 19.0 mg / mL, 19.5 mg / mL, 20.0 mg / mL, 20.5 mg / mL, 21.0 mg / mL, 21.5 mg / mL, 22.0 mg / mL, 22.5 mg / mL, 23.0 mg / mL, 23.5 mg / mL, 24.0 mg / mL, 24.5 mg / mL, 25.0 mg / mL, 25.5 mg / mL, 26.0 mg / mL, 26.5 mg / mL, 27.0 mg / mL, 27.5 mg / mL, 28.0 mg / mL, 28.5 mg / mL, 29.0 mg / mL, 29.5 mg / mL, or about 30.0 mg / mL.

[0217] It is pointed out that when it is referred herein to "first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively" this also encompasses "first and second polypeptide chains having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26 and SEQ ID NO: 2, respectively and preferably comprising the CDRL1, CDRL2, CDRL3, CDR|31, CDR|32, and CDR|33 according to SEQ ID NOs: 4, 5, 6, 12, 13, and 14, respectively, and comprising the CDRal, CDRa2, CDRa3, CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 16, 17, 18, 8, 9, and 10, respectively".

[0218] The skilled person is well aware which osmolarity or osmolality the herein described compositions have and / or how they can be determined. The described compositions may have an osmolality of about 100 mOsmol / kg to about 600 mOsmol / kg, such as 200 mOsmol / kg to about 500 mOsmol / kg, preferably about 300 mOsmol / kg to about 400 mOsmol / kg, most preferably about 310 mOsmol / kg to about 320 mOsmol / kg, such as about 317 mOsmol / kg. Accordingly, it is preferred that the described compositions have an osmolality of about 317 mOsmol / kg. In particular, it is envisaged that a composition consisting of about 4.5 mM methionine, about 292 mM trehalose, such as 292.2 mM trehalose, about 20 mM citric acid and about 0.02 % (w / v) poloxamer 188 (and the described antigen binding proteins) has an osmolality of about 317 mOsmol / kg. The recited osmolality values may represent the osmolality before pH adjustment.

[0219] The skilled person is well aware which chemicals to use in which amounts to arrive at the described concentrations. It is preferred that the chemicals used have the quality standard according to European Pharmacopoeia and / or United States Pharmacopoeia - National Formulary. The skilled person is also well aware of how the described compositions may be prepared. For example, the purified antigen binding protein may be provided in a different buffer and then formulated in the described composition by e.g. u Itraf i Itration / diafi Itration . It is envisaged that a composition comprising methionine, trehalose and citric acid, preferably 4.5 mM methionine, 292 mM trehalose and 20 mM citric acid, pH e.g. 6.5, is prepared, and that the purified antigen binding molecule is formulated, e.g. by ultrafiltration / diafiltration, using the prepared composition. Then poloxamer 188, preferably 0.02 % (w / v) poloxamer 188 is added. The pH may be adjusted using sodium hydroxide if the pH is too low. The pH may be adjusted using concentrated hydrochloric acid if the pH is too high. Preferably, the pH may be adjusted using sodium hydroxide.

[0220] Table 2 shows non-limiting and exemplary how the inventive composition / formulation may be prepared.

[0221] Table 2: A non-limiting example of preparing the described formulation is shown. The typical volume of a bulk drug product may be 50 liters corresponding to approximately 25,000 vials. It is shown which amount of the corresponding substances may be used for 50 liters or 1.7 ml (vial). It is of course evident for the skilled person that the substances may not be weighed according to the depicted amounts and then diluted. Rather a solution without the MAG-003 TCER® may be prepared and the TCER® introduced e.g. by ultrafiltration or dialysis.

[0222] Abbreviations: N / A = Not Applicable; q.s. = quantum satis; Ph. Eur. = European Pharmacopoeia; USP-NF = United States Pharmacopoeia - National Formulary

[0223] 3For pH 6.5 adjustment of the formulation buffer.

[0224] In a second aspect, the invention provides an injection device comprising the pharmaceutical composition of the first aspect and described throughout this application. The injection device may be a prefilled syringe. The syringe may comprise a syringe body having a hollow cylindrical configuration, forming a chamber holding the pharmaceutical composition. The syringe body may have a distal end portion and a proximal end portion, the proximal end portion having an opening through which a piston rod arrangement is insertable into the chamber, and the distal end portion having an opening through which the pharmaceutical composition can be dispensed. A Luer lock connector is preferably formed at the distal end portion.

[0225] In a third aspect, the invention provides a kit comprising one or more vials containing the pharmaceutical composition of the first aspect and described throughout this application. The invention also provides a vial containing the pharmaceutical composition of the first aspect and described throughout this application as such (i.e., without further components of a kit).

[0226] The kit may further comprise an injection device for administration of the pharmaceutical composition to a subject in need thereof. The injection device may be an injection device as described for the second aspect, with the difference that it may or may not be prefilled with the pharmaceutical composition.

[0227] The kit may comprise a) the pharmaceutical composition of the first aspect, b) optionally packaging material, and c) optionally a label or packaging insert contained within said packaging material indicating that said antigen binding protein is effective for treating cancer or for use for the treatment of cancer.

[0228] Components of the kits may be present in separate containers, or multiple components may be present in a single container. A suitable container includes a single tube, one or more wells of a plate (e.g., a 96-well plate, a 384-well plate, etc.), or the like.

[0229] It is envisaged that the antigen binding protein comprised in the pharmaceutical composition of the first aspect is contained in single and / or multi-chambered pre-filled syringes.

[0230] In one embodiment, the invention encompasses kits for producing a single-dose administration unit.

[0231] The aqueous formulation is typically an aqueous solution comprising pharmaceutically acceptable carriers as defined herein above in the section "pharmaceutical compositions".

[0232] In a fourth aspect, the invention provides a method of making an aqueous pharmaceutical composition, the method comprising providing: (i) an antigen binding protein as described herein, (ii) methionine, (iii) trehalose, (iv) citric acid, (v) Poloxamer 188, and (vi) sterile water, mixing or combining (i) to (vi) in sufficient amounts, and adjusting the pH to about 6.3 to 7.0, 6.3 to 6.9, 6.3 to 6.8, 6.4 to 6.7, 6.4 to 6.6 or about 6.5. The suitable amounts of methionine, trehalose, citric acid and poloxamer 188 are as described throughout this application.

[0233] In a fifth aspect, the invention provides the described pharmaceutical composition for use in medicine.

[0234] In a further aspect, the invention provides the described pharmaceutical composition for use in a method of treating a proliferative disease. The proliferative disease preferably is cancer. The skilled person is readily capable to determine diseases that may be treated with the described pharmaceutical compositions. For example, the cancer may be selected from the group consisting of lung cancer such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) or large cell lung cancer (LCLC), preferably non-small cell lung cancer adenocarcinoma (NSCLCadeno), squamous cell non-small cell lung cancer (NSCLCsquam) or large cell neuroendocrine tumor of the lung; liver cancer, preferably hepatocellular cancer (HCC); head and neck cancer, preferably head and neck squamous cell carcinoma (HNSCC) or salivary gland adenocarcinoma; skin cancer, preferably melanoma (MEL), preferably cutaneous melanoma or mucosal melanoma; renal cell cancer (RCC); brain cancer, preferably glioblastoma (GBM); gastric cancer (GC), preferably gastric adenocarcinoma; colorectal cancer (CRC); pancreatic cancer (PACA); prostate cancer (PRAD); leukemia, preferably acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL); lymphoma, preferably non-Hodgkin lymphoma (NHL); breast cancer (BRCA), preferably triple-negative breast cancer (TNBC); Merkel cell carcinoma; ovarian cancer (OC), preferably ovarian carcinoma or ovarian serous carcinoma, epithelial ovarian, fallopian tube, and primary peritoneal cancers (EOFPC); urinary bladder cancer (UBC), preferably urinary bladder carcinoma or bladder urothelial carcinoma; uterine cancer (UEC) , preferably uterine carcinosarcoma; cervical squamous cell carcinoma; gallbladder cancer (GBC), preferably gallbladder adenocarcinoma; bile duct cancer (CCC); sarcoma (SARC), preferably synovial sarcoma (spindle cell, biphasic, and poorly differentiated subtypes), sarcoma of the tonsil or osteosarcoma; esophageal cancer, preferably large cell neuroendocrine tumor of the esophagus or esophageal squamous cell carcinoma; gastroesophageal junction cancer (GEJC); Neuroendocrine neoplasm (NEN), preferably Neuroendocrine Tumor CUP; and testicular cancer, preferably testicular germ cell tumor, preferably the cancer is selected from the group consisting of (cutaneous or mucosal) melanoma (MEL); triple-negative breast cancer (TNBC); head and neck squamous cell carcinoma (HNSCC); synovial sarcoma; ovarian cancer (OC); gastric cancer (GC); squamous cell non-small cell lung cancer (NSCLCsquam); and Neuroendocrine neoplasm (NEN), preferably Neuroendocrine Tumor CUP (cancer of unknown primary), more preferably the cancer is cutaneous melanoma, mucosal melanoma, head and neck squamous cell carcinoma (HNSCC) or Neuroendocrine Tumor CUP.

[0235] The cancer may also be selected from the group consisting of adrenocortical carcinoma, bladder cancer, preferably (urinary) bladder carcinoma or bladder urothelial carcinoma, brain tumor, in particular glioblastoma, primary brain cancer, or atypical meningioma, breast cancer, in particular triple-negative breast cancer or breast carcinoma, cervical carcinoma, in particular cervical squamous cell carcinoma or endocervical adenocarcinoma, cholangiocellular carcinoma, colorectal cancer, in particular colon cancer, endometrial cancer, in particular uterine carcinoma or uterine carcinosarcoma, epithelial cancer of the larynx, esophageal cancer, preferably large cell neuroendocrine tumor of the esophagus, esophageal carcinoma or esophageal squamous cell carcinoma, gastroesophageal junction cancer (GEJC), fallopian tube cancer, gallbladder cancer, preferably gallbladder adenocarcinoma, gastrointestinal cancer, gastric cancer (GC), preferably gastric adenocarcinoma; colorectal cancer (CRC); pancreatic cancer (PACA), germ cell tumor, head and neck cancer, in particular head and neck adenocarcinoma, head and neck squamous cell carcinoma or cervical squamous cell carcinoma, liver cancer, in particular hepatocellular cancer or hepatocellular carcinoma, leukemia, in particular acute myeloid leukemia or chronic lymphocytic leukemia, lung cancer, in particular small cell lung cancer, non-small cell lung cancer, non-small cell lung adenocarcinoma, non-small cell lung squamous cell carcinoma (sqNSCLC), large cell neuroendocrine tumor of the lung or large cell carcinoma of the lung, lymphoma, in particular extranodal T / NK-cell lymphoma, non-Hodgkin lymphoma, or H. pylori-induced MALT nonHodgkin lymphoma, malignant peripheral nerve sheath tumors, skin cancer, in particular melanoma, in particular amelanotic melanoma, uveal melanoma, mucosal melanoma or cutaneous melanoma, mesothelioma, oral cavity carcinomas, oral squamous carcinoma, ovarian cancer, in particular epithelial ovarian cancer, serous ovarian cancer, ovarian carcinoma or ovarian carcinosarcoma, ovarian serous carcinoma, epithelial ovarian, fallopian tube, and primary peritoneal cancers (EOFPC), papillary thyroid carcinoma, primary peritoneal cancer, in particular restricted to serous, clear cell, and endometrioid subtypes, prostate cancer, renal cancer, in particular renal carcinoma, in particular renal clear cell carcinoma, renal papillary cell carcinoma, salivary duct carcinoma, sarcoma, in particular Ewing's sarcoma, fibrosarcoma, liposarcoma, osteosarcoma, sarcoma of the tonsil or synovial sarcoma (spindle cell, biphasic, and poorly differentiated subtypes), testicular cancer, in particular testicular germ cell tumor, thymoma, urothelial carcinoma, uterine cancer (UEC), preferably uterine carcinosarcoma or uterine carcinoma, Merkel cell carcinoma, Neuroendocrine neoplasms (NEN), preferably Neuroendocrine Tumor CUP, gallbladder cancer (GBC), preferably gallbladder adenocarcinoma and bile duct cancer (CCC).

[0236] In the context of the invention, the terms "treating" or "treatment", include both therapeutic treatment (i.e. on a subject having a given disease) and / or preventive or prophylactic treatment (i.e. on a subject susceptible of developing a given disease). Therapeutic treatment and means reversing, alleviating and / or inhibiting the progress of one or more symptoms of a disorder or condition. Prophylactic treatment means preventing the occurrence of one or more symptoms of a disorder or condition. Therefore, treatment does not only refer to a treatment that leads to a complete cure of the disease, but also to treatments that slow down the progression of the disease, prevent or delay the occurrence of the disease and / or prolong the survival of the subject.

[0237] A "disease" or "disorder" is any condition that would benefit from treatment with the described antigen binding protein or pharmaceutical composition. This includes chronic and acute disorders or diseases including those pathological conditions which predisposes the subject to the disorder in question. The term "in need of treatment" refers to a subject having already the disorder as well as those in which the disorder is to be prevented.

[0238] "Proliferative diseases", such as cancer, involve the unregulated and / or inappropriate proliferation of cells.

[0239] Among the texts providing guidance for cancer therapy is Cancer, Principles and Practice of Oncology, 4th Edition, DeVita et al, Eds. J. B. Lippincott Co., Philadelphia, Pa. (1993). An appropriate therapeutic approach is chosen according to the particular type of cancer, and other factors such as the general condition of the patient, as is recognized in the pertinent field. A pharmaceutical composition of the present invention can be used by itself or can be added to a therapy regimen using other anti-neoplastic agents in treating a cancer patient. Accordingly, the pharmaceutical composition can be administered concurrently with, before, or after a variety of drugs and treatments widely employed in cancer treatment such as, for example, chemotherapeutic agents, non-chemotherapeutic agents, anti-neoplastic agents, and / or radiation.

[0240] "Diagnosis" herein refers to a medical diagnosis and refers to determining which disease or condition explains a person's symptoms and signs.

[0241] By a "therapeutically effective amount" of the antigen binding protein or pharmaceutical composition thereof is meant a sufficient amount of the antigen binding protein to treat said proliferative disease, at a reasonable benefit / risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the pharmaceutical composition of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific antigen binding protein employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific polypeptide employed; the duration of the treatment; drugs used in combination or coincidental with the specific polypeptide employed; and like factors well known in the medical arts. For example, it is well known within the skill ofthe art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. Although evident for the skilled person it is pointed out that the disclosures in context of the methods described herein are disclosed as corresponding use mutatis mutandis. The disclosures in context of the use described herein are disclosed as corresponding methods mutatis mutandis.

[0242] Thus, in a sixth aspect, the invention provides e.g. a method of treating a proliferative disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition described herein.

[0243] The invention will now be described in more details with reference to the following figures, tables and examples. All literature and patent documents cited herein are hereby incorporated by reference. While the invention has been illustrated and described in detail in the foregoing description, the examples are to be considered illustrative or exemplary and not restrictive. Table 3 - amino acid sequences The present invention is illustrated by the appended non-limiting Figures and Examples

[0244] Description of Figures

[0245] Figure 1: Results of SE-HPLC analysis of IMA401 formulated either in PBS or in WP3_01 buffer and stored at 40°C. Samples were analysed at various timepoints after study start. Depicted are the peak areas of the monomer peak as (A) percentage of the total peak areas detected and (B) absolut peak area (in mAU*min). Detected HMWS are shown in C as relative peak areas.

[0246] Figure 2: Results of SE-HPLC analysis of IMA401 formulated in WP3_01 buffer at a concentration of 1 mg / ml or 10 mg / ml and stored at 25°C or 40°C. Samples were analysed at various timepoints after study start. Depicted are the peak areas of the monomer peak (A and C) and HMWS peak (B and D) as percentage of the total peak areas detected.

[0247] The Examples illustrate the invention.

[0248] Examples

[0249] Example 1

[0250] Example 1 demonstrates that the inventive formulation is superior compared to the prior art formulation in conveying stability to the tested antigen binding protein (MAG-003 TCER®).

[0251] The antigen binding protein of the invention was formulated in either PBS (Thermo Fisher, pH 7.2 - 7.4) by usage of sephadex spin columns (Thermo Fisher) or in the buffer WP3_01 (comprising 4.5 mM methionine, 292 mM trehalose, 20 mM citric acid and 0.02 % (w / v) poloxamer 188, pH 6.5) by ultra / diafiltration at concentrations of 1 mg / mL as determined by OD280 nm measured on a NanoDrop device (Thermo Fisher). Aliquots of the formulated proteins of 100 pL were prepared and stored at 40°C for up to 4 months. For each timepoint SE-HPLC analysis was performed. The amount of monomeric protein as well as high- molecular weight species (HMWS) was determined using a XBridge Premier SEC (4.6 x 150 mm, 2.5 pm) column (Waters) installed in a Vanquish uHPLC system (Thermo Fisher) equilibrated in 50 mM NaH2PO4+ 300 mM NaCI, pH 6.8. Eluting proteins were detected at 214 nm. The results are summarized in table 4 below and Figure 1.

[0252] Analysis of the formulated proteins before incubation at 40°C showed comparable and low levels of HMWS in PBS and WP3_01, respectively. Incubation of the protein solutions at 40°C resulted in increased HMWS formation. However, for all timepoints assessed lower levels of HMWS were detected for the antigen binding protein formulated in WP3_01, demonstrating increased stability of the antigen binding protein in this buffer.

[0253] Table 4

[0254] MAG-003 TCER® was either formulated in PBS or in the buffer WP3_01 (comprising 4.5 mM methionine, 292 mM trehalose, 20 mM citric acid and 0.02 % (w / v) poloxamer 188, pH 6.5) and stored at 40°C. The amount of monomeric protein as well as high-molecular weight species (HMWS) was determined at the indicated timepoints.

[0255] Example 2

[0256] The MAG-003 TCER® was formulated in the buffer WP3_01 (comprising 4.5 mM methionine, 292 mM trehalose, 20 mM citric acid and 0.02 % (w / v) poloxamer 188, pH 6.5) by ultra / diafiltration at concentrations of 1 mg / mL and 10 mg / mL, respectively, as determined by OD280 nm. Aliquots of the formulated proteins were prepared and stored at 25°C and 40°C for up to 12 months. For each timepoint SE-HPLC analysis was performed. The amount of monomeric protein as well as high-molecular weight species (HMWS) was determined using a Acquity UPLC BEH200 SEC column (1. 7 pm, 4.6 mm x 300 mm, Waters) installed in an Agilent 1290 uHPLC system (Agilent) equilibrated in 100 mM phosphate buffer + 200 mM NaCI, pH 6.8. Eluting proteins were detected at 280 nm. The results demonstrated that the stability of the formulation is independent of the concentration of the MAG-003 TCER® (Figure 2).

Claims

Claims1. A pharmaceutical composition comprising an antigen binding protein comprising one antigen binding site A, wherein said antigen binding site A comprises a TCR alpha variable domain (Va) comprising a complementarity determining region (CDR) CDRal having the amino acid sequence of SEQ ID NO: 16, a CDRa2 having the amino acid sequence of SEQ ID NO: 17, and a CDRa3 having the amino acid sequence of SEQ ID NO: 18, and a TCR beta variable domain (Vp) comprising a CDR 1 having the amino acid sequence of SEQ ID NO: 12, a CDR 2 having the amino acid sequence of SEQ ID NO: 13, and a CDR 3 having the amino acid sequence of SEQ ID NO: 14, wherein one or more of the CDRs may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution, wherein the pharmaceutical composition comprises i) 1 to 20 mM methionine, ii) 50 to 1000 mM trehalose, iii) 1 to 100 mM citric acid, and iv) 0.001 to 0.1 % (w / v) poloxamer 188, and wherein the pharmaceutical composition has a pH of about 6.3 to 7.0, preferably about 6.5.

2. The pharmaceutical composition according to claim 1, wherein the antigen binding site A comprises or consists of a T cell receptor (TCR) or a tumor antigen (TA) / MHC binding fragment thereof.

3. The pharmaceutical composition according to claim 1 or 2, wherein the antigen binding site A comprises(i) a Vacomprising or consisting of an amino acid sequence according to SEQ ID NO: 15, or a variant thereof, which comprises the CDRal, CDRa2, and CDRa3 according to SEQ ID NO: 16, 17, and 18, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 15, and(ii) a Vp comprising or consisting of an amino acid sequence according to SEQ ID NO: 11, or a variant thereof, which comprises the CDR|31, CDR|32, and CDR|33 accordingto SEQ ID NO: 12, 13, and 14, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 11.

4. The pharmaceutical composition according to any of claims 1 to 3, wherein the antigen binding protein is a bispecific antigen binding protein and comprises a further antigen binding site B.

5. The pharmaceutical composition according to claim 4, wherein the antigen binding site B specifically binds to an T cell receptor (TCR) / CD3 complex.

6. The pharmaceutical composition according to claim 4 or 5, wherein the antigen binding site B comprises or consists of an antibody or an antigen binding fragment thereof.

7. The pharmaceutical composition according to any of claims 4 to 6, wherein the antigen binding site B comprises(i) a VHcomprising a CDRH1 having the amino acid sequence of SEQ ID NO: 8, a CDRH2 having the amino acid sequence of SEQ ID NO: 9, and a CDRH3 having the amino acid sequence of SEQ ID NO: 10, and(ii) a VLcomprising a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 5, and a CDRL3 having the amino acid sequence of SEQ ID NO: 6, wherein one or more of the CDRs may comprise one, two orthree amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

8. The pharmaceutical composition according to any of claims 4 to 7, wherein the antigen binding site B comprises(i) a VHcomprising or consisting of the amino acid sequence of SEQ ID NO: 7 or a variant thereof, which comprises the CDRH1, CDRH2 and CDRH3 according to SEQ ID NO: 8, 9 and 10, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 7, and(ii) a VLcomprising or consisting of the amino acid sequence of SEQ ID NO: 27 or a variant thereof, which comprises the CDRL1, CDRL2, and CDRL3 according to SEQ ID NO: 4, 5 and 6, respectively, and has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to SEQ ID NO: 27, respectively.

9. The pharmaceutical composition according to any of claims 1 to 8, wherein the antigenbinding protein comprises or consists of a first polypeptide chain comprising a structure represented by the formula: VL-L1-VP; and a second polypeptide chain comprising a structure represented by the formula: Va-L2-VH; wherein LI and L2 are linkers.

10. The pharmaceutical composition according to any of claims 1 to 9, wherein the antigenbinding protein comprises or consists of a first polypeptide chain comprising a structure represented by the formula: VL-L1-VP-L3-FC1; and a second polypeptide chain comprising a structure represented by the formula: Va-L2-VH-L4-FC2; wherein LI, L2, L3 and L4 are linkers and may be present or absent, and FC1 and FC2 are Fc-domains and may be the same or different.

11. The pharmaceutical composition according to claim 10, whereinFC1 comprises or consists of the amino acid sequence according to SEQ ID NO: 19 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 19; and / orFC2 comprises or consists of the amino acid sequence according to SEQ ID NO: 20 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 20.

12. The pharmaceutical composition according to any of claims 1 to 11, wherein the antigen binding protein comprises or consists of(i) a first polypeptide chain comprising or consisting of an amino acid sequence according to SEQ ID NO: 26 or an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26, preferably comprising the CDRL1, CDRL2, CDRL3, CDR 1, CDR 2, and CDR 3 according to SEQ ID NOs: 4, 5, 6, 12, 13, and 14, respectively, and(ii) a second polypeptide chain comprising or consisting of an amino acid sequence according to SEQ ID NO: 2 or an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, preferably comprising the CDRal, CDRa2, CDRa3, CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 16, 17, 18, 8, 9, and 10, respectively.

13. The pharmaceutical composition according to any of claims 1 to 12, wherein the antigen binding protein comprises a modification of the N-terminal and / or C-terminal amino acid(s), preferably wherein an N-terminal glutamine is substituted by a pyro-glutamate.

14. The pharmaceutical composition according to any one of claims 1 to 13, comprising 4.5 mM methionine.

15. The pharmaceutical composition according any one of claims 1 to 14, comprising 292 mM trehalose.

16. The pharmaceutical composition according to any one of claims 1 to 15, comprising 20 mM citric acid.

17. The pharmaceutical composition according to any one of claims 1 to 16, comprising 0.02 % (w / v) poloxamer 188.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the pharmaceutical composition has a pH of 6.5 and comprises 4.5 mM methionine, 292 mM trehalose, 20 mM citric acid, and 0.02 % (w / v) poloxamer 188.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the pharmaceutical composition is a solution, preferably an aqueous solution.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the concentration of the antigen binding protein is from 0.1 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 12.5 mg / mL, about 0.1 mg / mL to about 15 mg / mL, about 0.1 mg / mL to about 20 mg / mL, about 0.1 mg / mL to about 25 mg / mL, about 0.1 mg / mL to about 30 mg / mL, about 0.1 mg / mL to about 35 mg / mL, about 0.1 mg / mL to about 40 mg / mL, about 0.1 mg / mL to about 45 mg / mL, about 0.1 mg / mL to about 50 mg / mL, about 0.2 mg / mL to about 8 mg / mL, about 0.25 mg / mL to about 7.5 mg / mL, about 0.5 mg / mL to about 5 mg / mL, about 0.75 mg / mL to about 1.25 mg / mL, about 1 mg / mL, about 1 mg / mL to about 100 mg / mL, about 2 mg / mL to about 80 mg / mL, about 2.5 mg / mL to about 75 mg / mL, about 5 mg / mL to about 50 mg / mL, about 7.5 mg / mL to about 12.5 mg / mL, or about 10 mg / mL, in particular, about 1 mg / mL to about 90 mg / mL, about 1 mg / mL to about 80 mg / mL, about 1 mg / mL to about 70 mg / mL, about 1 mg / mL to about 60 mg / mL, about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 40 mg / mL, about 1 mg / mL to about 35 mg / mL, about 1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 25 mg / mL, about 1 mg / mL to about 20 mg / mL, about 1 mg / mL to about 19 mg / mL, about 1 mg / mL to about 18 mg / mL, about 1 mg / mL to about 17 mg / mL, about 1 mg / mL to about 16 mg / mL, about 1 mg / mL to about 15 mg / mL, about 1 mg / mL to about 14 mg / mL, about 1 mg / mL to about 13 mg / mL, about 1 mg / mL to about 12 mg / mL, about 1 mg / mL to about 11 mg / mL, or about 1 mg / mL to about 10 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, about 1 mg / mL to about 20 mg / mL, or about 1 mg / mL to about 30 mg / mL.

21. The pharmaceutical composition according to any one of items 1 to 20, wherein the concentration of the antigen binding protein is selected from the group consisting of about 1.0 mg / mL, about 1.5 mg / mL, about 2.0 mg / mL, about 2.5 mg / mL, about 3.0 mg / mL, about 3.5 mg / mL, about 4.0 mg / mL, about 4.5 mg / mL, about 5.0 mg / mL, about 5.5 mg / mL, about 6.0 mg / mL, about 6.5 mg / mL, about 7.0 mg / mL, about 7.5 mg / mL, about 8.0 mg / mL, about 8.5 mg / mL, about 9.0 mg / mL, about 9.5 mg / mL, about 10.0mg / mL, about 10.5 mg / mL, about 11.0 mg / mL, about 11.5 mg / mL, about 12.0 mg / mL, about 12.5 mg / mL, about 13.0 mg / mL, about 13.5 mg / mL, about 14.0 mg / mL, about14.5 mg / mL, about 15.0 mg / mL, about 15.5 mg / mL, about 16.0 mg / mL, about 16.5 mg / mL, about 17.0 mg / mL, about 17.5 mg / mL, about 18.0 mg / mL, about 18.5 mg / mL, about 19.0 mg / mL, about 19.5 mg / mL, about 20.0 mg / mL, about 20.5 mg / mL, about 21.0 mg / mL, about 21.5 mg / mL, about 22.0 mg / mL, about 22.5 mg / mL, about 23.0 mg / mL, about 23.5 mg / mL, about 24.0 mg / mL, about 24.5 mg / mL, about 25.0 mg / mL, about 25.5 mg / mL, about 26.0 mg / mL, about 26.5 mg / mL, about 27.0 mg / mL, about about 27.5 mg / mL, about 28.0 mg / mL, about 28.5 mg / mL, about 29.0 mg / mL, about29.5 mg / mL, or about 30.0 mg / mL.

22. An injection device comprising the pharmaceutical composition of any one of claims 1 to 21, preferably wherein the injection device is a prefilled syringe.

23. A kit comprising one or more vials containing the pharmaceutical composition of any one of claims 1 to 21, preferably wherein the kit further comprises an injection device for administration of the pharmaceutical composition to a subject in need thereof.

24. A method of making an aqueous pharmaceutical composition, the method comprising providing:(i) an antigen binding protein as defined in claims 1 to 13,(ii) methionine,(iii) trehalose,(iv) citric acid;(v) poloxamer 188, and(vi) sterile water, mixing or combining (i) to (vi) in sufficient amounts, and adjusting the pH to around 6.3 to 7.0.

25. A pharmaceutical composition of any one of claims 1 to 21 for use in medicine.

6. A method of treating a proliferative disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 21.

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