Anti-KMA antibody formulations

Abstract

The present disclosure relates to anti-KMA antibody formulations with diethylenetriaminepentaacetic acid (DTPA) and uses thereof. Such formulations may be particularly suitable for antibodies which bind to free kappa light chain and not associated with heavy chain.

Description

[0001] Anti-KMA Antibody Formulations

[0002] Related Application Data

[0003] The present application claims priority from Australian Patent Application No. 2024901031 filed on 12 April 2024 entitled “ Anti -KMA Antibody Formulations”. The entire contents of which is hereby incorporated by reference.

[0004] Sequence Listing

[0005] The present application is filed with a Sequence Listing, which has been submitted in electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on 8 April 2025, is named “541414PCT sequence listing” and is 12.7 kilobytes in size.

[0006] Field

[0007] The present disclosure relates to anti-KMA antibody formulations and uses thereof. Such formulations may be particularly suitable for antibodies which bind to free kappa light chain not associated with heavy chain.

[0008] Background

[0009] Antibodies, like most proteins, must maintain their higher order structure in order to maintain their biological activity. One problem faced by companies selling therapeutic antibodies is the identification of conditions under which the antibody can exist for an extended period without degrading and thus, losing biological activity. Antibodies are unique, and thus conditions for optimal stability can vary.

[0010] The method of antibody production may also add complexity on the stability and potency fronts, given that the production of antibodies commonly relies on recombinant DNA technology and the use of cell lines, which can result in the accumulation of undesirable components in cell culture fluid. Undesirable components can include high molecular weight aggregates and, in some instances, antibody complexes comprising the antibody of interest and an antigen.

[0011] Anti-KMA antibodies bind human free kappa light chains and an antigen expressed on the surface of certain malignant cells. This antigen is designated as kappa myeloma antigen or KMA(Boux, HA. et al. (1983) J Exp Med. 158: 1769). Antibody complexes may be particularly pronounced when certain cell lines are used to produce anti-KMA antibodies, as some cell lines, such as commonly used CHO cell lines, secrete free kappa light chains into their cell culture fluid. Poor stability and / or potency is disadvantageous on multiple fronts, as it can impact product release, safety, and overall cost. Thus, there is a need in the art for new formulations of anti -KM A antibodies.

[0012] Summary

[0013] The present disclosure is based, at least in part, on the inventors’ unexpected finding that a pharmaceutical formulation comprising an anti-KMA antibody has improved stability and / or improved biological activity when formulated with diethylenetriaminepentaacetic acid (DTPA). This finding was particularly surprising in view of the interaction between free kappa light chains and anti-KMA antibodies, notably that anti-KMA antibodies complex with free kappa light chains secreted during cell culture and, presence of these complexes in resulting anti-KMA antibody formulations. In view of this nuance of anti-KMA antibody manufacture, the findings of the present inventors underpin a new way of formulating anti-KMA antibodies to improve stability and / or potency of the overarching composition.

[0014] In addition, the present inventors have surprisingly shown that administering a pharmaceutical formulation comprising anti-KMA antibody and DTPA, is unexpectedly well tolerated by patients.

[0015] Thus, the present disclosure provides a pharmaceutical formulation comprising an anti- KMA antibody and DTPA.

[0016] In an example, the anti-KMA antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising a complementarity determining region (CDR) 1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8.

[0017] In an example, the anti -KM A antibody comprises an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2.

[0018] In an example, the anti-KMA antibody is present in the pharmaceutical formulation at a concentration of 5 mg / mL to 60 mg / mL. In an example, the anti-KMA antibody is present in the pharmaceutical formulation at a concentration of 5 mg / mL to 30 mg / mL. In an example, the anti-KMA antibody is present in the pharmaceutical formulation at a concentration of 5 mg / mL to 20 mg / mL. In an example, the anti-KMA antibody is present in the pharmaceutical formulation at a concentration of 9 mg / mL to 11 mg / mL. In an example, the anti-KMA antibody is present in the pharmaceutical formulation at a concentration of 10 mg / mL.

[0019] In an example, the anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 is present in the pharmaceutical formulation at a concentration of 5 mg / mL to 60 mg / mL. In an example, the anti-KMA antibody is present in the pharmaceutical formulation at a concentration of 5 mg / mL to 30 mg / mL.

[0020] In an example, the anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 is present in the pharmaceutical formulation at a concentration of 5 mg / mL to 20 mg / mL. In an example, the anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 is present in the pharmaceutical formulation at a concentration of 9 mg / mL to 11 mg / mL.

[0021] In an example, the anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 is present in the pharmaceutical formulation at a concentration of 5 mg / mL to 60 mg / mL. In an example, the anti-KMA antibody is present in the pharmaceutical formulation at a concentration of 5 mg / mL to 30 mg / mL. In an example, the anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 is present in the pharmaceutical formulation at a concentration of 5 mg / mL to 20 mg / mL. In an example, the anti-KMA antibody is present in the pharmaceutical formulation at a concentration of 9 mg / mL to 11 mg / mL.

[0022] In an example, the DTPA is present in the pharmaceutical formulation at a concentration of 0.01 mg / mL to 0.05 mg / mL.

[0023] For example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 5 mg / mL to 60 mg / mL and DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL. In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 9 mg / mL to 11 mg / mL and DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL. In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 10 mg / mL and DTPA at a concentration of 0.02 mg / mL.

[0024] For example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 5 mg / mL to 60 mg / mL and DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL.

[0025] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 to 11 mg / mL and DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL.

[0026] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 10 mg / mL and DTPA at a concentration of 0.02 mg / mL.

[0027] For example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 5 mg / mL to 60 mg / mL and DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL. In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 to 11 mg / mL and DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL.

[0028] In an example, the pharmaceutical formulation comprises an anti-KMA antibody and DTPA, wherein the anti-KMA antibody comprises: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8, wherein the antibody is provided at a concentration of 10 mg / mL.

[0029] In an example, the ratio of anti-KMA antibody to DTPA is between 450: 1 and 550: 1. For example, the ratio of anti-KMA antibody to DTPAis at least 450: 1, at least 455: 1, at least 460: 1, at least 465: 1, at least 470: 1, at least 475: 1, at least 480: 1, at least 485: 1, at least 490: 1, at least 495: 1, at least 500:1, at least 505:1, 510: 1, at least 515:1, at least 520: 1, at least 525: 1, at least 530: 1, at least 535: 1, at least 540: 1, at least 545: 1, or at least 550: 1.

[0030] In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 5 mg / mL to 60 mg / mL and DTPA at a concentration 0.01 mg / mL to 0.05 mg / mL and wherein the ratio of anti-KMA antibody to DTPAis between about 425 : 1 and 550: 1.

[0031] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 5 mg / mL to 60 mg / mL and DTPA at a concentration 0.01 mg / mL to 0.05 mg / mL and wherein the ratio of anti -KM A antibody to DTPA is between about 425:1 and 550: 1.

[0032] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 5 mg / mL to 60 mg / mL and DTPA at a concentration 0.01 mg / mL to 0.05 mg / mL, and wherein the ratio of anti-KMA antibody to DTPA is between about 425: 1 and 550: 1.

[0033] In an example, the pharmaceutical formulation is an aqueous formulation.

[0034] In an example, the pharmaceutical formulation has a pH of between 5 to 8. In an example, the pharmaceutical formulation has a pH of between 5.6 to 6.4. In an example, the pharmaceutical formulation has a pH of between 6.

[0035] For example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 5 mg / mL to 60 mg / mL and DTPA at a concentration 0.01 mg / mL to 0.05 mg / mL, wherein the pH is between 5 to 8. In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 5 mg / mL to 60 mg / mL and DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, wherein the pH is between 5.6 to 6.4. In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 5 mg / mL to 60 mg / mL and DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, wherein the pH is between 6.

[0036] For example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 5 mg / mL to 60 mg / mL and DTPA at a concentration 0.01 mg / mL to 0.05 mg / mL, wherein the pH is between 5 to 8.

[0037] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL and DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, wherein the pH is between 5.6 to 6.4.

[0038] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL and DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, wherein the pH is 6.

[0039] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 5 mg / mL to 60 mg / mL and DTPA at a concentration 0.01 mg / mL to 0.05 mg / mL, wherein the pH is between 5.6 to 6.4, and wherein the ratio of anti-KMA antibody to DTPA is between 450: 1 and 550: 1.

[0040] For example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 5 mg / mL to 60 mg / mL and DTPA at a concentration 0.01 mg / mL to 0.05 mg / mL, wherein the pH is between 5 to 8.

[0041] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL and DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, wherein the pH is between 5.6 to 6.4.

[0042] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL and DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, wherein the pH is 6.

[0043] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL and DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, wherein the pH is between 5.6 to 6.4, and wherein the ratio of anti-KMA antibody to DTPA is between 450: 1 and 550: 1.

[0044] In an example, the pharmaceutical formulation further comprises a non-ionic surfactant. For example, the non-ionic surfactant is selected from the group consisting of polysorbate 80, polysorbate 20 and poloxamer 188. For example, the pharmaceutical formulation comprises an anti-KMA antibody, DTPA and a non-ionic surfactant.

[0045] In an example, the non-ionic surfactant is polysorbate 80. In an example, the pharmaceutical formulation comprises an anti-KMA antibody, DTPA and polysorbate 80. In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8, DTPA and polysorbate 80. In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2, DTPA and polysorbate 80.

[0046] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8, DTPA and polysorbate 80, and wherein the ratio of anti-KMA antibody to DTPA is between 450: 1 and 550: 1. In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2, DTPA and polysorbate 80, and wherein the ratio of anti-KMA antibody to DTPA is between 450: 1 and 550: 1.

[0047] In an example, the non-ionic surfactant is present in the pharmaceutical formulation at a concentration of 0.2 mg / mL to 0.6 mg / mL. In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 5 mg / mL to 60 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL.

[0048] In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, wherein the pH is between 5.6 to 6.4. In an example, the pharmaceutical formulation comprises an anti- KMA antibody at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.4 mg / mL. In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non- ionic surfactant at a concentration of 0.4 mg / mL, wherein the pH is 6.

[0049] In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, wherein the pH is between 5.6 to 6.4, and wherein the ratio of anti-KMA antibody to DTPA is between 450: 1 and 550: 1.

[0050] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 5 mg / mL to 60 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL.

[0051] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, wherein the pH is between 5.6 to 6.4.

[0052] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.4 mg / mL.

[0053] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.4 mg / mL, wherein the pH is 6.

[0054] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, wherein the pH is between 5.6 to 6.4, and wherein the ratio of anti-KMA antibody to DTPA is between 450: 1 and 550: 1.

[0055] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 5 mg / mL to 60 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL.

[0056] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, wherein the pH is between 5.6 to 6.4.

[0057] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.4 mg / mL.

[0058] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.4 mg / mL, wherein the pH is 6.

[0059] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL and a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, wherein the pH is between 5.6 to 6.4, and wherein the ratio of anti-KMA antibody to DTPA is between 450: 1 and 550: 1.

[0060] In an example, the pharmaceutical formulation further comprises a buffer. For example, the buffer is selected from the group consisting of acetate, succinate, gluconate, citrate, histidine, acetic acid, phosphate, phosphoric acid, ascorbate, tartaric acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate and carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate, acetate, malate, imidazole, tris and phosphate. For example, the pharmaceutical formulation comprises an anti-KMA antibody, DTPA and a buffer. In an example, the pharmaceutical formulation comprises an anti-KMA antibody, DTPA, a non-ionic surfactant and a buffer.

[0061] In an example, the buffer is sodium citrate dihydrate. In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation at a concentration of 4 mg / mL to 8 mg / mL. In an example, the buffer is citric acid monohydrate. In an example, the citric acid monohydrate is present in the pharmaceutical formulation at a concentration of 0.2 mg / mL to 0.6 mg / mL.

[0062] In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 5 mg / mL to 60 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL and citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL.

[0063] In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL and citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL, wherein the pH is 5.6 to 6.4.

[0064] In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL and citric acid monohydrate at a concentration of 0.423 mg / mL.

[0065] In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.02 mg / mL, a non-ionic surfactant at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL and citric acid monohydrate at a concentration of 0.423 mg / mL, wherein the pH is 6.

[0066] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 5 mg / mL to 60 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL and citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL.

[0067] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL and citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL, wherein the pH is 5.6 to 6.4.

[0068] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL and citric acid monohydrate at a concentration of 0.423 mg / mL.

[0069] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.02 mg / mL, a non-ionic surfactant at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL and citric acid monohydrate at a concentration of 0.423 mg / mL, wherein the pH is 6.

[0070] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL and citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL, wherein the pH is 5.6 to 6.4, and wherein the ratio of anti-KMA antibody to DTPA is between 450: 1 and 550: 1.

[0071] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 5 mg / mL to 60 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL and citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL. In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL and citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL, wherein the pH is 5.6 to 6.4.

[0072] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL and citric acid monohydrate at a concentration of 0.423 mg / mL.

[0073] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.02 mg / mL, a non-ionic surfactant at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL and citric acid monohydrate at a concentration of 0.423 mg / mL, wherein the pH is 6.

[0074] In an example, the pharmaceutical formulation further comprises a salt. For example, the salt is selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride and calcium chloride. In an example, the salt is sodium chloride. For example, the pharmaceutical formulation comprises an anti-KMA antibody, DTPA and a salt. In an example, the pharmaceutical formulation comprises an anti-KMA antibody, DTPA, a non-ionic surfactant, a buffer and salt.

[0075] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8, DTPA and a salt. In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8, DTPA, a non-ionic surfactant, a buffer and salt.

[0076] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2, DTPA and a salt. In an example, the pharmaceutical formulation comprises an anti- KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2, DTPA, a non-ionic surfactant, a buffer and salt. In an example, the salt is present in the pharmaceutical formulation at a concentration of 2 mg / mL to 10 mg / mL. For example, the sodium chloride is present in the pharmaceutical formulation at a concentration of 2 mg / mL to 10 mg / mL.

[0077] In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 5 mg / mL to 60 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL, citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL and salt at a concentrati on of 2 mg / mL to 10 mg / mL . In an exampl e, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL, citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL and salt at a concentration of 2 mg / mL to 10 mg / mL, wherein the pH is 5.6 to 6.4.

[0078] In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL, citric acid monohydrate at a concentration of 0.423 mg / mL and salt at a concentration of 5.84 mg / mL. In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.02 mg / mL, a non-ionic surfactant at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL citric acid monohydrate at a concentration of 0.423 mg / mL and salt at a concentration of 5.84 mg / mL, wherein the pH is 6.

[0079] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 5 mg / mL to 60 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL, citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL and salt at a concentration of 2 mg / mL to 10 mg / mL.

[0080] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL, citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL and salt at a concentration of 2 mg / mL to 10 mg / mL, wherein the pH is 5.6 to 6.4.

[0081] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL, citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL and salt at a concentration of 2 mg / mL to 10 mg / mL, wherein the pH is 5.6 to 6.4, and wherein the ratio of anti-KMA antibody to DTPA is between 450: 1 and 550: 1.

[0082] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL, citric acid monohydrate at a concentration of 0.423 mg / mL and salt at a concentration of 5.84 mg / mL.

[0083] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL citric acid monohydrate at a concentration of 0.423 mg / mL and salt at a concentration of 5.84 mg / mL, wherein the pH is 6.

[0084] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL, citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL and salt at a concentration of 2 mg / mL to 10 mg / mL, wherein the pH is 5.6 to 6.4, and wherein the ratio of anti-KMA antibody to DTPA is between 450: 1 and 550: 1.

[0085] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 5 mg / mL to 60 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL, citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL and salt at a concentration of 2 mg / mL to 10 mg / mL.

[0086] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.2 mg / mL to 0.6 mg / mL, sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL, citric acid monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL and salt at a concentration of 2 mg / mL to 10 mg / mL, wherein the pH is 5.6 to 6.4.

[0087] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, a non-ionic surfactant at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL, citric acid monohydrate at a concentration of 0.423 mg / mL and salt at a concentration of 5.84 mg / mL.

[0088] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.02 mg / mL, a non-ionic surfactant at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL citric acid monohydrate at a concentration of 0.423 mg / mL and salt at a concentration of 5.84 mg / mL, wherein the pH is 6.

[0089] In an example, the pharmaceutical formulation further comprises a polyol. For example, the polyol is selected from the group consisting of mannitol, trehalose, sorbitol, erythritol, isomalt, lactitol, maltitol, xylitol, glycerol, lactitol, propylene glycol, polyethylene glycol and inositol. In an example, the polyol is mannitol.

[0090] In an example, the polyol is present in the pharmaceutical formulation at a concentration of 10 mg / mL to 20 mg / mL. For example, mannitol is present in the pharmaceutical formulation at a concentration of 10 mg / mL to 20 mg / mL.

[0091] In an example, the pharmaceutical formulation has a volume in the range of 5 mL to 30 mL. In an example, the pharmaceutical formulation has a volume in the range of 5 mL to 20 mL. In an example, the pharmaceutical formulation has a volume in the range of 9 mL to 11 mL.

[0092] In an example, the pharmaceutical formulation is stable up to at least 60 months. In an example, the pharmaceutical formulation is stable up to at least 108 months. In an example, the pharmaceutical formulation is stable up to at least 120 months.

[0093] In an example, the pharmaceutical formulation comprises an anti-KMA antibody, DTPA, a non-ionic surfactant, a buffer, a salt and a polyol.

[0094] In an example, the pharmaceutical formulation comprises an anti-KMA antibody, DTPA, polysorbate 80, sodium citrate dihydrate, citric acid monohydrate, sodium chloride, and mannitol.

[0095] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8; DTPA; polysorbate 80; sodium citrate dihydrate; citric acid monohydrate; sodium chloride; and mannitol.

[0096] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2; polysorbate 80; sodium citrate dihydrate; citric acid monohydrate; sodium chloride; and mannitol.

[0097] In an example, the pharmaceutical formulation comprises an anti-KMA antibody at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, polysorbate 80 at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL, citric acid monohydrate at a concentration of 0.423 mg / mL, sodium chloride at a concentration of 5.84 mg / mL, and mannitol at a concentration of 15 mg / mL.

[0098] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, polysorbate 80 at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL, citric acid monohydrate at a concentration of 0.423 mg / mL, sodium chloride at a concentration of 5.84 mg / mL, and mannitol at a concentration of 15 mg / mL.

[0099] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising: a VH and a VL, the VH comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, polysorbate 80 at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL, citric acid monohydrate at a concentration of 0.423 mg / mL, sodium chloride at a concentration of 5.84 mg / mL, mannitol at a concentration of 15 mg / mL, and wherein the ratio of anti-KMA antibody to DTPA is between 450: 1 and 550: 1.

[0100] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, polysorbate 80 at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL, citric acid monohydrate at a concentration of 0.423 mg / mL, sodium chloride at a concentration of 5.84 mg / mL, and mannitol at a concentration of 15 mg / mL.

[0101] In an example, the pharmaceutical formulation comprises an anti-KMA antibody comprising an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 at a concentration of 9 mg / mL to 11 mg / mL, DTPA at a concentration of 0.01 mg / mL to 0.05 mg / mL, polysorbate 80 at a concentration of 0.4 mg / mL, sodium citrate dihydrate at a concentration of 5.29 mg / mL, citric acid monohydrate at a concentration of 0.423 mg / mL, sodium chloride at a concentration of 5.84 mg / mL, and mannitol at a concentration of 15 mg / mL, and wherein the ratio of anti-KMA antibody to DTPA is between 450: 1 and 550: 1.

[0102] The present disclosure also provides a method of treating multiple myeloma in a subject, the method comprising administering a pharmaceutical formulation described herein to the subject.

[0103] The present disclosure also provides a method of treating a KMA-expressing malignancy in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition described herein.

[0104] The present disclosure also provides the use of a pharmaceutical composition described herein in the manufacture of a medicament for treating a KMA-expressing malignancy in a subject.

[0105] The present disclosure provides a method of adjuvant therapy comprising administering to a subject having multiple myeloma, following or in combination with a primary treatment, an effective amount of a pharmaceutical formulation described herein. The present disclosure provides an adjuvant method of treating multiple myeloma in a subject, the method comprising administering an effective amount pharmaceutical formulation described herein in combination with an existing therapeutic protocol. In one example, the multiple myeloma is relapsed and / or refractory. In one example, the multiple myeloma is relapsed. In one example, the multiple myeloma is refractory.

[0106] The present disclosure provides a method of adjuvant therapy comprising administering to a subject having a plasma cell dyscrasias, following or in combination with a primary treatment, an effective amount of a pharmaceutical composition described herein. The present disclosure provides an adjuvant method of treating plasma cell dyscrasias in a subject, the method comprising administering an effective amount of a pharmaceutical composition described herein in combination with an existing therapeutic protocol.

[0107] The present disclosure also provides a method of treating a plasma cell dyscrasias in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition described herein.

[0108] The present disclosure also provides the use of a pharmaceutical composition described herein in the manufacture of a medicament for treating a plasma cell dyscrasias in a subject.

[0109] The present disclosure also provides a composition comprising a pharmaceutical composition described herein for use in treating a plasma cell dyscrasias in a subject.

[0110] In one example, the KMA-expressing malignancy is selected from the group consisting of: multiple myeloma, plasmacytoma, extramedullary plasmacytoma, B cell lymphoproliferative disorders (BLPD), smoldering myeloma and monoclonal gammopathy of undetermined significance (MGUS).

[0111] In one example, the KMA-expressing malignancy is multiple myeloma. In one example, the KMA-expressing malignancy is plasmacytoma. In one example, the KMA-expressing malignancy is extramedullary plasmacytoma. In one example, the KMA-expressing malignancy is B cell lymphoproliferative disorders (BLPD). In one example, the KMA- expressing malignancy is smoldering myeloma. In one example, the KMA-expressing malignancy is monoclonal gammopathy of undetermined significance (MGUS).

[0112] In one example, the subject is refractory to therapy. In one example, the subject has received at least one, at least two, at least three, at least four, at least five, at least six prior lines of therapy. In another example, the subject has achieved at least a minimal response (25% reduction in M protein) to their most recent line of therapy. In another example, the subject comprises no M protein in their serum sample. In another example, the subject is refractory to at least one, at least two, at least three, at least four prior lines of therapy.

[0113] In another example, the subject is refractory to at least one proteasome inhibitor. In one example, the subject is refractory to anti -BCM A therapy. In an example, the subject is refractory to an anti-cancer therapy. In one example, the subject is refractory to anti-CD38 monoclonal antibodies.

[0114] In one example, the subject is refractory to daratumumab. In one example, the subject is refractory to isatuximab. In one example, the subject is refractory to cyclophosphamide. In one example, the subject is refractory to bortezomib. In one example, the subject is refractory to dexamethasone.

[0115] In one example, the subject has relapsed myeloma. In one example, the subject has refractory myeloma. In another example, the subject has primary refractory myeloma. In another example, the subject has refractory amyloidosis. In one example, the subject has relapsed KMA-expressing malignancy. For example, the subject has relapsed myeloma. In one example, the subject has relapsed amyloidosis. In another example, the subject has relapsed and refractory myeloma. In an example, the subject has relapsed and refractory amyloidosis.

[0116] In one example, the KMA-expressing malignancy is relapsed multiple myeloma. In one example, the KMA-expressing malignancy is relapsed and refractory multiple myeloma. In one example, the KMA-expressing malignancy is relapsed amyloidosis. In one example, the KMA- expressing malignancy is relapsed and refractory amyloidosis.

[0117] In one example, the KMA-expressing malignancy is refractory to anti -BCM A therapy. In an example, the KMA-expressing malignancy is refractory to an anti-cancer therapy. In one example, the KMA-expressing malignancy is refractory to daratumumab. In one example, the KMA-expressing malignancy is refractory to cyclophosphamide. In one example, the KMA- expressing malignancy is refractory to bortezomib. In one example, the KMA-expressing malignancy is refractory to dexamethasone.

[0118] The present disclosure also provides a kit for use in treating multiple myeloma in a subject, the kit comprising: a. at least one pharmaceutical formulation described herein; b. instructions for using the kit in treating the multiple myeloma in the subject; and c. optionally, at least one further therapeutically active compound or drug.

[0119] The present disclosure also provides a prefilled syringe comprising a pharmaceutical formulation described herein.

[0120] The present disclosure also provides an autoinjector device comprising a pharmaceutical formulation described herein.

[0121] Particularly preferred embodiments are described herein, including in the independent claims.

[0122] Brief Description of the Figures

[0123] Figure 1 is a computer-generated model of the potential degradation sites of KappaMab.

[0124] Figure 2 is a representative differential scanning calorimetry (DSC) scan in 20 mM phosphate buffer illustrating the two thermal transitions observed for KappaMab.

[0125] Figure 3 is a contour plot based on the main transition (Tml). Higher Tm represents greater thermal stability.

[0126] Figure 4 is an SDS-PAGE of KappaMab showing (A) reduced and (B) non-reduced conditions.

[0127] Figure 5 is a SE-HPLC comparison of different KappaMab formulations after 39 days of incubation. % Area = monomer peak.

[0128] Figure 6 illustrates the potency results for ISTa002 and ISTa003. Linear trendlines added. Figure 7 illustrates the potency results for pooled mean of ISTa002 and ISTa003, extrapolated to 120 months using linear (A) and exponential (B) trendlines. Percentage is relative to reference standard.

[0129] Figure 8 illustrates the calculated potency for ISTa002 / 3 batches with (A) 80%, (B) 90% and (C) 95% confidence intervals.

[0130] Figure 9 illustrates the SE-HPLC results for KappaMab over a 102-month stability program.

[0131] Figure 10 illustrates non-reducing SDS-PAGE results for KappaMab over a 54-month stability program.

[0132] Key to Sequence Listing

[0133] SEQ ID NO: 1 Amino acid sequence of heavy chain variable region (VH) of KappaMab

[0134] SEQ ID NO: 2 Amino acid sequence of light chain variable region (VL) of KappaMab

[0135] SEQ ID NO: 3 Amino acid sequence of heavy chain complementarity determining region (CDR) 1 of KappaMab

[0136] SEQ ID NO: 4 Amino acid sequence of heavy chain CDR2 of KappaMab

[0137] SEQ ID NO: 5 Amino acid sequence of heavy chain CDR3 of KappaMab

[0138] SEQ ID NO: 6 Amino acid sequence of light chain CDR1 of KappaMab

[0139] SEQ ID NO: 7 Amino acid sequence of light chain CDR2 of KappaMab

[0140] SEQ ID NO: 8 Amino acid sequence of light chain CDR3 of KappaMab

[0141] SEQ ID NO: 9 Amino acid sequence of KMA switch region in kappa light chain

[0142] SEQ ID NO: 10 Amino acid sequence of KappaMab epitope

[0143] SEQ ID NO: 11 Amino acid sequence of KappaMab epitope 2 (improved binding)

[0144] SEQ ID NO: 12 Amino acid sequence of VH of K121

[0145] SEQ ID NO: 13 Amino acid sequence of VL of K121

[0146] Detailed Description

[0147] General

[0148] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, feature, composition of matter, group of steps or group of features or compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, features, compositions of matter, groups of steps or groups of features or compositions of matter.

[0149] Those skilled in the art will appreciate that the present disclosure is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. Thus, each feature of any particular example or embodiment of the present disclosure may be applied mutatis mutandis to any other example or embodiment of the present disclosure unless specifically stated otherwise.

[0150] The present disclosure is not to be limited in scope by the specific examples described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions and methods are clearly within the scope of the present disclosure.

[0151] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (for example, in cell culture, molecular genetics, immunology, immunohistochemistry, protein chemistry, and biochemistry).

[0152] Unless otherwise indicated, any recombinant DNA, recombinant protein, cell culture, immunological and statistical techniques utilised in the present disclosure are standard procedures, well known to those skilled in the art. Such techniques are described and explained throughout the literature in sources such as, J. Perbal, A Practical Guide to Molecular Cloning, John Wiley and Sons (1984), J. Sambrook et al. Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989), T.A. Brown (editor), Essential Molecular Biology: A Practical Approach, Volumes 1 and 2, IRL Press (1991), D.M. Glover and B.D. Hames (editors), DNA Cloning: A Practical Approach, Volumes 1-4, IRL Press (1995 and 1996), and F.M. Ausubel et al. (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience (1988, including all updates until present), Ed Harlow and David Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, (1988), and J.E. Coligan et al. (editors) Current Protocols in Immunology, John Wiley & Sons (including all updates until present).

[0153] The description and definitions of variable regions and parts thereof, antibodies and fragments thereof herein may be further clarified by the discussion in Kabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991.

[0154] The term “EU numbering system of Kabat” will be understood to mean the numbering of an antibody heavy chain is according to the EU index as taught in Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institutes of Health, Bethesda. The EU index is based on the residue numbering of the human IgGl EU antibody.

[0155] Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, is understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers but not the exclusion of any other step or element or integer or group of elements or integers.

[0156] The term “and / or”, e.g., “X and / or Y” shall be understood to mean either “X and Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning. As used herein, the singular forms of “a”, “and” and “the” include plural forms of these words, unless the context clearly dictates otherwise.

[0157] Selected Definitions

[0158] One of skill in the art will be aware that an “antibody” is generally considered to be a protein that comprises a variable region made up of a plurality of polypeptide chains, e.g., a polypeptide comprising a VL and a polypeptide comprising a VH. An antibody also generally comprises constant domains, some of which can be arranged into a constant region or constant fragment or fragment crystallizable (Fc). A VH and a VL interact to form a variable fragment (Fv) comprising an antigen binding region that specifically binds to one or a few closely related antigens. Generally, a light chain from mammals is either a K light chain or a X light chain and a heavy chain from mammals is a, 5, a, y, or p. Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass. The term “antibody” also encompasses humanised antibodies, primatised antibodies, human antibodies and chimeric antibodies.

[0159] As used herein, “variable region” refers to the portions of the light and / or heavy chains of an antibody as defined herein that specifically binds to an antigen and, for example, includes amino acid sequences of complementarity determining regions (CDRs); i.e., CDR1, CDR2, and CDR3, and framework regions (FRs). For example, the variable region comprises three or four FRs (e.g., FR1, FR2, FR3 and optionally FR4) together with three CDRs. VH refers to the variable region of the heavy chain. VL refers to the variable region of the light chain.

[0160] The terms “complementarity determining regions” and “CDRs” are used in the context of the present disclosure to refer to the amino acid residues of an antibody variable region the presence of which are major contributors to specific antigen binding. Each variable region typically has three CDR regions identified as CDR1, CDR2 and CDR3. The amino acid positions assigned to CDRs and FRs can be defined according to Kabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991 or other numbering systems in the performance of this disclosure, e.g., the canonical numbering system of Chothia and Lesk J. Mol Biol. 196: 901-917, 1987; Chothia et al. Nature 342, 877- 883, 1989; and / or Al-Lazikani et al., J Mol Biol 273: 927-948, 1997; the IMGT numbering system of Lefranc et al., Devel. And Compar. Immunol., 27: 55-77, 2003; or the AHO numbering system of Honnegher and Pliikthun J. Mol. Biol., 309: 657-670, 2001. For example, according to the numbering system of Kabat, VH framework regions (FRs) and CDRs are positioned as follows: residues 1-30 (FR1), 31-35 (CDR1), 36-49 (FR2), 50-65 (CDR2), 66-94 (FR3), 95-102 (CDR3) and 103- 113 (FR4). According to the numbering system of Kabat, VL FRs and CDRs are positioned as follows: residues 1-23 (FR1), 24-34 (CDR1), 35-49 (FR2), 50-56 (CDR2), 57-88 (FR3), 89-97 (CDR3) and 98-107 (FR4). The present disclosure is not limited to FRs and CDRs as defined by the Kabat numbering system, but includes all numbering systems, including those discussed above. In one example, reference herein to a CDR (or a FR) is in respect of those regions according to the Kabat numbering system.

[0161] The terms “framework regions” and “FR” will be understood to refer to variable domain residues other than the CDR residues.

[0162] The term “fragment crystallisable” or “Fc” or “Fc region” or “Fc portion” (which can be used interchangeably herein) refers to a region of an antibody comprising at least one constant domain and which is generally (though not necessarily) glycosylated and which is capable of binding to one or more Fc receptors and / or components of the complement cascade. The heavy chain constant region can be selected from any of the five isotypes: a, 5, a, y, or p. Furthermore, heavy chains of various subclasses (such as the IgG subclasses of heavy chains) are responsible for different effector functions and thus, by choosing the desired heavy chain constant region, proteins with desired effector function can be produced. Exemplary heavy chain constant regions are gamma 1 (IgGl), gamma 2 (IgG2), gamma 3 (IgG3) and gamma 4 (IgG4), or hybrids thereof.

[0163] The term “constant region” as used herein, refers to a portion of heavy chain or light chain of an antibody other than the variable region. In a heavy chain, the constant region generally comprises a plurality of constant domains and a hinge region, e.g., a IgG constant region comprises the following linked components, a constant heavy CH CHI, a linker, a CH2 and a CH3. In a light chain, a constant region generally comprises one constant domain (a CL1).

[0164] As used herein, the term “binds” is a reference to an interaction of a protein with another molecule that is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on that molecule. For example, an antibody recognises and binds to a specific protein structure rather than to proteins generally. If an antibody binds to epitope "A", the presence of a molecule containing epitope “A” (or free, unlabelled “A”), in a reaction containing labelled “A” and the protein, will reduce the amount of labelled “A” bound to the antibody.

[0165] As used herein, the term “specifically binds” or “binds specifically” shall be taken to mean that the binding interaction between an antibody and kappa myeloma antigen is dependent on the presence of the antigenic determinant or epitope of kappa myeloma antigen bound by the antibody. Accordingly, the antibody preferentially binds or recognizes a kappa myeloma antigen determinant or epitope even when present in a mixture of other molecules or organisms. In one example, the antibody reacts or associates more frequently, more rapidly, with greater duration and / or with greater affinity with kappa myeloma antigen or a cell expressing the same than it does with alternative antigens or cells. It is also understood by reading this definition that, for example, an antibody that specifically binds to kappa myeloma antigen may or may not specifically bind to a second antigen. As such, “specific binding” does not necessarily require exclusive binding or non-detectable binding of another antigen. The term “specifically binds” can be used interchangeably with “selectively binds” herein. Generally, reference herein to binding means specific binding, and each term shall be understood to provide explicit support for the other term. Methods for determining specific binding will be apparent to the skilled person. In an example, an anti-KMA antibody according to the present disclosure is contacted with kappa myeloma antigen or a cell expressing same or a mutant form thereof or an alternative antigen. The binding of the antibody to the kappa myeloma antigen or mutant form or alternative antigen is then determined and an antibody that binds as set out above to the kappa myeloma antigen rather than the mutant or alternative antigen is considered to specifically bind to kappa myeloma antigen.

[0166] Pharmaceutical Formulation

[0167] As described herein, the present disclosure provides a pharmaceutical formulation comprising an anti-KMA antibody and diethylenetriaminepentaacetic acid (DTPA). Preparation of the pharmaceutical formulation is performed according to standard methods known in the art and / or according to methods described herein.

[0168] Anti-KMA antibody

[0169] The term “anti-KMA antibody” is used in the context of the present disclosure to refer to an antibody that binds or specifically binds Kappa Myeloma Antigen (KMA).

[0170] KMA is a membrane-bound light chain with selectivity for kappa myeloma cells (Boux, HA. et al. (1983) J Exp Med. 158: 1769). KMA is a unique cell-surface antigen expressed on malignant plasma cells in kappa restricted multiple myeloma (KMM), some lymphomas, occasional tonsillar B cells and in vitro activated B cells, but not on normal B cells in bone marrow.

[0171] In an example, an anti-KMA antibody is capable of binding KMA bearing cells. In another example, an anti-KMA antibody is capable of killing KMA bearing cells. For example, anti-KMA antibodies according to the present disclosure can bind and kill KMA bearing malignant plasma cells. In an example, anti-KMA antibodies according to the present disclosure do not bind intact immunoglobulin. Put another way, exemplary anti-KMA antibodies do not recognise kappa light chains that are in association with immunoglobulin heavy chain such as in an intact immunoglobulin.

[0172] In an example, anti-KMA antibodies of the disclosure do not bind kappa light chain associated with heavy chain. For example, anti-KMA antibodies do not bind the kappa chain of an antibody which also comprises a heavy chain.

[0173] In an example, the anti-KMA antibody can be the “K121 antibody” disclosed in Hutchinson et al. 2011, a variant, or humanised form thereof.

[0174] An exemplary humanised form is referred to in the context of the present disclosure as “KappaMab” or “KM” used interchangeably, an antibody having a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 2. Thus, in an example, the anti-KMA antibody is KappaMab.

[0175] In an example, the anti-KMA antibody binds to or specifically binds to an epitope of KMA that is specifically bound by KappaMab or that competes with KappaMab for binding to KMA, wherein KappaMab has a VH comprising the amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 2.

[0176] KappaMab binds an epitope of KMA located in the switch region of kappa light chain (SEQ ID NO: 9). Amino acid substitution in the epitope can increase binding affinity of KappaMab (Hutchinson et al. 2011). Accordingly, in an example, an anti-KMA antibody according to the present disclosure competes with an antibody that binds or specifically binds a region comprising an amino acid sequence as shown in SEQ ID NO: 9 with at least one, at least two or at least three amino acid substitutions. In another example, an anti-KMA antibody according to the present disclosure competes with an antibody that binds or specifically binds an epitope comprising an amino acid sequence as shown in SEQ ID NO: 10 with at least one, at least two or at least three amino acid substitutions. Exemplary substitutions include conservative amino acid substitutions such as those described below in Table 1. In an example, aspartic acid (Asp (D)) in SEQ ID NO: 10 is substituted with glutamic acid (Glu (E)) (SEQ ID NO: 11). Accordingly, in an example, an anti-KMA antibody according to the present disclosure competes with an antibody that binds or specifically binds an epitope comprising an amino acid sequence as shown in SEQ ID NO: 11.

[0177] Table 1. Exemplary substitutions.

[0178] In another example, an anti-KMA antibody according to the present disclosure competes with an antibody that binds or specifically binds an epitope consisting of an amino acid sequence as shown in SEQ ID NO: 9. In another example, an anti-KMA antibody according to the present disclosure competes with an antibody that binds or specifically binds an epitope consisting of the amino acid sequence as shown in SEQ ID NO: 10. In another example, an anti-KMA antibody according to the present disclosure competes with an antibody that binds or specifically binds an epitope consisting of the amino acid sequence as shown in SEQ ID NO: 11. Antibodies may be identified by their ability to compete for binding to KMA or a region or epitope thereof using various methods known in the art. For example, antibody binding to KMA on kappa human myeloma cell lines (KHMCL) such as KMS-11, KMS-26 and JJN3 can be assessed (Asvadi et al. 2015). In this procedure, an anti-KMA antibody (e.g., KappaMab) is conjugated with biotin using established procedures (Hofmann K, et al. (1982) Biochemistry 21 : 978-84). Antibodies are then evaluated by their capacity to compete with the binding of the biotinylated KappaMab antibody to KMA on KHMCL cells. The binding of biotinylated KappaMab to KHMCL cells may be assessed by the addition of fluorescein-labelled streptavidin which will bind to biotin on the labelled antibody. Fluorescence staining of cells is then quantified by flow cytometry, and the competitive effect of antibodies expressed as a percentage of the fluorescence levels obtained in the absence of the competitor.

[0179] In another example, the anti-KMA antibody has a VH comprising the CDRs as shown in SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and a VL. In another example, the anti- KMA antibody has a VH and a VL comprising CDRs as shown in SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8. In another example, the anti-KMA antibody has a VH comprising CDRs as shown in SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and a VL comprising CDRs as shown in SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8. In one example, the anti-KMA antibody is KappaMab.

[0180] In another example, the anti-KMA antibody has a VH comprising CDRs as shown in SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, an amino acid sequence at least 90 %, at least 95%, at least 98%, at least 99% identical to SEQ ID NO: 1 and a VL comprising CDRs as shown in SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and an amino acid sequence at least 90 %, at least 95%, at least 98%, at least 99% identical to SEQ ID NO: 2.

[0181] In another example, the anti-KMA antibody has a VH comprising the amino acid sequence shown in SEQ ID NO: 1 and a VL comprising the amino acid sequence shown in SEQ ID NO: 2.

[0182] In another example, the anti-KMA antibody has the CDRs shown in SEQ ID NO: 1 and SEQ ID NO: 2, wherein the CDRs are assigned using the Kabat numbering system. In another example, the anti-KMA antibody has the CDRs shown in SEQ ID NO: 1 and SEQ ID NO: 2, wherein the CDRs are assigned using the IMGT numbering system. In another example, the anti-KMA antibody has the CDRs shown in SEQ ID NO: 1 and SEQ ID NO: 2, wherein the CDRs are assigned using EU numbering system of Kabat.

[0183] In an example, the anti-KMA antibody is a naked antibody. In other examples, the anti- KMA antibody is a full-length antibody, intact antibody or whole antibody. In an example, the anti-KMA antibody is monospecific.

[0184] In another example, the anti-KMA antibody is an antibody comprising CDRs as shown in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8. In another example, the anti-KMA antibody has a VH comprising the amino acid sequence shown in SEQ ID NO: 12 or a humanised variant thereof and a VL comprising the amino acid sequence shown in SEQ ID NO: 13 or a humanised variant thereof.

[0185] In another example, the anti-KMA antibody has the CDRs shown in SEQ ID NO: 12 and SEQ ID NO: 13 or humanised variants thereof, wherein the CDRs are assigned using the Kabat numbering system. In another example, the anti-KMA antibody has the CDRs shown in SEQ ID NO: 12 and SEQ ID NO: 13 or humanised variants thereof, wherein the CDRs are assigned using the IMGT numbering system. In another example, the anti-KMA antibody has the CDRs shown in SEQ ID NO: 12 and SEQ ID NO: 13 or humanised variants thereof, wherein the CDRs are assigned using EU numbering system of Kabat.

[0186] In an example, an anti-KMA antibody as described herein is present in the pharmaceutical formulation at a concentration of 5 mg / mL to 60 mg / mL. In an example, an anti-KMA antibody as described herein is present in the pharmaceutical formulation at a concentration of from 5 mg / mL to 30 mg / mL. In an example, an anti-KMA antibody as described herein is present in the pharmaceutical formulation at a concentration of from 5 mg / mL to 15 mg / mL. In an example, an anti-KMA antibody as described herein is present in the pharmaceutical formulation at a concentration of from 9 mg / mL to 11 mg / mL. In an example, an anti-KMA antibody as described herein is present in the pharmaceutical formulation at a concentration of 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL or 60 mg / mL. In an example, an anti-KMA antibody as described herein is present in the pharmaceutical formulation at a concentration of 5 mg / mL. In an example, an anti-KMA antibody as described herein is present in the pharmaceutical formulation at a concentration of 10 mg / mL. In an example, an anti- KMA antibody as described herein is present in the pharmaceutical formulation at a concentration of 20 mg / mL. In an example, an anti-KMA antibody as described herein is present in the pharmaceutical formulation at a concentration of 30 mg / mL. In an example, an anti-KMA antibody as described herein is present in the pharmaceutical formulation at a concentration of 40 mg / mL. In an example, an anti-KMA antibody as described herein is present in the pharmaceutical formulation at a concentration of 50 mg / mL. In an example, an anti-KMA antibody as described herein is present in the pharmaceutical formulation at a concentration of 60 mg / mL.

[0187] In an example, formulations of the disclosure comprise low levels of anti-KMA antibody bound to free light chain not associated with heavy chain. Such formulations may be preferred because of increased therapeutic potency resulting in more effective treatment or, potentially, lower dosing and therefore increased safety and / or more cost effective manufacture.

[0188] In an example, less than 20% of anti-KMA antibodies in the formulation are in complex with free light chain not associated with heavy chain. In another example, less than 15% of anti-KMA antibodies in the formulation are in complex with free light chain not associated with heavy chain. In another example, less than 10% of anti-KMA antibodies in the formulation are in complex with free light chain not associated with heavy chain. In another example, less than 6% of anti-KMA antibodies in the formulation are in complex with free light chain not associated with heavy chain. For example, a pharmaceutical formulation as described herein comprises less than 15%, or less than 10% or less than 6% of anti-KMA antibodies in complex with free light chain not associated with heavy chain and DTPA.

[0189] Diethylenetriaminepentaacetic acid (DTPA)

[0190] Advantageously, DTPA provides a pharmaceutical formulation of the present disclosure with improved stability and / or biological activity compared to other pharmaceutical formulations such as those comprising ethylenediaminetetraacetic acid (EDTA). This is despite the understanding that DTPA in an antibody formulation may be problematic. For example, it is known that DTPA can contribute to oxidative damage in proteins and form unstable complexes, which can further lead to degradation of the antibody in the formulation.

[0191] The terms “diethylenetriaminepentaacetic acid” and “DTPA” shall be understood to refer a synthetic polyamino carboxylic acid with eight coordinate bond forming sites that can sequester metal ions and form highly stable DTPA-metal ion complexes.

[0192] In an example, DTPA is present in the pharmaceutical formulation at a concentration of 0.01 mg / mL to 0.05 mg / mL. In an example, DTPA is present in the pharmaceutical formulation at a concentration of 0.03 mg / mL to 0.05 mg / mL. In an example, DTPA is present in the pharmaceutical formulation at a concentration of 0.01 mg / mL to 0.03 mg / mL. In an example, DTPA is present in the pharmaceutical formulation at a concentration of 0.01 mg / mL, 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL or 0.05 mg / mL. In an example, DTPA is present in the pharmaceutical formulation at a concentration of 0.02 mg / mL.

[0193] In an example, DTPA is present in the pharmaceutical formulation in a molarity of 10 pM to 70 pM. In an example, DTPA is present in the pharmaceutical formulation in a molarity of 30 pM to 60 pM. In an example, DTPA is present in the pharmaceutical formulation in a molarity of 45 pM to 55 pM. In an example, DTPA is present in the pharmaceutical formulation in a molarity of 10 pM, 15 pM, 20 pM, 25 pM, 30 pM, 35 pM, 40 pM, 45 pM, 50 pM, 55 pM, 60 pM, 65 pM or 70 pM. In an example, DTPA is present in the pharmaceutical formulation in a molarity of 50 pM.

[0194] In an example, the ratio of anti-KMA antibody to DTPA in any of the pharmaceutical formulation described herein is between 450: 1 and 550: 1. For example, the ratio of anti-KMA antibody to DTPA in any of the pharmaceutical formulation described herein is at least 450: 1, at least 455: 1, at least 460: 1, at least 465: 1, at least 470: 1, at least 475: 1, at least 480: 1, at least 485: 1, at least 490:1, at least 495:1, at least 500: 1, at least 505: 1, 510: 1, at least 515: 1, at least 520: 1, at least 525: 1, at least 530: 1, at least 535: 1, at least 540: 1, at least 545: 1, or at least 550: 1. Non-Ionic Surfactants

[0195] A pharmaceutical formulation of the present disclosure may further comprise a non-ionic surfactant.

[0196] Suitable non-ionic surfactants for use in the present disclosure will be apparent to the skilled person and include, for example, polyoxyethylensorbitan fatty acid esters (e.g., polysorbate 20 and polysorbate 80), polyethylene-polypropylene copolymers, polyethylenepolypropylene glycols, polyoxyethylene-stearates, polyoxyethylene alkyl ethers, e.g., polyoxyethylene monolauryl ether, alkylphenylpolyoxyethylene ethers (Triton-X), polyoxyethylene-polyoxypropylene copolymer (Poloxamer, Pluronic), sodium dodecyl sulphate (SDS).

[0197] In an example, a pharmaceutical formulation of the present disclosure further comprises a non-ionic surfactant selected from the group consisting of polysorbate 80, polysorbate 20 and poloxamer 188.

[0198] In an example, the non-ionic surfactant is polysorbate 80.

[0199] The amount of non-ionic surfactant added to the pharmaceutical formulation will be apparent to the skilled person and is in an amount such that it suppresses aggregation (e.g., by preventing surface denaturation), increases stabilisation (e.g., during thermal and / or physical stress), minimises the formation of particulates in the pharmaceutical formulation (e.g., sub- visible and / or visible particle formation), reduces surface adsorption and / or assists in protein refolding.

[0200] For example, the non-ionic surfactant is present in the pharmaceutical formulation at a concentration of 0.2 mg / mL to 0.6 mg / mL. In an example, the non-ionic surfactant is present in the pharmaceutical formulation at a concentration of 0.4 mg / mL to 0.6 mg / mL. In an example, the non-ionic surfactant is present in the pharmaceutical formulation at a concentration of 0.5 mg / mL to 0.6 mg / mL. In an example, the polysorbate 80 is present in the pharmaceutical formulation at a concentration of 0.2 mg / mL to 0.6 mg / mL. In an example, the polysorbate 80 is present in the pharmaceutical formulation at a concentration of 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL or 0.6 mg / mL. For example, the polysorbate 80 is present in the pharmaceutical formulation at a concentration of 0.4 mg / mL.

[0201] Buffer

[0202] A pharmaceutical formulation of the present disclosure may further comprise a buffer.

[0203] It will be apparent to the skilled person that buffers suitable for use in the present disclosure will be stable and effective at the desired pH and will provide sufficient buffer capacity to maintain the desired pH over the range of conditions to which it will be exposed during formulation and storage of the product. For example, a stable buffer will provide thermal aggregation stability (e.g., during freeze / thaw or elevated temperatures), not be affected by oxidation of physical degradation (e.g., insoluble particulate formation) and provide the desired poly dispersity (i.e., particle distribution). Suitable buffers will not form deleterious complexes with metal ions, be toxic, or unduly penetrate, solubilise, or absorb on membranes or other surfaces. Furthermore, the skilled person will recognise that such buffers should not interact with other components of the composition in any manner which decreases their availability or effectiveness. Additionally, the buffering agent of the pharmaceutical formulation must be safe for administration, compatible with other components of the composition over the shelf-life of the product, and acceptable for administration to the subject.

[0204] Suitable buffers for use in the present disclosure will be apparent to the skilled person and include, for example, histidine buffers (e.g., histidine chloride, histidine acetate, histidine phosphate, histidine sulfate, etc.), glutamate buffers (e.g., monosodium glutamate, etc.), citrate buffers (e.g., monosodium citrate-disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid-monosodium citrate mixture, etc.), succinate buffers (e.g., succinic acid- monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid- disodium succinate mixture, etc.), tartrate buffers (e.g., tartaric acid-sodium tartrate mixture, tartaric acid-potassium tartrate mixture, tartaric acid-sodium hydroxide mixture, etc.), fumarate buffers (e.g., fumaric acid-monosodium fumarate mixture, fumaric acid-disodium fumarate mixture, monosodium fumarate-di sodium fumarate mixture, etc.) gluconate buffers (e.g., gluconic acid-sodium gluconate mixture, gluconic acid-sodium hydroxide mixture, gluconic acid-potassium gluconate mixture, etc.), oxalate buffers (e.g., oxalic acid-sodium oxalate mixture, oxalic acid-sodium hydroxide mixture, oxalic acid-potassium oxalate mixture, etc.), lactate buffers (e.g., lactic acid-sodium lactate mixture, lactic acid-sodium hydroxide mixture, lactic acid-potassium lactate mixture, etc.) and acetate buffers (e.g., acetic acid-sodium acetate mixture, acetic acid-sodium hydroxide mixture, etc.).

[0205] In an example, the buffer is a citrate buffer. For example, the citrate buffer is a sodium citrate dihydrate. In another example, the citrate buffer is a citric acid monohydrate. In one example, the citrate buffer is a sodium citrate dihydrate and citric acid monohydrate.

[0206] In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation at a concentration of 4 mg / mL to 8 mg / mL. In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation at a concentration of 5 mg / mL to 6 mg / mL. In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation at a concentration of 4 mg / mL to 6 mg / mL. In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation at a concentration of 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL or 8 mg / mL. In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation at a concentration of 5.29 mg / mL.

[0207] In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation in a molarity of 10 mM to 30 mM. In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation in a molarity of 16 mM to 20 mM. In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation in a molarity of 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM or 30 mM. In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation in a molarity of 17 mM. In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation in a molarity of 18 mM. In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation in a molarity of 19 mM. In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation in a molarity of 20 mM.

[0208] In an example, the sodium citrate monohydrate is present in the pharmaceutical formulation at a concentration of 0.2 mg / mL to 0.6 mg / mL. In an example, the sodium citrate monohydrate is present in the pharmaceutical formulation at a concentration of 0.4 mg / mL to 0.5 mg / mL. In an example, the sodium citrate monohydrate is present in the pharmaceutical formulation at a concentration of 0.4 mg / mL to 0.6 mg / mL. In an example, the sodium citrate monohydrate is present in the pharmaceutical formulation at a concentration of 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL or 0.8 mg / mL. In an example, the sodium citrate monohydrate is present in the pharmaceutical formulation at a concentration of 0.423 mg / mL.

[0209] In an example, the sodium citrate monohydrate is present in the pharmaceutical formulation in a molarity of 1 mM to 3 mM. In an example, the sodium citrate monohydrate is present in the pharmaceutical formulation in a molarity of 1 mM to 2 mM. In an example, the sodium citrate monohydrate is present in the pharmaceutical formulation in a molarity of 1 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM or 3 mM. In an example, the sodium citrate monohydrate is present in the pharmaceutical formulation in a molarity of 1.9 mM. In an example, the sodium citrate monohydrate is present in the pharmaceutical formulation in a molarity of 2 mM.

[0210] In an example, the buffer comprises sodium citrate dihydrate at a concentration of 4 mg / mL to 8 mg / mL and sodium citrate monohydrate at a concentration of 0.2 mg / mL to 0.6 mg / mL. In an example, the buffer comprises sodium citrate dihydrate at a concentration of 5 mg / mL to 6 mg / mL and sodium citrate monohydrate at a concentration of 0.4 mg / mL to 0.5 mg / mL. In an example, the buffer comprises sodium citrate dihydrate at a concentration of 5.29 mg / mL and sodium citrate monohydrate at a concentration of 0.423 mg / mL.

[0211] In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation in a molarity of 10 mM to 30 mM and the sodium citrate monohydrate is present in the pharmaceutical formulation in a molarity of 1 mM to 3 mM. In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation in a molarity of 16 mM to 20 mM and the sodium citrate monohydrate is present in the pharmaceutical formulation in a molarity of 1 mM to 2 mM. In an example, the sodium citrate dihydrate is present in the pharmaceutical formulation in a molarity of 18 mM and the sodium citrate monohydrate is present in the pharmaceutical formulation in a molarity of 1.9 mM.

[0212] Salt

[0213] A pharmaceutical formulation of the present disclosure may further comprise a salt.

[0214] Suitable salts for use in a pharmaceutical formulation of the present disclosure will be apparent to the skilled person and include, for example, sodium chloride, potassium chloride, magnesium chloride and calcium chloride.

[0215] In an example, the salt is sodium chloride.

[0216] In an example, the salt is present in the pharmaceutical formulation at a concentration of

[0217] 2 mg / mL to 10 mg / mL. In an example, the salt is present in the pharmaceutical formulation at a concentration of 4 mg / mL to 8 mg / mL. In an example, the salt is present in the pharmaceutical formulation at a concentration of 4 mg / mL to 6 mg / mL. In an example, the salt is present in the pharmaceutical formulation at a concentration of 4 mg / mL to 5 mg / mL. In an example, the salt is present in the pharmaceutical formulation at a concentration of 2 mg / mL to 3 mg / mL. In an example, the salt is present in the pharmaceutical formulation at a concentration of 8 mg / mL to 9 mg / mL. In an example, the salt is present in the pharmaceutical formulation at a concentration of 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL or 8 mg / mL, 9 mg / mL, 10 mg / mL. In an example, the salt is present in the pharmaceutical formulation at a concentration of 5.84 mg / mL.

[0218] In an example, the sodium chloride is present in the pharmaceutical formulation at a concentration of 2 mg / mL to 10 mg / mL. In an example, the sodium chloride is present in the pharmaceutical formulation at a concentration of 4 mg / mL to 8 mg / mL. In an example, the sodium chloride is present in the pharmaceutical formulation at a concentration of 4 mg / mL to 6 mg / mL. In an example, the sodium chloride is present in the pharmaceutical formulation at a concentration of 5 mg / mL to 6 mg / mL. In an example, the sodium chloride is present in the pharmaceutical formulation at a concentration of 4 mg / mL to 5 mg / mL. In an example, the sodium chloride is present in the pharmaceutical formulation at a concentration of 2 mg / mL to

[0219] 3 mg / mL. In an example, the sodium chloride is present in the pharmaceutical formulation at a concentration of 8 mg / mL to 9 mg / mL. In an example, the sodium chloride is present in the pharmaceutical formulation at a concentration of 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL or 8 mg / mL, 9 mg / mL, 10 mg / mL. In an example, the sodium chloride is present in the pharmaceutical formulation at a concentration of 5.84 mg / mL.

[0220] In an example, the sodium chloride is present in the pharmaceutical formulation in a molarity of 50 mM to 150 mM. In an example, the sodium chloride is present in the pharmaceutical formulation in a molarity of 70 mM to 130 mM. In an example, the sodium chloride is present in the pharmaceutical formulation in a molarity of 90 mM to 110 mM. In an example, the sodium chloride is present in the pharmaceutical formulation in a molarity of 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM or 130 mM. In an example, the sodium chloride is present in the pharmaceutical formulation in a molarity of 100 mM.

[0221] Polyol

[0222] A pharmaceutical formulation of the present disclosure may further comprise a polyol.

[0223] As used herein, the term “polyol” refers to a substance having a plurality of hydroxyl groups.

[0224] Suitable polyols for use in a pharmaceutical formulation of the present disclosure will be apparent to the skilled person and include, for example, mannitol, trehalose, sorbitol, erythritol, isomalt, lactitol, maltitol, xylitol, glycerol, lactitol, propylene glycol, polyethylene glycol and inositol.

[0225] In an example, the polyol is mannitol.

[0226] In an example, the polyol is present in the pharmaceutical formulation at a concentration of 10 mg / mL to 20 mg / mL. In an example, the polyol is present in the pharmaceutical formulation at a concentration of 12 mg / mL to 18 mg / mL. In an example, the polyol is present in the pharmaceutical formulation at a concentration of 14 mg / mL to 16 mg / mL. In an example, the polyol is present in the pharmaceutical formulation at a concentration of 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL or 20 mg / mL.

[0227] In an example, the mannitol is present in the pharmaceutical formulation at a concentration of 10 mg / mL to 20 mg / mL. In an example, the mannitol is present in the pharmaceutical formulation at a concentration of 12 mg / mL to 18 mg / mL. In an example, the mannitol is present in the pharmaceutical formulation at a concentration of 14 mg / mL to 16 mg / mL. In an example, the mannitol is present in the pharmaceutical formulation at a concentration of 15 mg / mL. In an example, the mannitol is present in the pharmaceutical formulation at a concentration of 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL or 20 mg / mL. pH and volume

[0228] In an example, a pharmaceutical formulation of the present disclosure has a pH of between 5 to 8. In an example, a pharmaceutical formulation of the present disclosure has a pH of between 5.5 to 7.5. In an example, a pharmaceutical formulation of the present disclosure has a pH of between 5.6 to 6.4. In an example, a pharmaceutical formulation of the present disclosure has a pH of 5, 5.5, 6, 6.5, 7, 7.5 or 8. In an example, a pharmaceutical formulation of the present disclosure has a pH of 6.

[0229] In some examples, the pharmaceutical formulation is an aqueous pharmaceutical formulation. In one example, the pharmaceutical formulation is suitable for intravenous administration. In an example, the pharmaceutical formulation has a volume in the range of 5 mL to 30 mL. In an example, the pharmaceutical formulation has a volume in the range of 10 mL to 20 mL. In an example, the pharmaceutical formulation has a volume in the range of 18 mL to 22 mL. In an example, the pharmaceutical formulation has a volume in the range of 8 mL to 12 mL. In an example, the pharmaceutical formulation has a volume of 10 mL. In an example, the pharmaceutical formulation has a volume of 20 mL. In an example, the pharmaceutical formulation has a volume of 30 mL. The skilled person can easily adjust to smaller or larger volumes as required.

[0230] For example, the pharmaceutical formulation is provided in a single-dose vial.

[0231] In one example, the pharmaceutical formulation has not previously been lyophilised. In one example, the pharmaceutical formulation is not a reconstituted formulation.

[0232] In one example, the pharmaceutical formulation does not comprise EDTA.

[0233] Stability

[0234] A “stable” formulation is one in which the protein (e.g., an anti-KMA antibody) therein essentially retains its physical stability and / or chemical stability and / or biological activity upon storage. Various analytical techniques for measuring protein stability are described herein and are available in the art and are reviewed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y, Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993). Stability can be measured at a selected temperature for a selected time period.

[0235] In an example, the pharmaceutical formulation is stable at a temperature of 2 °C to 8 °C for at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, at least 60 months, at least 67 months, at least 72 months, at least 84 months, at least 90 months, at least 96 months, at least 102 months, at least 108 months or at least 120 months.

[0236] In an example, the pharmaceutical formulation is stable at a temperature of -15 °C to -25 °C for at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, at least 60 months, at least 67 months, at least 72 months, at least 84 months, at least 90 months, at least 96 months, at least 102 months, at least 108 months or at least 120 months.

[0237] In an example, the anti-KMA antibody is stable at a temperature of 2 °C to 8 °C for at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, at least 60 months, at least 67 months, at least 72 months, at least 84 months, at least 90 months, at least 96 months, at least 102 months, at least 108 months or at least 120 months.

[0238] In an example, the anti-KMA antibody is stable at a temperature of -15 °C to -25 °C for at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, at least 60 months, at least 67 months, at least 72 months, at least 84 months, at least 90 months, at least 96 months, at least 102 months, at least 108 months or at least 120 months.

[0239] In an example, the pharmaceutical formulation retains its physical stability, chemical stability and biological activity at a temperature of 2 °C to 8 °C for at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, at least 60 months, at least 67 months, at least 72 months, at least 84 months, at least 90 months, at least 96 months, at least 102 months, at least 108 months or at least 120 months.

[0240] In an example, the pharmaceutical formulation retains its physical stability, chemical stability and biological activity at a temperature of -15 °C to -25 °C for at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, at least 60 months, at least 67 months, at least 72 months, at least 84 months, at least 90 months, at least 96 months, at least 102 months, at least 108 months or at least 120 months.

[0241] In an example, the anti-KMA antibody retains its physical stability, chemical stability and biological activity at a temperature of 2 °C to 8 °C for at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, at least 60 months, at least 67 months, at least 72 months, at least 84 months, at least 90 months, at least 96 months, at least 102 months, at least 108 months or at least 120 months.

[0242] In an example, the anti-KMA antibody retains its physical stability, chemical stability and biological activity at a temperature of -15 °C to -25 °C for at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, at least 60 months, at least 67 months, at least 72 months, at least 84 months, at least 90 months, at least 96 months, at least 102 months, at least 108 months or at least 120 months.

[0243] In one example, the stability of a pharmaceutical formulation of the present disclosure is assessed. For example, the stability is assessed using a bacterial endotoxin test (i.e., Limulus Amebocyte Lysate (LAL)).

[0244] In one example, the pharmaceutical formulation comprises no more than 0.5 endotoxin units (EU) / mg. In some examples, the pharmaceutical formulation comprises no more than 0.1 EU / mg. In some examples, the pharmaceutical formulation comprises no more than 0.01 EU / mg. In some examples, the pharmaceutical formulation comprises no more than 0.001 EU / mg. Physical Stability

[0245] An antibody “retains its physical stability” in a pharmaceutical formulation if it shows no significant increase of aggregation, precipitation and / or denaturation upon visual examination of colour and / or clarity, as measured by size exclusion high performance liquid chromatography (SE-HPLC), and / or as measured by a USP Particulate test.

[0246] In one example, the physical stability of a pharmaceutical formulation of the present disclosure is assessed upon visual examination to determine, for example, the colour and clarity or for the presence of visible particles.

[0247] In one example, the pharmaceutical formulation comprises no more than 6000 particles / vial as determined using a USP Particulate test. In one example, the pharmaceutical formulation comprises no more than 600 particles / vial as determined using a USP Particulate test. In one example, the pharmaceutical formulation comprises no more than 60 particles / vial as determined using a USP Particulate test.

[0248] In one example, the physical stability of a pharmaceutical formulation of the present disclosure is assessed using differential scanning calorimetry (DSC).

[0249] In an example, the physical stability of the pharmaceutical formulation is assessed using SE-HPLC (e.g., HPLC-GPC). SE-HPLC separates lower and higher molecular mass variants of the protein, as well as any impurities. According to this method, the results are described as the summation of aggregation peaks and summation of degradation peaks. For example, the physical stability of a pharmaceutical formulation of the present disclosure can be determined by comparing the chromatographic retention time of the major peaks with the retention time of the major peak of a reference standard.

[0250] For example, the physical stability of the pharmaceutical formulation may be assessed by measuring total high molecular weight species (HMWS) and / or monomer content. Methods for assessing accumulation of HMWS and / or monomer content of the pharmaceutical formulation will be apparent to the skilled person and / or described herein. In one example, the percent HMWS of the anti-KMA antibody in the pharmaceutical formulation is determined by SE-HPLC.

[0251] In the context of the present disclosure, the term “monomer” or “monomeric” refers to the correctly folded protein (e.g., an antibody). For example, a monomer of an anti-KMA antibody according to the present disclosure relates to the standard tetrameric antibody comprising two identical, glycosylated heavy and light chains respectively. An “aggregate” is a non-specific association of two or more protein molecules (e.g., HMWS). The terms HMWS and aggregate are used interchangeably herein.

[0252] In one example, the pharmaceutical formulation comprises no more than 10% HMWS. In some examples, the pharmaceutical formulation comprises no more than 5% HMWS. For example, the pharmaceutical formulation comprises no more than 10%, or no more than 9%, or no more than 8%, or no more than 7%, or no more than 6%, or no more than 5%, or no more than 4%, or no more than 3%, or no more than 2%, or no more than 1% HMWS.

[0253] In some examples, the pharmaceutical formulation comprises no more than 5% HMWS as determined by SE-HPLC.

[0254] In some examples, the pharmaceutical formulation comprises no more than 5% HMWS after storage for a period of at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, at least 60 months, at least 102 months or at least 120 months at a temperature in the range of 2 °C to 8 °C. In one example, the formulation comprises no more than 5% HMWS after storage for a period of at least 12 months at a temperature of 2 °C to 8 °C. In one example, the pharmaceutical formulation comprises no more than 3% HMWS after storage for a period of at least 12 months at a temperature of 2 °C to 8 °C. In one example, the pharmaceutical formulation comprises no more than 5% HMWS after storage for a period of at least 18 months at a temperature of 2 °C to 8 °C. In another example, the pharmaceutical formulation comprises no more than 3% HMWS after storage for a period of at least 18 months at a temperature of 2 °C to 8 °C. In another example, the pharmaceutical formulation comprises no more than 3% HMWS after storage for a period of at least 24 months at a temperature of 2 °C to 8 °C.

[0255] In some examples, at least 95% of the anti-KMA antibody in the pharmaceutical formulation is a monomer. In some examples, at least 95% of anti-KMA antibody in the pharmaceutical formulation is a monomer, as determined by SE-HPLC.

[0256] In some examples, at least 96% of the anti-KMA antibody in the pharmaceutical formulation is a monomer. In some examples, at least 96%, or at least 97%, or at least 98%, or at least 99% of the anti-KMA antibody in the pharmaceutical formulation is a monomer.

[0257] In some examples, at least 95% of the anti-KMA antibody in the pharmaceutical formulation is a monomer after storage for a period of at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, at least 60 months, at least 102 months or at least 120 months at a temperature in the range of 2 °C to 8 °C. In one example, at least 95% of the anti-KMA antibody in the pharmaceutical formulation is a monomer after storage for a period of at least 12 months at a temperature of 2 °C to 8 °C. In one example, at least 97% of the anti-KMA antibody in the pharmaceutical formulation is a monomer after storage for a period of at least 12 months at a temperature of 2 °C to 8 °C. In one example, at least 95% of the anti-KMA antibody in the pharmaceutical formulation is a monomer after storage for a period of at least 18 months at a temperature of 2 °C to 8 °C. In one example, at least 97% of the anti-KMA antibody in the pharmaceutical formulation is a monomer after storage for a period of at least 18 months at a temperature of 2 °C to 8 °C. In one example, at least 97% of the anti-KMA antibody in the pharmaceutical formulation is a monomer after storage for a period of at least 24 months at a temperature of 2 °C to 8 °C.

[0258] Chemical Stability

[0259] An antibody “retains its chemical stability” in a pharmaceutical formulation, if it shows no significant chemical alteration. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein. Degradation processes that often alter the protein chemical structure include hydrolysis or clipping (evaluated by methods such as size exclusion chromatography and SDS-PAGE).

[0260] In one example, the chemical stability of a pharmaceutical formulation of the present disclosure is evaluated by assessing degradation.

[0261] In one example, aggregation is assessed using sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE). For example, both reduced SDS-PAGE and non-reduced SDS-PAGE may be performed.

[0262] A “low molecular weight species” (LMWS) is typically a degraded or fragmented protein.

[0263] In some examples, the pharmaceutical formulation of the present disclosure comprises at least 90% monomer protein and / or less than (i.e., no more than) 10% HMWS and / or LMWS. In one example, the pharmaceutical formulation comprises at least 95% monomer protein and / or less than (i.e., no more than) 5% HMWS and / or LMWS.

[0264] In some examples, the pharmaceutical formulation comprises no more than 5% LMWS. In some examples, the pharmaceutical formulation comprises no more than 5% LMWS, as determined by SDS-PAGE under non-reducing conditions.

[0265] In some examples, the pharmaceutical formulation comprises no more than 5%, or no more than 4%, or no more than 3%, or no more than 2%, or no more than 1% LMWS.

[0266] In some examples, the pharmaceutical formulation comprises no more than 5% LMWS after storage for a period of at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, at least 60 months or at least 120 months at a temperature in the range of 2 °C to 8 °C. In one example, the pharmaceutical formulation comprises no more than 5% LMWS after storage for a period of at least 12 months at a temperature of 2 °C to 8 °C. In one example, the pharmaceutical formulation comprises no more than 1% LMWS after storage for a period of at least 12 months at a temperature of 2 °C to 8 °C. In one example, the pharmaceutical formulation comprises no more than 5% LMWS after storage for a period of at least 18 months at a temperature of 2 °C to 8 °C. In one example, the pharmaceutical formulation comprises no more than 1% LMWS after storage for a period of at least 18 months at a temperature of 2 °C to 8 °C. In one example, the pharmaceutical formulation comprises no more than 1% LMWS after storage for a period of at least 24 months at a temperature of 2 °C to 8 °C.

[0267] Biological Activity

[0268] An antibody “retains its biological activity” in a pharmaceutical formulation, if the biological activity of the antibody at a given time is within a predetermined range of the biological activity exhibited at the time the pharmaceutical formulation was prepared. The biological activity of an antibody can be determined, for example, by an antigen binding assay. Pharmaceutical formulations of the present disclosure include antibodies and fragments thereof that are biologically active when reconstituted or in liquid form. By retaining biological activity of the pharmaceutical formulation, typically the potency of the antibody is also retained.

[0269] Methods for assessing binding to a target are known in the art, e.g., as described in Scopes (In: Protein purification: principles and practice, Third Edition, Springer Verlag, 1994). Such a method generally involves labelling the target (i.e., KMA) and contacting it with immobilized protein (i.e., the anti-KMA antibody). Following washing to remove non-specific bound target, the amount of label and, as a consequence, bound target is detected. Of course, the target can be immobilised and the protein can be labelled. Panning-type assays can also be used. Alternatively, or additionally, surface plasmon resonance assays can be used.

[0270] In one example, the biological activity of a pharmaceutical formulation of the present disclosure is assessed. For example, the biological activity is assessed using an enzyme-linked immunosorbent assay (ELISA).

[0271] In an example, the biological activity of the pharmaceutical formulation is within 50- 150%, 60-140%, or 80-120% of the control or reference. In an example, the biological activity of the pharmaceutical formulation is within 50-150% of the control or reference. In an example, the biological activity of the pharmaceutical formulation is within 60-140% of the control or reference. In an example, the biological activity of the pharmaceutical formulation is within 80-120% of the control or reference.

[0272] Uses of the Pharmaceutical Formulation

[0273] As discussed herein, the present disclosure provides a method of treating multiple myeloma in a subject, comprising administering a pharmaceutical formulation of the present disclosure to the subject. In one example, the present disclosure provides a method of treating multiple myeloma in a subject in need thereof.

[0274] The present disclosure also provides a method of treating a KMA-expressing malignancy in a subject, comprising administering a pharmaceutical formulation of the present disclosure to the subject.

[0275] The present disclosure also provides for use of a pharmaceutical formulation of the present disclosure for treating multiple myeloma in a subject comprising administering the pharmaceutical formulation of the present disclosure to the subject. In one example, the present disclosure provides for use of a pharmaceutical formulation of the present disclosure for treating multiple myeloma in a subject in need thereof.

[0276] The present disclosure also provides for use of a pharmaceutical formulation of the present disclosure for treating KMA-expressing malignancy in a subject comprising administering the pharmaceutical formulation of the present disclosure to the subject.

[0277] The present disclosure provides methods of treating plasma cell dyscrasias by administering a binding protein, antibody or composition described herein. In one example, the plasma cell dyscrasias is refractory and / or relapsed. In one example, the plasma cell dyscrasias is refractory. In one example, the plasma cell dyscrasias is relapsed.

[0278] As used herein, the terms “treating”, “treat” or “treatment” include administering a therapeutically effective amount of a pharmaceutical formulation described herein to reduce or delay the onset or progression of multiple myeloma, or to reduce or eliminate at least one symptom of multiple myeloma.

[0279] The term “plasma cell dyscrasias” or “PCDs” as used herein refer to a spectrum of disorders characterised by the abnormal proliferation of plasma cells, which produce a monoclonal protein (M protein). These disorders range from benign conditions like monoclonal gammopathy of undetermined significance (MGUS) to malignant diseases such as multiple myeloma and Waldenstrom macroglobulinemia. The term “kappa plasma cell dyscrasias” as used herein refers to PCDs where the monoclonal protein produced is primarily composed of kappa light chains (i.e., KMA), as opposed to lambda light chains.

[0280] The term “KMA-expressing malignancy” as used herein refers to any proliferative disease that expresses KMA. Exemplary related pathologies include multiple myeloma, plasmacytoma, extramedullary plasmacytoma, amyloidosis, B cell lymphoproliferative disorders (BLPD), smoldering myeloma, and monoclonal gammopathy of undetermined significance (MGUS). In one example, the KMA-expressing malignancy is multiple myeloma. In one example, the KMA-expressing malignancy is plasmacytoma. In one example, the KMA- expressing malignancy is amyloidosis. In one example, the KMA-expressing malignancy is B cell lymphoproliferative disorders (BLPD). For example, a mature B cell lymphoproliferative disorder. In one example, the KMA-expressing malignancy is smoldering myeloma. In one example, the KMA-expressing malignancy is extramedullary plasmacytoma. In one example, the KMA-expressing malignancy is a monoclonal gammopathy of undetermined significance.

[0281] The terms “amyloidosis”, “amyloid light-chain (AL) amyloidosis” and “primary amyloidosis” are used interchangeably herein and refer to a clonal plasma cell disorder associated with secretion of immunoglobulin free light chains. Fragments of the light chain variable domain play a critical role in forming amyloid fibrils that deposit in peripheral organs leading to organ dysfunction. The terms “monoclonal gammopathy of unknown significance” or “MGUS” as used herein refers to a condition where an abnormal protein, known as monoclonal protein or M protein, is found in the blood. This condition is typically asymptomatic and is often discovered incidentally during blood tests for other reasons. While MGUS itself is benign, it can progress to more serious conditions, including multiple myeloma, at a rate of about 1% per year.

[0282] The terms “smoldering myeloma”, “SMM” and “smoldering multiple myeloma” as used herein refer to an asymptomatic, intermediate stage between MGUS and active multiple myeloma. It is typically characterised by higher levels of M protein and a greater percentage of plasma cells in the bone marrow compared to MGUS, but without the symptoms or organ damage seen in active myeloma. SMM has a high risk of progressing to active myeloma.

[0283] As used herein, the term “plasmacytoma” refers to a type of plasma cell tumor that can occur either within the bone marrow or outside of it. When it occurs outside the bone marrow, it is referred to as an extramedullary plasmacytoma (EMP).

[0284] The terms “extramedullary plasmacytoma” or “EMP” as used herein refer to a type of plasma cell tumor that occurs outside the bone marrow, typically in the soft tissues. These tumours are commonly found in the upper respiratory tract but can occur in other soft tissues throughout the body. EMPs are rare and can sometimes progress to multiple myeloma.

[0285] The terms “multiple myeloma” or “myeloma” or “MM” are used in the context of the present disclosure to refer to cancer of plasma cells. In the context of the present disclosure, these terms encompass secretory myeloma, non-secretory myeloma, light chain only myeloma, smouldering myeloma and related pathologies. Exemplary related pathologies include plasmacytoma, amyloidosis, monoclonal gammopathy of undetermined significance.

[0286] As used herein, the term “adjuvant” can be used to refer to a drug or other substance such as, for example, a pharmaceutical formulation of the present disclosure, that is used to increase the efficacy or potency of other drugs and / or improve patient outcomes. For example, a pharmaceutical formulation of the present disclosure can act as an adjuvant that enhances or increases the potency of other drugs such as, for example, a combination dosing regimen comprising treatment with an anti-BCMA therapy. In one example, a pharmaceutical formulation of the present disclosure may act as an adjuvant that enhances or improves patient outcomes.

[0287] As used herein, the phrase “adjuvant therapy” can be used to refer to, in the broadest sense, treatment, such as, for example, treatment with a pharmaceutical formulation of the present disclosure, given after or in addition to the primary therapy to kill or aid in killing any malignant tumor cells that may have spread, even if the spread cannot be detected by radiologic or laboratory tests and / or to prevent recurrence of a cancer such as, for example, multiple myeloma. The primary treatment can be any line of therapy known in the art for use in treating a cancer such as, for example, multiple myeloma. The primary treatment can be an anti-BCMA therapy. For example, the primary treatment can be selected from the group consisting of belantamab mafodotin (BLENREP), idecabtagene vicleucel (Abecma) ciltacabtagene autoleucel (Carytki), teclistamab or elranatamab. The primary treatment may be belantamab mafodotin (BLENREP). The primary treatment may be idecabtagene vicleucel (Abecma). The primary treatment may be ciltacabtagene autoleucel (Carytki). The primary treatment may be teclistamab. The primary treatment may be elranatamab. In one embodiment, the composition dosing regimen comprises an anti-BCMA therapy. The terms “adjuvant therapy” or “adjunct therapy” or “adjuvant care” can be used interchangeably herein.

[0288] In one example, the present disclosure relates to a method of adjuvant therapy comprising administering to a subject having multiple myeloma, an effective amount of a pharmaceutical formulation of the present disclosure. In one example, the present disclosure relates to a method of adjuvant therapy comprising administering to a subject having refractory and / or relapsed multiple myeloma, an effective amount of a pharmaceutical formulation of the present disclosure.

[0289] In another example, the present disclosure relates to an adjuvant method of treating multiple myeloma in a subject, the method comprising administering an effective amount of a pharmaceutical formulation of the present disclosure in combination with an existing therapeutic protocol.

[0290] In another example, the present disclosure relates to a method of adjuvant therapy comprising administering to a subject having multiple myeloma, an effective amount of a pharmaceutical formulation of the present disclosure.

[0291] In another example, the present disclosure relates to an adjuvant method of treating multiple myeloma in a subject, the method comprising administering an effective amount of a pharmaceutical formulation of the present disclosure in combination with an existing therapeutic protocol

[0292] In some examples, a pharmaceutical formulation of the present disclosure may be used as an adjuvant therapy in combination with an IMiD or CELMoD and a steroid to increase therapeutic potency, improve patient outcomes and provide a favourable safety profile.

[0293] In an example, a pharmaceutical formulation of the present disclosure may be used as an adjuvant therapy in combination with an IMiD or CELMoD and a steroid to increase therapeutic potency of the primary treatment. In an example, a pharmaceutical formulation of the present disclosure may be used as an adjuvant therapy in combination with an IMiD or CELMoD and a steroid to improve patient outcomes. For example, a pharmaceutical formulation of the present disclosure may be used as an adjuvant therapy in combination with an IMiD or CELMoD and a steroid to improve overall response rate (ORR), overall survival (OS) and / or progression free survival (PFS). In one example, a pharmaceutical formulation of the present disclosure may be used as an adjuvant therapy in combination with an IMiD or CELMoD and a steroid to reduce minimal residual disease. In one example, a pharmaceutical formulation of the present disclosure may be used as an adjuvant therapy in combination with an IMiD or CELMoD and a steroid to reduce adverse events. In one example, a pharmaceutical formulation of the present disclosure may be used as an adjuvant therapy in combination with an IMiD or CELMoD and a steroid to improve duration of response. In one example, a pharmaceutical formulation of the present disclosure may be used as an adjuvant therapy in combination with an IMiD or CELMoD and a steroid to time to next treatment.

[0294] In one example, a pharmaceutical formulation of the present disclosure is administered after another compound or agent as maintenance treatment for multiple myeloma. For example, a pharmaceutical formulation of the present disclosure is administered as a maintenance treatment for multiple myeloma after treatment with lenalidomide and autologous stem cell transplant.

[0295] In one example, the present disclosure encompasses methods of treating B-cell malignancy, wherein the malignant B-cells express KMA by administering a pharmaceutical composition described herein. In another example, the present disclosure encompasses methods of treating multiple myeloma and related pathologies by administering a pharmaceutical composition described herein. For example, the present disclosure encompasses methods of treating plasmacytoma by administering a pharmaceutical composition described herein. For example, the present disclosure encompasses methods of treating B cell lymphoproliferative disorders (BLPD) by administering a pharmaceutical composition described herein. For example, the present disclosure encompasses methods of treating smoldering myeloma by administering a pharmaceutical composition described herein. For example, the present disclosure encompasses methods of treating monoclonal gammopathy of undetermined significance (MGUS) by administering a pharmaceutical composition described herein.

[0296] In one example, a pharmaceutical composition described herein is administered in combination with an additional therapy useful for treating or preventing or delaying progression or reducing or inhibiting or hindering development of a disease or condition described herein, either as combined or additional treatment steps or as additional components of a therapeutic formulation.

[0297] In one example, the additional therapy may be a standard of care therapy for the complication associated with a KMA-expressing malignancy. In one example, the additional therapy may be a standard of care therapy for the KMA-expressing malignancy.

[0298] Standard of care therapies for treatment of a complication associated with KMA- expressing malignancies will be apparent to the skilled person and / or are described herein.

[0299] In one example, the additional therapy is plasmapheresis. As will be known by those skilled in the art, plasmapheresis is a process in which the plasma is removed from blood cells by a device known as a cell separator. The separator works either by spinning the blood at high speed to separate the cells from the fluid or by passing the blood through a membrane with pores so small that only the plasma can pass through. The cells are returned to the subject, while the plasma, which contains the free kappa light chains, is discarded and replaced with other fluids. Medication to keep the blood from clotting (e.g., an anticoagulant) may be given through a vein during the procedure.

[0300] In one example, the additional therapy is autologous stem cell transplant.

[0301] In one example, a pharmaceutical composition described herein is administered in combination with an anti-BCMA therapy useful for treating or preventing or delaying progression or reducing or inhibiting or hindering development of a disease or condition described herein, either as combined or additional treatment steps or as additional components of a therapeutic formulation. In one example, a pharmaceutical composition described herein is administered in combination with an anti-BCMA therapy for treating a KMA-expressing malignancy. In one example, a pharmaceutical composition described herein is administered in combination with idecabtagene vicleucel (Abecma) for treating a KMA-expressing malignancy. In one example, a pharmaceutical composition described herein is administered in combination with idecabtagene vicleucel (Abecma) for treating relapsed or refractory multiple myeloma. In one example a pharmaceutical composition described herein is administered in combination with ciltacabtagene autoleucel (Carytki) for treating a KMA-expressing malignancy. In one example, a pharmaceutical composition described herein is administered in combination with ciltacabtagene autoleucel (Carytki) for treating relapsed or refractory multiple myeloma.

[0302] In another example, the methods of the present disclosure further comprise administering one or more additional anti-cancer agents. Exemplary anti-cancer agents include chemotherapy, proteasome inhibitors such as bortezomib, immunomodulatory drugs (i.e., IMiD or CELMoD) such as thalidomide, lenalidomide and pomalidomide, histone deacetylase inhibitors such as panobinostat or vorinostat, antibodies such as 10B3 (as described in WO2019 / 161443), elotuzumab, anti-CD38 monoclonal antibodies such as daratumumab and isatuximab and anti-PDl antibodies such as pembrolizumab, nivolumab and atezolizumab, anti-BCMA therapies such as known in the art or described herein, or a steroid such as dexamethasone. In an example, the additional anti-cancer agent is a proteasome inhibitor. In an example, the additional anti-cancer agent is dexamethasone. In another example, the additional anti-cancer agent is lenalidomide. In one example, the additional anti-cancer agent is daratumumab.

[0303] In an example, at least two additional anti-cancer agents are administered. In one example, the at least two additional anti-cancer agents are an IMiD or CELMoD and a steroid. In one example, at least two additional anti-cancer agents are an IMiD or CELMoD and a proteasome inhibitor. In one example, at least two additional anti-cancer agents are a steroid and a proteasome inhibitor. For example, dexamethasone and lenalidomide can be administered. In one example, lenalidomide and bortezomib are administered. In one example, dexamethasone and bortezomib are administered. In other examples, at least three, at least four, at least five, at least six additional anticancer agents are administered. In one example, the at least three additional anti-cancer agents are an IMiD or CELMoD, a proteasome inhibitor and a steroid. For example, the at least three additional anti-cancer agents are lenalidomide, bortezomib and dexamethasone.

[0304] In one example, a pharmaceutical composition described herein is administered simultaneously with another compound or agent. For example, a pharmaceutical composition described herein is administered simultaneously with daratumumab.

[0305] In one example, a pharmaceutical composition described herein is administered before another compound or agent.

[0306] In one example, a pharmaceutical composition described herein is administered after another compound or agent. For example, a pharmaceutical composition described herein is administered after daratumumab.

[0307] For example, the present disclosure encompasses administrating a pharmaceutical composition described herein to a subject in combination with daratumumab.

[0308] In addition, the anti-cancer agent may increase KMA-expression on malignant plasma cells in a subject.

[0309] In one example, a pharmaceutical composition described herein is administered after another compound or agent as maintenance treatment for a KMA-expressing malignancy. For example, a pharmaceutical composition described herein is administered as a maintenance treatment for a KMA-expressing malignancy after treatment with lenalidomide and autologous stem cell transplant.

[0310] In one example, a pharmaceutical composition described herein is administered in combination with 10B3 for treating or preventing or delaying progression or reducing or inhibiting or hindering development of a rheumatoid arthritis or systemic lupus erythematosus.

[0311] In an example, the multiple myeloma is kappa type myeloma. For example, the multiple myeloma expresses KMA. In another example, the multiple myeloma expresses kappa light chain. In an example, the multiple myeloma expresses IgG Kappa. In a further example, the multiple myeloma expresses IgA Kappa.

[0312] Subjects with multiple myeloma can be characterised into various subject populations. Exemplary populations are described in (Rajkumar et al. 2011).

[0313] In an example, a subject’s multiple myeloma can be characterised as progressive disease (Rajkumar et al. 2011). Put another way, the methods of the present disclosure relate to the treatment of progressive multiple myeloma in a subject. Exemplary indicators of “progressive disease” include an increase of 25% from the lowest response value in any one of the following: Serum M-component (absolute increase > or equal to 0.5 g / dL) and / or Urine M-component (absolute increase must be > or equal to 200 mg / 24 h). Other exemplary indicators include definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium > 11.5 mg / dL) that can be attributed solely to the multiple myeloma. In an example, the subject’s multiple myeloma has relapsed and is characterised as progressive disease. In this example, the subject’s multiple myeloma can also be refractory to therapy.

[0314] In an example, the subject’s multiple myeloma has relapsed. “Relapsed myeloma” is used to refer to previously treated myeloma that progresses and requires the initiation of salvage therapy but does not meet criteria for either “primary refractory myeloma”.

[0315] In another example, the subject has primary refractory myeloma. “Primary refractory myeloma” is used to refer to disease that is nonresponsive in subjects who have never achieved a minimal response or better with any therapy.

[0316] In another example, the subject has refractory myeloma. The term “refractory myeloma” is used to refer to disease that is nonresponsive while on primary or salvage therapy, or progresses within 60 days of last therapy. In an example, a subject’s multiple myeloma is refractory to an anti-cancer therapy. The term “refractory” is used in this context to refer to a line of anti-cancer therapy that is no longer therapeutically effective against a subject’s multiple myeloma.

[0317] In another example, the subject is refractory to anti-B cell maturation antigen (BCMA) therapy.

[0318] The term “refractory” as used herein refers to a line of anti-cancer therapy that is no longer therapeutically effective against an KMA-expressing malignancy. In an example, a refractory patient retains malignant plasma cells which express KMA after administration of one or more prior lines of therapy.

[0319] In an example, the amyloidosis is relapsed multiple myeloma. “Relapsed multiple myeloma” is used to refer to previously treated multiple myeloma that progresses and requires the initiation of salvage therapy but does not meet criteria for either “primary refractory multiple myeloma”.

[0320] In another example, the subject has primary refractory multiple myeloma. “Primary refractory multiple myeloma” is used to refer to disease that is nonresponsive in patients who have never achieved a minimal response or better with any therapy.

[0321] In an example, the amyloidosis is relapsed amyloidosis. “Relapsed amyloidosis” is used to refer to previously treated amyloidosis that progresses and requires the initiation of salvage therapy but does not meet criteria for either “primary refractory amyloidosis”.

[0322] In another example, the subject has primary refractory amyloidosis. “Primary refractory amyloidosis” is used to refer to disease that is nonresponsive in patients who have never achieved a minimal response or better with any therapy.

[0323] In another example, the subject has refractory amyloidosis. The term “refractory amyloidosis” is used to refer to disease that is nonresponsive while on primary or salvage therapy or progresses within 60 days of last therapy. In an example, the amyloidosis is refractory to an anti-cancer therapy. For example, the amyloidosis is refractory to daratumumab. In one example, the amyloidosis is refractory to cyclophosphamide. In one example, the amyloidosis is refractory to bortezomib. In one example, the amyloidosis is refractory to dexamethasone.

[0324] In an example, a subject treated by the methods of the present disclosure can be refractory to at least one proteasome inhibitor. For example, a subject can be refractory to bortezomib. A “line of therapy” is defined as one or more cycles of a planned treatment program. This may consist of one or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous stem cell transplantation, followed by maintenance is considered one line of therapy.

[0325] In another example, subj ects are refractory to at least two prior lines of therapy. In another example, a subject may be refractory to at least three, at least four, at least five, at least six prior lines of therapy. In an example, at least one line of therapy may be lenalidomide. In an example, at least one line of therapy may be pomalidomide.

[0326] In another example, the subject has relapsed and refractory myeloma. “Relapsed and refractory myeloma” is used to refer to disease that is nonresponsive while on salvage therapy, or progresses within 60 days of last therapy in subjects who have achieved minimal response (MR) or better at some point previously before then progressing in their disease course.

[0327] In an example, the multiple myeloma treated according to the present disclosure is characterised as stable disease at the time of first administration. Put another way, subjects can be in plateau phase at the time of first administration. Exemplary criteria for stable disease can include stabilization of the M-protein without further tumour regression despite continued treatment, few or no symptoms from myeloma and / or no blood transfusion requirement (Blade et al. 1998).

[0328] Subjects treated according to the methods of the present disclosure have multiple myeloma or a related pathology encompassed by the present disclosure.

[0329] In an example, a subject treated according to the present disclosure has received at least one line of prior therapy for their multiple myeloma. For example, a subject’s multiple myeloma can have relapsed. In another example, a subject has received at least two, at least three, at least four, at least five, at least six prior lines of therapy. In these examples, a subject can have achieved at least a minimal response ( 25% reduction in M protein) to their most recent line of therapy.

[0330] In another example, a subject has serum kappa free light chain levels less than 350 mg / mL. In another example, a subject has serum kappa free light chain levels less than 300 mg / mL. In another example, a subject has serum kappa free light chain levels less than 275 mg / mL. In another example, a subject has serum kappa free light chain levels less than 250 mg / mL. In another example, the methods of the present disclosure also relate to treating multiple myeloma in subjects with high serum cytokine levels. For example, the methods of the present disclosure relate to treating multiple myeloma in a subject, the method comprising selecting a subject who has high serum levels of one or more of the following factors relative to control serum levels: hepatocyte growth factor (HGF), macrophage inhibitory factor (MIF), CCL27, G-CSF, CXCL9, and CXCL10; and administering to the subject an anti-KMA antibody. In one aspect of the examples herein, serum analyte levels described herein are determined by immunoassay.

[0331] In an example, a high serum level of HGF is above 0.5 ng / mL. In an example, a high serum level of HGF is above 0.6 ng / mL, 0.7 ng / mL, 0.8 ng / mL, 0.9 ng / mL, 1.0 ng / mL, 1.1 ng / mL, 1.2 ng / mL, 1.3 ng / mL, 1.4 ng / mL, 1.5 ng / mL. In another example, a high serum level of HGF is at least 1.6 ng / mL.

[0332] In another example, a high serum level of MIF is above 5000 pg / mL. In another example, a high serum level of MIF is above 5200 pg / mL, 5400 pg / mL, 5600 pg / mL, 5800 pg / mL, 6000 pg / mL, 6200 pg / mL, 6400 pg / mL, 6600 pg / mL, 6800 pg / mL, 7200 pg / mL.

[0333] In another example, a high serum level of CCL27 is above 500 pg / mL. In another example, a high serum level of CCL27 is above 600 pg / mL, 700 pg / mL, 800 pg / mL, 900 pg / mL, 1000 pg / mL, 1100 mL pg / mL, 1200 pg / mL, 1300 pg / mL, 1400 pg / mL, 1500 pg / mL.

[0334] In another example, a high serum level of G-CSF is above 55 pg / mL. In another example, a high serum level of G-CSF is above 65 pg / mL, 75 pg / mL, 85 pg / mL, 95 pg / mL, 105 pg / mL, 115 pg / mL, 125 pg / mL, 135 pg / mL, 145 pg / mL, 155 pg / mL.

[0335] In another example, a high serum level of CXCL9 is above 550 pg / mL. In another example, a high serum level of CXCL9 is above 600 pg / mL, 650 pg / mL, 700 pg / mL, 750 pg / mL, 800 pg / mL, 850 pg / mL, 900 pg / mL, 950 pg / mL, 1000 pg / mL, 1050 pg / mL.

[0336] In another example, a high serum level of CXCL10 is above 850 pg / mL. In another example, a high serum level of CXCL10 is above 900 pg / mL, 950 pg / mL, 1000 pg / mL, 1050 pg / mL, 1100 pg / mL, 1150 pg / mL, 1200 pg / mL, 1250 pg / mL, 1300 pg / mL, 1350 pg / mL.

[0337] High serum cytokine levels may be determined in a sample obtained from the subject.

[0338] In another example, the KMA-expressing malignancy is refractory to at least two prior lines of therapy. In another example, the KMA-expressing malignancy may be refractory to at least three, at least four, at least five, at least six prior lines of therapy. In one example, the subject is refractory to anti-BCMA therapy. In another example, the KMA-expressing malignancy is relapsed and refractory myeloma.

[0339] In another example, the KMA-expressing malignancy is relapsed and refractory amyloidosis. “Relapsed and refractory amyloidosis” is used to refer to disease that is nonresponsive while on salvage therapy or progresses within 60 days of last therapy in patients who have achieved minimal response (MR) or better at some point previously before then progressing in their disease course. In an example, the amyloidosis treated according to the present disclosure is characterised as stable disease at the time of first administration.

[0340] In another example, the methods of the present disclosure can be used to treat B cell lymphoma and / or macroglobulinemia.

[0341] In another example, the methods of the present disclosure can be used to treat POEMS. As used herein “POEMS syndrome” is a rare blood disorder that damages the nerves and affects many other parts of the body. “POEMS” stands for these signs and symptoms: Polyneuropathy: numbness, tingling and weakness in the legs and over time in the hands and difficulty breathing; Organomegaly: enlarged spleen, liver or lymph nodes; Endocrinopathy: abnormal hormone levels that can result in underactive thyroid (hyperthyroidism), diabetes, sexual problems, fatigue, swelling in the limbs and problems with metabolism and other essential functions; Monoclonal plasma-proliferative disorder: abnormal bone marrow cells (plasma cells) that produce a protein that can be found in the bloodstream; Skin changes: more color than normal on the skin, possibly thicker skin and increased facial and / or leg hair.

[0342] In another example, a pharmaceutical composition described herein can be administered to a subject to treat an autoimmune disorder. In an example, the autoimmune disorder is characterised by aberrant proliferation of plasma cell precursors expressing KMA as membrane free light chain (mFLC). For example, a pharmaceutical composition described herein can be administered to a subject to treat an autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus, diabetes mellitus, multiple sclerosis, Crohn's disease, immune thrombocytopenic purpura, pemphigis vulgaris, autoimmune urticaria, celiac disease, dermatitis herpetiformis, acute rhematic fever, Grave's disease, myasthenic gravis, Sjogren's syndrome, Goodpasture's syndrome, poststreptococcal glomerulonephritis, contact dermatitis, autoimmune thyroiditis, Hashimoto's thyroiditis, Addison's disease, autoimmune haemolytic anaemia, pernicious anaemia, vasculitis caused by anti-neutrophil cytoplasmic antibodies (ANCA), polyarteritis nodosa, autoimmune hepatitis, and primary biliary cirrhosis. For example, the methods of the present disclosure can be used to treat rheumatoid arthritis, systemic lupus erythematosus, diabetes mellitus, and multiple sclerosis. Accordingly, in an example, the methods of the present disclosure can be used to treat rheumatoid arthritis. In another example, the present disclosure can be used to treat systemic lupus erythematosus. In another example, a pharmaceutical composition described herein can be used to treat diabetes mellitus. In another example, a pharmaceutical composition described herein can be used to treat multiple sclerosis.

[0343] In another example, a pharmaceutical composition described herein can be used to reduce kappa free light chain levels in a subject (i.e., reduce the amount of kappa light chain in a subject that is not expressed on the cell membrane, e.g., kappa light chain in serum). Such methods comprise administering a pharmaceutical composition described herein with a high affinity for free kappa light chain. A pharmaceutical composition described herein may be administered in combination as part of performing the methods of the present disclosure may be administered simultaneously or sequentially.

[0344] A pharmaceutical composition described herein may be administered in any amount to provide the optimum therapeutic response.

[0345] Kits and Other Compositions of Matter

[0346] Another example of the disclosure provides kits containing a pharmaceutical formulation of the present disclosure useful for treating multiple myeloma in a subject.

[0347] In one example, the kit comprises (a) a container comprising a pharmaceutical formulation of the present disclosure; and (b) a package insert with instructions for treating multiple myeloma in the subject.

[0348] In one example, the kit comprises (a) at least one pharmaceutical formulation of the present disclosure; (b) instructions for using the kit in multiple myeloma in the subject; and (c) optionally, at least one further therapeutically active compound or drug.

[0349] In accordance with this example of the disclosure, the package insert is on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds or contains a composition that is effective for treating a neutrophil-mediated condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The label or package insert indicates that the composition is used for treating a subj ect eligible for treatment, e.g., one having or predisposed to developing multiple myeloma, with specific guidance regarding dosing amounts and intervals of the pharmaceutical formulation and any other medicament being provided. The kit may further include other materials desirable from a commercial and user standpoint, including filters, needles, and syringes. In some examples of the present disclosure, the pharmaceutical formulation can be present in an injectable device (e.g., an injectable syringe, e.g., a prefilled injectable syringe). The syringe may be adapted for individual administration, e.g., as a single vial system including an autoinjector (e.g., a peninjector device). In one example, the injectable device is a prefilled pen or other suitable auto injectable device, optionally with instruction for use and administration.

[0350] The kit optionally further comprises a container comprising a second medicament, wherein the pharmaceutical formulation is a first medicament, and which article further comprises instructions on the package insert for treating the subject with the second medicament, in an effective amount. The second medicament may be an IMiD, a CELMoD, a steroid, an anti-cancer agent and / or a proteasome inhibitor. In one example, the disclosure provides a prefilled syringe or autoinjector comprising a pharmaceutical formulation of the present disclosure. In one example, the prefilled syringe is a glass luer syringe with plunger.

[0351] In one example, the disclosure provides a vial comprising a pharmaceutical formulation of the disclosure.

[0352] It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[0353] All publications discussed and / or referenced herein are incorporated herein in their entirety.

[0354] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each of the appended claims.

[0355] In order that preferred embodiments of the present disclosure may be fully understood and put into practical effect, reference is made to the following non-limiting examples.

[0356] Examples

[0357] Example 1. KappaMab Pre-formulation Studies

[0358] Computer Modelling Studies

[0359] A predictive model of KappaMab was created by which potential sites of degradation and modification could be identified. These sites were scored based on probable reaction. The sequence and molecular model KappaMab were analysed using the predictive model to understand the most likely sites of degradation and modification. Table 2 shows the predictive analysis results of KappaMab.

[0360] Table 2. The results of an analysis of KappaMab using the predictive model.

[0361] Note: Results that have been bolded indicate sites found in the variable region. Results that have been underlined and italicised are the sites with scores great than 6.

[0362] Using the results from the computer modelling two potential deamidation / isomerisation motifs (H55: N - G and H65: Q - G), one metal-catalysed oxidation sites (H34: Met) and two photo-catalysed oxidation sites (H101 and H104: Tyr) were identified. These sites are all found on the variable regions of the heavy chain. Three potential sites of hydrolytic cleavage on the constant region were also predicted (L197, H223, and H225). Figure 1 illustrates the potential degradation sites of KappaMab.

[0363] Differential Scanning Calorimetry (DSC)

[0364] A four-corner plus the centre point screening of pH range and salt concentrations in 20 mM sodium phosphate buffer by DSC was conducted to evaluate the range for optimal thermal stability. KappaMab has two thermal transitions (Figure 2). The first transition is the main transition. Figure 3 suggests that KappaMab’s thermal stability increases as pH decreases from 7.5 to 5.5 and increases as sodium chloride concentration decreased from 150 mM to 50 mM. Example 2. KappaMab Formulation Studies

[0365] Experimental Setup

[0366] Purified KappaMab material was buffer exchanged and concentrated using a tangential flow filtration (TFF) system, followed by filtering through a 0.22 pm filter. Excipients were spiked into each formulation using stock solutions. Samples were assigned in two groups, group 1 : three incubation temperatures at 25 °C, 37 °C and 45 °C, group 2: 4 °C incubation (Table 3). Samples were placed in 2 mL glass vials to conduct particle count analysis. Samples were subject to analysis by visual examination, SDS-PAGE, SE-HPLC, Particle Count and ELISA.

[0367] Table 3. Setup Sample Table.

[0368] Visual Examination

[0369] Vials were visually inspected by holding them in front of in-house white light with a black background. Each vial was inverted once to suspend any potential particulates. The physical appearance of the formulation is a colourless, clear to slightly opalescent solution that is essentially free of particles based on experience with the formulation.

[0370] Visual examinations showed the KappaMab at 10 mg / mL concentration maintained a good appearance (Tables 4 and 5).

[0371] Table 4. Group 1 visual observations (25 °C, 37 °C and 45 °C).

[0372] Note: D = days of incubation C = Clear, P = visible particles (number denotes scale 1-5, with IP- for least particles and 5P for most particles)

[0373] Table 5. Group 2 visual observations (4 °C). Note: D = days of incubation C = Clear, P = visible particles (number denotes scale 1-5, with IP- for least particles and 5P for most particles)

[0374] Sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE)

[0375] SDS-PAGE were carried out under reduced and non-reduced conditions in pre-cast 4%- 15% acrylamide gradient gels (Bio-Rad or equivalent). Samples were prepared in TRIS-

[0376] Glycine-SDS buffer, pH 6.8, with or without reducing agent and loaded into their respective individual wells. The running buffer is TRIS-Glycine-SDS, pH 8.3. Samples were electrophoresed through the gel at 150 volts for 1 to 2 hours depending on the size of the test proteins. Molecular weight standards were electrophoresed on the same gel. The gels are stained with Silver, destained and bands visualized (Figure 4). Table 6 illustrates samples corresponding to the lane numbers.

[0377] Table 6. Reduced and Non-reduced SDS-PAGE of KappaMab.

[0378] Size exclusion-high performance liquid chromatography (SE-HPLC)

[0379] A TSK-G3000 SWXL column with a TSK SWXL guard column was used on a Water 2690 system. The flow rate was 0.86 mL / min in a IxPBS buffer system. 50 pg of sample was injected. Figure 5 demonstrates varying levels of aggregation and degradation. Condition 4 (i.e., formulation comprising DTPA) was identified to be the best condition for maintaining KappaMab stability.

[0380] Table 7, KappaMab Formulation Characterisation Enzyme-linked immunosorbent assay (ELISA)

[0381] The plate was coated with purified human kappa light chain, blocked, and then KappaMab is bound to the target. The sample's potency was detected by developing horseradish peroxidase (HRP) substrate in the wells of the plate which directly correlates to how much KappaMab is bound to its target receptor. The sample data was analysed in comparison to the standard curve of KappaMab T=0 reference material.

[0382] As shown in Table 8, KappaMab samples incubated at 37 °C maintained higher binding activity than samples incubated at 45 °C. Condition 4 (i.e., formulation comprising DTPA) was identified to be the best condition for maintaining high binding activity. Notably, the formulation containing DTPA (Condition 4) was associated with improved potency relative to the formulation containing EDTA (Condition 3) at both 37 °C and 45 °C.

[0383] Table 8. ELISA results

[0384] Example 3. KappaMab Long Term Stability Data

[0385] ISTa002 and ISTa003 are drug product batches of KappaMab dispensed by the same manufacturer (Nova Laboratories, UK) using the same lot of drug substance (Batch 374664, Lonza Biologies, UK), at similar times (11 and 20 February 2014). Both batches were stored at 2 °C to 8 °C under controlled conditions since dispensing. Both drug product batches are therefore considered to be similar. All stability testing was conducted at the same contractor (Eurofins, MO, USA).

[0386] All stability testing conducted to date at all time points for both ISTa002 and ISTa003 meet specifications. There were no downtrends for any assay (see Figures 9 and 10), except for ELISA. The specifications for the ELISA test are 50-150% relative potency, a common range for early-phase biological investigational products.

[0387] Methods and Results

[0388] The full data set for batches ISTa002 and ISTa003 are plotted in Figure 6, fitted with linear trendlines for each batch. Extrapolating the trends to 120 months, both batches suggest a 60% potency value. This supports the premise that both batches can be considered similar. In order to increase the dataset reliability, potency results conducted at common test points for both batches were averaged to produce a pooled data set of ISTa002 and ISTa003 results. These are plotted with both linear and exponential trendlines in Figure 7. The results show that the regression trendline fit for the exponential curve is similar (R2= 0.44) to the linear (R2= 0.43), with both analyses indicating that the potency results are tending to plateau. The 120-month prediction is similar for each trendline (62% v. 61%), yielding potency values that fall within the specification for KappaMab drug product.

[0389] Using the pooled data as representative of both batches, linear trendlines were fitted to the data set from 0 to 108 months, and the formula used to calculate predicted data from 0 to 120 months. Confidence intervals of 80%, 90% and 95% (Figure 8) were assigned. These confidence intervals were chosen to allow for normal ELISA variation (Bioanalytical Method Validation Guidance for Industry, May 2018, USFDA).

[0390] The analysis demonstrated that assuming a linear regression fit with an 80% confidence interval, the potency result will be between 54% and 66% at 120 months, or 56% and 67% at 114 months. With a 90% confidence interval, the result would be between 53% and 68% at 120 months, or 55% and 69% at 114 months. With a 95% confidence interval the result would be between 51% and 70% at 120 months, or 53% and 71% at 114 months.

[0391] An exponential curve fit with a superior regression fit is likely to result in slightly higher predicted potency values. Based on this analysis, with an 80% confidence interval, the ELISA will be within specification at 120 months storage at 2-8 °C. With a 95% confidence interval, the ELISA will be in specification at 114 months. All other assay results were within specifications at the time of testing. Assay results indicated no notable changes in KappaMab aggregates, degradation products or contaminants. Exemplary data for SE-HPLC and SDS- PAGE analysis under non-reducing conditions is shown in Figures 9 and 10 respectively. While quantitative assessment of KappaMab stability by non-reducing SDS-PAGE analysis was not performed beyond 54-month timepoint, visual comparison to reference standard data indicated conformance within specification at the 67 month, 90 month and 102 month timepoints.

[0392] Example 4. Exemplary formulation

[0393] An exemplary antibody formulation, based on the results described above, is shown in Table 9.

[0394] Table 9. Exemplary antibody formulation

[0395] Component Amount

[0396] Antibody 9 - 11 mg / mL

[0397] Sodium Citrate, Dihydrate, Crystal, USP 5.29 mg / mL

[0398] Citric Acid Monohydrate, USP 0.423 mg / mL

[0399] Sodium Chloride, USP 5.84 mg / mL Mannitol, USP 15 mg / mL

[0400] Diethylenetriaminepentaacetic acid (DTPA), USP 0.02 mg / mL

[0401] Polysorbate 80 (Tween® 80), N.F. multi-compendial 0.4 mg / mL pH 5.6 - 6.4

Claims

Claims1. A pharmaceutical formulation comprising: an anti -KM A antibody; and diethylenetriaminepentaacetic acid (DTPA).

2. The pharmaceutical formulation of claim 1, wherein the anti-KMA antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising a complementarity determining region (CDR) 1 comprising an amino acid sequence as shown in SEQ ID NO: 3, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 4 and a CDR3 comprising a sequence as shown in SEQ ID NO: 5 and the VL comprising a CDR1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8.

3. The pharmaceutical formulation of claim 1 or claim 2, wherein the anti-KMA antibody comprises an antibody variable region comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2.

4. The pharmaceutical formulation of any one of claims 1 to 3, wherein the anti-KMA antibody is present in the formulation at a concentration of 5 mg / mL to 60 mg / mL.

5. The pharmaceutical formulation of any one of claims 1 to 4, wherein the DTPA is present in the formulation at a concentration of 0.01 mg / mL to 0.05 mg / mL.

6. The pharmaceutical formulation of any one of claims 1 to 5, wherein the ratio of the anti-KMA antibody to DTPA is between 450: 1 and 550: 1.

7. The pharmaceutical formulation of any one of claims 1 to 6, wherein the formulation is an aqueous formulation.

8. The pharmaceutical formulation of any one of claims 1 to 7, wherein the formulation has a pH of 5.5 to 7.5.

9. The pharmaceutical formulation of any one of claims 1 to 8, wherein the formulation further comprises a non-ionic surfactant.

10. The pharmaceutical formulation of claim 9, wherein the non-ionic surfactant is selected from the group consisting of polysorbate 80, polysorbate 20 and poloxamer 188.

11. The pharmaceutical formulation of claim 9 or claim 10, wherein the non-ionic surfactant is present in the formulation at a concentration of 0.2 mg / mL to 0.6 mg / mL.

12. The pharmaceutical formulation of claim 11, wherein the non-ionic surfactant is polysorbate 80.

13. The pharmaceutical formulation of any one of claims 1 to 12, wherein the formulation further comprises a buffer.

14. The pharmaceutical formulation of claim 13, wherein the buffer is selected from the group consisting of acetate, succinate, gluconate, citrate, histidine, acetic acid, phosphate, phosphoric acid, ascorbate, tartaric acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate acid, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate, acetate, malate, imidazole, tris and phosphate.

15. The pharmaceutical formulation of claim 13 or claim 14, wherein the buffer is a citrate buffer, preferably sodium citrate dihydrate and / or citric acid monohydrate.

16. The pharmaceutical formulation of claim 15, wherein the sodium citrate dihydrate is present in the formulation at a concentration of 4 mg / mL to 8 mg / mL.

17. The pharmaceutical formulation of claims 15 or claim 16, wherein the citric acid monohydrate is present in the formulation at a concentration of 0.2 mg / mL to 0.6 mg / mL.

18. The pharmaceutical formulation of any one of claims 1 to 17, wherein the formulation further comprises a salt.

19. The pharmaceutical formulation of claim 18, wherein the salt is selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride and calcium chloride.

20. The pharmaceutical formulation of claim 18 or claim 19, wherein the salt is present in the formulation at a concentration of 2 mg / mL to 10 mg / mL.

21. The pharmaceutical formulation of any one of claims 18 to 20, wherein the salt is sodium chloride.

22. The pharmaceutical formulation of any one of claims 1 to 21, wherein the formulation further comprises a polyol.

23. The pharmaceutical formulation of claim 22, wherein the polyol is selected from the group consisting of mannitol, trehalose, sorbitol, erythritol, isomalt, lactitol, maltitol, xylitol, glycerol, lactitol, propylene glycol, polyethylene glycol and inositol.

24. The pharmaceutical formulation of claim 23, wherein the polyol is mannitol.

25. The pharmaceutical formulation of claim 23 or claim 24, wherein the polyol is present in the formulation at a concentration of 10 mg / mL to 20 mg / mL.

26. The pharmaceutical formulation of any one of claims 1 to 25, wherein the formulation has a volume in the range of 5 mL to 30 mL.

27. The pharmaceutical formulation of any one of claims 1 to 24, wherein the formulation is stable up to at least 60 months.

28. The pharmaceutical formulation of any one of claims 1 to 27, wherein the formulation comprises: an anti -KM A antibody; diethylenetriaminepentaacetic acid (DTPA); polysorbate 80; sodium citrate dihydrate; citric acid monohydrate; sodium chloride; and mannitol.

29. The pharmaceutical formulation of any one of claims 1 to 27, wherein the formulation comprises: an anti -KM A antibody at a concentration of 10 mg / mL; di ethylenetriaminepentaacetic acid (DTPA) at a concentration of 0.02 mg / mL; polysorbate 80 at a concentration of 0.4 mg / mL; sodium citrate dihydrate at a concentration of 5.29 mg / mL; citric acid monohydrate at a concentration of 0.423 mg / mL; sodium chloride at a concentration of 5.84 mg / mL; and mannitol at a concentration of 15 mg / mL.

30. A method of treating multiple myeloma in a subject, the method comprising administering the formulation of any one of claims 1 to 29 to the subject.

31. A kit for use in treating multiple myeloma in a subj ect, the kit comprising: a. at least one pharmaceutical formulation of any one of claims 1 to 29; b. instructions for using the kit in treating the multiple myeloma in the subject; and c. optionally, at least one further therapeutically active compound or drug.

32. A prefilled syringe comprising the pharmaceutical formulation of any one of claims 1 to 29.

33. An autoinjector device comprising the pharmaceutical formulation of any one of claims1 to 29.

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