MDX-1097 explained

Drug Name:KappaMab
Type:mab
Cas Number:1793022-75-9
Synonyms:IST-1097; KappaMab; MDX-1097

MDX-1097 (formerly called IST-1097, now called KappaMab) is a monoclonal antibody therapy that in 2023 has been assessed in a Phase IIb clinical trial in conjunction with lenalidomide and dexamethasone as a treatment for multiple myeloma, a type of white blood cell cancer.[1] [2] MDX-1097 was originally developed by scientists at Immune System Therapeutics Ltd.[3] In 2015, Haemalogix Ltd acquired the rights to MDX-1097 and are taking it through clinical testing.[4]

Development

Originally, a mouse (murine) antibody was used for initial experiments. This murine monoclonal antibody, called K-1-21, was raised against purified human kappa Bence Jones proteins (BJP).[5] K-1-21 was shown to be specific for a cell-surface antigen that was named kappa myeloma antigen (KMA). KMA was found on malignant B cells (plasma cells) isolated from the bone marrow of patients with kappa restricted multiple myeloma (kMM), lymphoma and Waldenström macroglobulinemia.[6] KMA was also detected in cell culture on the surface of human myeloma cell lines derived from patients with kappa restricted myeloma (kHMCLs). The K-1-21 antibody was re-named mKap.

The next step was to produce an antibody for use in humans that was based on the murine version. The heavy and light chain variable region genes (VH and Vk) of MDX-1097 were isolated from mKap hybridoma cells using recombinant DNA methodologies.[7] MDX-1097, a chimeric (murine plus human) monoclonal antibody, was manufactured according by Medarex Inc. (subsidiary of Bristol-Myers Squibb). MDX-1097 has retained the specificity and affinity observed for mKap. MDX-1097 has been used in the clinical trials described below, as well as in vitro studies.

Pharmacology

Mechanism of action

KMA is a membrane-bound form of free kappa light chain on malignant B-cells, in-vitro activated B cells and rare tonsillar B-cells.[8] [9] [10] KMA is not found on normal human leucocytes. KappaMab (MDX-1097) is specific for KMA and binds to a unique conformational epitope in the kappa constant region that is presented when kappa free light chain (kFLC) associates with sphingomyelin in the cell membrane.[11] KappaMab does not bind to kappa immunoglobulin (Igκ) and it has a 5-fold higher affinity for membrane-bound KMA (IC50 4nM) when compared to serum kappa Free Light Chain (IC50 20nM). Moreover, in vitro studies demonstrated that KM induces selective antibody-dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP) of kappa-positive MM cells and that lenalidomide (LEN) exposure upregulates KMA expression on MM cells promoting enhanced KM-induced NK-mediated ADCC.

Clinical trials

In an initial Phase 1 clinical trial,[12] MDX-1097 was administered intravenously to multiple myeloma patients with stable kappa-type disease, with doses ranging from 0.3 mg/kg to 10.0 mg/kg. The study primarily aimed to evaluate MDX-1097's safety profile across these dose levels.[13]

In a Phase 2a clinical trial involving 19 patients with stable kappa-type multiple myeloma, MDX-1097 was administered at a dose of 10 mg/kg weekly for 8 doses to assess safety and efficacy.,[14] [15]

In a Phase 2b investigator-initiated clinical trial, repeated doses of KappaMab were administered either alone or in combination with lenalidomide and dexamethasone to patients with kappa-type relapsed, refractory multiple myeloma (MM). The study, conducted across multiple centers, aimed to assess safety and efficacy in both treatment cohorts.[2]

Notes and References

  1. Web site: A Phase IIb, open label, sequential cohort study comparing KappaMab alone to KappaMab in combination with lenalidomide and low dose dexamethasone (MRd) in Relapsed Refractory Multiple Myeloma . Australian New Zealand Clinical Trials Registry . Trial number ACTRN-12616001164482 .
  2. Spencer A, Kalff A, Shortt J, Quach H, Wallington-Gates C, Reynolds J, Walker P, Harrison SJ, Dunn R, Wellard C . A sequential cohort study evaluating single-agent KappaMab and KappaMab combined with lenalidomide and low-dose dexamethasone in relapsed and/or refractory kappa light chain-restricted multiple myeloma (AMaRC 01-16) . British Journal of Haematology . 202 . 4 . 801–811 . August 2023 . 37357593 . 10.1111/bjh.18955 . free .
  3. Hutchinson AT, Jones DR, Raison RL . Preclinical and clinical development of an anti-kappa free light chain mAb for multiple myeloma . Molecular Immunology . 67 . 2 Pt A . 89–94 . October 2015 . 25964097 . 10.1016/j.molimm.2015.04.013 .
  4. Web site: KappaMab (formerly MDX-1097) Clinical Trials . Haemalogix Website.
  5. Boux HA, Raison RL, Walker KZ, Hayden GE, Basten A . A tumor-associated antigen specific for human kappa myeloma cells . The Journal of Experimental Medicine . 158 . 5 . 1769–1774 . November 1983 . 6195295 . 2187149 . 10.1084/jem.158.5.1769 .
  6. Boux HA, Raison RL, Walker KZ, Musgrove E, Basten A . The surface expression of a tumor-associated antigen on human kappa myeloma cells . European Journal of Immunology . 14 . 3 . 216–222 . March 1984 . 6423392 . 10.1002/eji.1830140304 .
  7. Dunn RD, Weston KM, Longhurst TJ, Lilley GG, Rivett DE, Hudson PJ, Raison RL . Antigen binding and cytotoxic properties of a recombinant immunotoxin incorporating the lytic peptide, melittin . Immunotechnology . 2 . 3 . 229–240 . September 1996 . 9373315 . 10.1016/s1380-2933(96)00055-3 .
  8. Book: Walker KZ, Boux HA, Hayden GE, Goodnow CC, Raison RL . Microenvironments in the Lymphoid System . A monoclonal antibody with selectivity for human kappa myeloma and lymphoma cells which has potential as a therapeutic agent . Advances in Experimental Medicine and Biology . 186 . 833–41 . 1985 . 3931433 . 10.1007/978-1-4613-2463-8_101 . 978-1-4612-9495-5 .
  9. Hutchinson AT, Jones DR, McCauley Winter P, Tangye SG, Raison RL . Cell membrane associated free kappa light chains are found on a subset of tonsil and in vitro-derived plasmablasts . Human Immunology . 75 . 9 . 986–990 . September 2014 . 25149546 . 10.1016/j.humimm.2014.08.196 .
  10. Asvadi P, Cuddihy A, Dunn RD, Jiang V, Wong MX, Jones DR, Khong T, Spencer A . MDX-1097 induces antibody-dependent cellular cytotoxicity against kappa multiple myeloma cells and its activity is augmented by lenalidomide . British Journal of Haematology . 169 . 3 . 333–343 . May 2015 . 25653020 . 10.1111/bjh.13298 .
  11. Hutchinson AT, Ramsland PA, Jones DR, Agostino M, Lund ME, Jennings CV, Bockhorni V, Yuriev E, Edmundson AB, Raison RL . Free Ig light chains interact with sphingomyelin and are found on the surface of myeloma plasma cells in an aggregated form . Journal of Immunology . Baltimore, Md. . 185 . 7 . 4179–4188 . October 2010 . 20817866 . 10.4049/jimmunol.1001956 .
  12. Web site: An Open-label Phase I Study of the Safety and Efficacy of MDX-1097, an human IgG1k chimeric monoclonal antibody, in the Treatment of Previously Treated Kappa Light Chain Restricted Multiple Myeloma Patients with Stable Measurable Disease to determine the Safety, Tolerability and Maximum Tolerated Dose . Australian New Zealand Clinical Trials Registry . Trial number ACTRN-12608000336381 . 2024-03-26 .
  13. Spencer A, Walker P, Asvadi P, Campbell DH, Reed K, Herbert BR, Breen EJ, Copeman MC, Dunn RD . A preliminary study of the anti-κ myeloma antigen monoclonal antibody KappaMab (MDX-1097) in pretreated patients with κ-restricted multiple myeloma . Blood Cancer Journal . 9 . 8 . 58 . July 2019 . 31366914 . 6668455 . 10.1038/s41408-019-0217-5 .
  14. Web site: Australian New Zealand Clinical Trials Registry . This is a Phase II, Open-label, Multi-Dose Study of the Monoclonal Antibody MDX-1097 to determine the efficacy of the antibody in patients who have received prior treatment for myeloma and have kappa light chain restricted multiple myeloma with stable measurable disease. . Trial number ACTRN-12610000700033 .
  15. Dunn R, Spencer A, Augustson B, Mollee P, Copeman M, Asvadi P . Phase 2a, open-label, multi-dose study of anti-kappa monoclonal antibody, MDX-1097, in relapsed kappa-chain restricted multiple myeloma with stable measurable disease. . Haematologica . June 2013 . 98 . 324–325 .

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