MDX-1097

KappaMab

Clinical data
Other names	IST-1097; KappaMab; MDX-1097
Identifiers
CAS Number	1793022-75-9

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

Development of MDX-1097/KappaMab and discovery of KMA

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). 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 Waldenstrom’s macroglobulinemia. 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. MDX-1097, a chimeric (murine plus human) monoclonal antibody, was manufactured according to Good Manufacturing Practice (GMP) by Medarex Inc. (subsidiary of Bristol-Myers Squibb) using the Lonza GS expression system. 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.

Further characterization of KMA

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. 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. 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 with MDX-1097/KappaMab

In a first-in-human clinical trial, single intravenous adminstrations of MDX-1097 were given to 12 multiple myeloma patients with kappa-type disease that was stable at the start of the study. Patient were given one of the following doses of MDX-1097: 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg or 10.0 mg/kg, starting with the lowest dose and ascending to the highest dose (n=3 patients per dose level). The primary goal was to evaluate the safety profile of MDX-1097 at four dose levels. In the 12 patients (n = 3/dose) treated with MDX-1097, no dose-limiting toxicities or serious adverse events (AEs) were reported and the maximum-tolerated dose was not reached at the highest dose (10.0 mg/kg). During the study there was a low incidence of Adverse Events, primarily grade 1 or 2 in severity (grading based on the Common Terminology Criteria for Adverse Events (CTCAE). No patients experienced a dose-limiting toxicity or discontinued the study due to an AE. There were no dose-related trends or other clinically important safety findings. No indications of treatment-emergent renal impairment were observed and there were no clinical or laboratory parameters, suggesting immune complex formation or serum sickness in any patient treated with MDX-1097. Testing for human anti-chimeric antibody at day 45 post infusion revealed that no antibody response to MDX-1097 was detected in any patients.

In a Phase 2a clinical trial, 19 patients with stable kappa-type multiple myeloma were given repeated doses of MDX-1097 at 10 mg/kg weekly for 8 doses. This study aimed to test safety and efficacy of MDX-1097. Repeated MDX-1097 dosing was well tolerated: based on CTCAE criteria, 4 patients had Grade 1-2 drug-related infusion reactions; 4 patients had Grade 3 Adverse Events (complete heart block, pneumonia, anaemia and pancreatitis) that were considered unlikely to be related to MDX-1097. There was no evidence of serum sickness, no alteration of renal function, no evidence of increased immunosuppression and no ECG changes. For disease response, one patient had a very good partial response (VGPR) maintained for 12 months post MDX-1097 therapy. A second patient had a partial response (PR). A third patient with light-chain-only myeloma had PR. Disease responses were based on IMWG response criteria. On study, 26% of patients continued IMiD maintenance therapy; with no signs that MDX-1097 affected their safety profile.

In a Phase 2b investigator-initiated clinical trial, repeated doses of KappaMab were given as monotherapy or in conjunction with lenalidomide and dexamethasone. This multicentre, open-label sequential cohort study evaluated KappaMab alone (stage 1) followed by KappaMab in combination with lenalidomide (LEN) and dexamethasone (DEX) (stage 2) in kappa-type relapsed, refractory MM patients. Key inclusion criteria were progressive kappa-restricted MM (as per IMWG criteria), one to three prior lines of therapy and no prior LEN exposure. Patients previously treated with allogeneic stem cell transplant were excluded. The aims of the study were to test the safety and efficacy in both cohorts. KappaMab demonstrated a highly favourable toxicity profile. In the monotherapy group, 3/19 patients (15.8%) experienced an infusion-related reaction (IRRs), with one grade 1 and two grade 2 reactions (using CTCAE criteria). In the KappaMab plus LEN and DEX cohort, eight IRRs were observed; six with the first infusion. There was one grade 3 IRR and seven grade 1-2 IRRs, and no patients discontinued treatment because of IRRs. In particular, the patient with the grade 3 IRR recovered following hydrocortisone, salbutamol and loratadine administration in the clinic. There were no haematological toxicities, and in particular no lymphopenias, reported with KappaMab, whereas the rates of anaemia (12.5%), neutropenia (32.5%) and thrombocytopenia (18%) seen in the combination cohort were as expected with LEN/DEX administration alone. For patients with kappa-restricted MM, the combination arm demonstrated significant efficacy with an ORR of 82.5%.