MDX‐1097 induces antibody‐dependent cellular cytotoxicity against kappa multiple myeloma cells and its activity is augmented by lenalidomide

Abstract

SummaryMDX-1097 is an antibody specific for a unique B cell antigen called kappa myeloma antigen (KMA) that consists of cell membrane-associated free kappa light chain (jFLC). KMA was detected on kappa human multiple myeloma cell lines (jHMCLs), on plasma cells (PCs) from kappa multiple myeloma (jMM) patients and on jPC dyscrasia tissue cryosections. In primary jMM samples, KMA was present on CD38+ cells that were CD138 and CD45 positive and/or negative. MDX-1097 exhibited a higher affinity for KMA compared to jFLC and the latter did not abrogate binding to KMA. MDX-1097-mediated antibody-dependent cellular cytotoxicity (ADCC) and in vitro exposure of target cells to the immunomodulatory drug lenalidomide resulted in increased KMA expression and ADCC. Also, in vitro exposure of peripheral blood mononuclear cells (PBMCs) to lenalidomide enhanced MDX-1097-mediated ADCC. PBMCs obtained from myeloma patients after lenalidomide therapy elicited significantly higher levels of MDX-1097-mediated ADCC than cells obtained prior to lenalidomide treatment. These data establish KMA as a relevant cell surface antigen on MM cells that can be targeted by MDX-1097. The ADCC-inducing capacity of MDX-1097 and its potentiation by lenalidomide provide a powerful rationale for clinical evaluation of MDX-1097 alone and in combination with lenalidomide.

A preliminary study of the anti-κ myeloma antigen monoclonal antibody KappaMab (MDX-1097) in pretreated patients with κ-restricted multiple myeloma

“…MDX-1097 binds to serum κ FLC (κFLC), albeit with lower affinity than to malignant MM cells, and importantly, KMA is not found on normal human leucocytes 6–8 . KMA is non-covalently associated with lipids in the plasma membrane and MDX-1097 binding to KMA may induce changes to the cell membrane, potentially activating immune cell signal transduction pathways 7 . Further, our in vitro studies demonstrated that MDX-1097 induces ADCC and this effect is augmented in the presence of lenalidomide 7 .…”

“…KMA is non-covalently associated with lipids in the plasma membrane and MDX-1097 binding to KMA may induce changes to the cell membrane, potentially activating immune cell signal transduction pathways 7 . Further, our in vitro studies demonstrated that MDX-1097 induces ADCC and this effect is augmented in the presence of lenalidomide 7 . Given that KMA is expressed on malignant B cells, we feel that this mAb has therapeutic potential for treating MM.…”

“…On the contrary, the antibody clearance increased with increasing dose. MDX-1097 has a lower affinity for soluble antigen compared with the cellular antigen; therefore, preferential binding to KMA due to “avidity” of bivalent binding is likely 7 . In addition, the derived volume of distribution ( V z ) was consistent with the confinement of MDX-1097 to the blood and extracellular fluid spaces, suggesting that off-target binding of MDX-1097 is unlikely (Supplementary Table 2).…”

“…This decision was based on both the preliminary study and the phase 2a study showing that no AEs were observed in patients on maintenance lenalidomide therapy following dosing of MDX-1097. In addition, our existing data show that lenalidomide increases KMA expression and enhances MDX-1097 activity 7 ; hence, there was a compelling rationale for combining MDX-1097 with lenalidomide. The primary objective is to assess overall response rate.…”

Epigenetics in the Biology and Treatment of Multiple Myeloma

“…81 In mice studies, both anti-PD-1 and anti-cytotoxic T-lymphocyteassociated antigen-4 (CTLA-4) antibodies were unable to eradicate large, modestly immunogenic CT26 tumours or metastatic 4T1 tumours. …”