Harnessing NK Cells with AFM26: A Promising Bispecific TandAb Therapy for Multiple Myeloma

Multiple myeloma, a prevalent blood cancer, is marked by the proliferation of cancerous plasma cells in bone marrow and excessive monoclonal immunoglobulin. Though once deemed incurable, recent advancements in monoclonal antibodies targeting plasma cell surface antigens have opened new avenues for treatment. However, the challenge of relapse and resistance to treatment persists, necessitating innovative immunotherapeutic strategies. B-cell maturation antigen (BCMA) is a prime target due to its limited presence in healthy tissues and widespread expression in myeloma cells.

Natural killer (NK) cells, part of the innate immune system, are adept at eliminating infected and cancerous cells. Their cytotoxic capabilities can be harnessed therapeutically through CD16A receptor engagement with monoclonal antibodies, leading to tumor cell lysis without the systemic side effects associated with T-cell therapies. NK cells are known to infiltrate bone marrow, contributing to the effectiveness of current myeloma treatments, making them a promising avenue for therapy.

The article introduces AFM26, a new bispecific tandem diabody with high specificity and affinity for BCMA and CD16A, which induces effective myeloma cell lysis. This compound features an enhanced anti-CD16A domain, binding bivalently to NK cells for increased avidity and retention time. AFM26 demonstrates potent NK-cell-mediated lysis of BCMA-expressing target cells at low concentrations and ratios, even in the presence of polyclonal IgG. This indicates that unlike traditional antibodies, AFM26 maintains its activity at low concentrations and in the presence of serum IgG, which is significant given the high IgG M-protein levels in many MM patients.

AFM26 also shows high protein stability, compatibility with cynomolgus antigens, and no binding to APRIL and TACI receptors. These characteristics make AFM26 a strong candidate for myeloma treatment. The study was presented at the American Association for Cancer Research Annual Meeting in 2017.