Potent in vitro and in vivo activity of an Fc-engineered humanized anti-HM1.24 antibody against multiple myeloma via augmented effector function

Abstract

HM1.24, an immunologic target for multiple myeloma (MM) cells, has not been effectively targeted with therapeutic monoclonal antibodies (mAbs). In this study, we investigated in vitro and in vivo anti-MM activities of XmAb5592, a humanized anti-HM1.24 mAb with Fc-domain engineered to significantly enhance FcγR binding and associated immune effector functions. XmAb5592 increased antibody-dependent cellular cytotoxicity (ADCC) several fold relative to the anti-HM1.24 IgG1 analog against both MM cell lines and primary patient myeloma cells. XmAb5592 also augmented antibody dependent cellular phagocytosis (ADCP) by macrophages. Natural killer (NK) cells became more activated by XmAb5592 than the IgG1 analog, evidenced by increased cell surface expression of granzyme B-dependent CD107a and MM cell lysis, even in the presence of bone marrow stromal cells. XmAb5592 potently inhibited tumor growth in mice bearing human MM xenografts via FcγR-dependent mechanisms, and was significantly more effective than the IgG1 analog. Lenalidomide synergistically enhanced in vitro ADCC against MM cells and in vivo tumor inhibition induced by XmAb5592. A single dose of 20 mg/kg XmAb5592 effectively depleted both blood and bone marrow plasma cells in cynomolgus monkeys. These results support clinical development of XmAb5592, both as a monotherapy and in combination with lenalidomide, to improve patient outcome of MM.

Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

“…12 Macrophages are known to be abundantly present in the bone marrow of MM patients, 4,5 and macrophage-mediated phagocytosis has been demonstrated to be induced by several mAbs targeting MM cells. [13][14][15] The capacity of DARA to induce macrophage-mediated phagocytosis has not been studied thus far.…”

RANKL Expression, Function, and Therapeutic Targeting in Multiple Myeloma and Chronic Lymphocytic Leukemia

“…Several Fcengineered antilymphoma antibodies that mediate markedly enhanced ADCC are presently in preclinical and early clinical development, and it is hoped that their therapeutic activity is increased accordingly (18,19). As multiple myeloma cells do not express CD20, the target antigen of rituximab and its successors, novel antibodies directed to multiple myeloma antigens are presently being developed, and recently an Fcmodified antibody that potently targets multiple myeloma cells for NK cell reactivity was reported (20,21).…”

Monoclonal Antibody-Based Immunotherapy for Multiple Myeloma

“…XmAb5592 is a humanized anti-HM1.24 mAb with an engineered Fc domain that specifically increases affinity for Fcg receptors. It has demonstrated potent anti-MM activity both in vitro and in vivo, which is most probably mediated via superior induction of NK cell activation and degranulation [90]. Furthermore, the anti-MM activity of XmAb5592 shows synergism when combined with lenalidomide pretreatment of effector cells.…”

“…XmAb5592 is a humanized anti-HM1.24 mAb with two amino acid substitutions (S239D/I332E) in the IgG 1 Fc portion of the molecule [90]. Compared with the IgG 1 analog, XmAb5592 has significantly enhanced binding to all human FcgR receptors, regardless of their polymorphism [20,91,92].…”