Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Yu-Tzu Tai1,
  2. Holly M. Horton2,
  3. Sun-Young Kong3,
  4. Erik Pong2,
  5. Hsing Chen2,
  6. Saso Cemerski2,
  7. Matthew J. Bernett2,
  8. Duc-Hanh T. Nguyen2,
  9. Sher Karki2,
  10. Seung Y. Chu2,
  11. Greg A. Lazar2,
  12. Nikhil C. Munshi1,
  13. John R. Desjarlais2,
  14. Kenneth C. Anderson1, and
  15. Umesh S. Muchhal2,*
  1. 1 LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States;
  2. 2 Xencor, Inc., Monrovia, CA, United States;
  3. 3 Research Institute and Hospital, National Cancer Center, Goyang, Korea, Republic of
  1. * Corresponding author; email: umuchhal{at}xencor.com

Abstract

HM1.24, an immunological 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 20mg/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.

  • Submitted June 29, 2011.
  • Accepted December 23, 2011.