IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect.
Multiple myeloma (MM) patients who receive killer cell Ig-like receptor (KIR) ligand-mismatched, T cell-depleted, allogeneic transplantation may have a reduced risk of relapse compared with patients who receive KIR ligand-matched grafts, suggesting the importance of this signaling axis in the natural killer (NK) cell-versus-MM effect. Expanding on this concept, IPH2101 (1-7F9), an anti-inhibitory KIR mAb, enhances NK-cell function against autologous MM cells by blocking the engagement of inhibitory KIR with cognate ligands, promoting immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells. IPH2101 prevents negative regulatory signals by inhibitory KIR, whereas lenalidomide augments NK-cell function and also appears to up-regulate ligands for activating NK-cell receptors on MM cells. Lenalidomide and a murine anti-inhibitory NK-cell receptor Ab mediate in vivo rejection of a lenalidomide-resistant tumor. These mechanistic, preclinical data support the use of a combination of IPH2101 and lenalidomide in a phase 2 trial for MM.
Division of Hematology, The Ohio State University, Columbus, OH, USA. don.benson@osumc.edu
Don M
DM
Benson
Courtney E
CE
Bakan
Shuhong
S
Zhang
Shauna M
SM
Collins
Jing
J
Liang
Shivani
S
Srivastava
Craig C
CC
Hofmeister
Yvonne
Y
Efebera
Pascale
P
Andre
Francois
F
Romagne
Mathieu
M
Bléry
Cécile
C
Bonnafous
Jianying
J
Zhang
David
D
Clever
Michael A
MA
Caligiuri
Sherif S
SS
Farag
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000936:Antigen-Antibody Complex; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000077269:Lenalidomide; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D054340:Receptors, KIR / Q000037:antagonists & inhibitors*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000936:Antigen-Antibody Complex; D000970:Antineoplastic Agents; D008024:Ligands; D054340:Receptors, KIR; D013792:Thalidomide; C558235:IPH-2101; D000077269:Lenalidomide