IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect.

Abstract

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.

• Authors: Don M Benson Jr, Courtney E Bakan, Shuhong Zhang, Shauna M Collins, Jing Liang, Shivani Srivastava, Craig C Hofmeister, Yvonne Efebera, Pascale Andre, Francois Romagne, Mathieu Bléry, Cécile Bonnafous, Jianying Zhang, David Clever, Michael A Caligiuri, Sherif S Farag
• Journal: Blood (Blood) Vol. 118 Issue 24 Pg. 6387-91 (Dec 08 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 22031859 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antigen-Antibody Complex
• Antineoplastic Agents
• Ligands
• Receptors, KIR
• Thalidomide
• IPH-2101
• Lenalidomide

Topics

• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antigen-Antibody Complex
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cells, Cultured
• Cytotoxicity, Immunologic (drug effects)
• Drug Evaluation, Preclinical
• Humans
• Immunomodulation (drug effects)
• Killer Cells, Natural (drug effects, immunology, metabolism)
• Lenalidomide
• Leukocytes, Mononuclear (drug effects, immunology, metabolism)
• Ligands
• Mice
• Mice, Inbred C57BL
• Multiple Myeloma (blood, drug therapy, immunology, metabolism)
• Receptors, KIR (antagonists & inhibitors)
• Thalidomide (analogs & derivatives, pharmacology, therapeutic use)
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays