Date: 2014-12-09
Type of information: Presentation of results at a congress
phase: preclinical
Announcement: presentation of results at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition, being held December 6-9 in San Francisco, CA
Company: BMS (USA - NY) Innate Pharma (France)
Product: lirilumab (BMS-986015) and elotuzumab (BMS-901608)
Action
mechanism: Lirilumab is a fully human monoclonal antibody (mAb) that blocks the interaction between Killer-cell immunoglobulin-like receptors (KIR) on NK cells and their ligands. Blocking these receptors facilitates activation of NK cells and, potentially, destruction of tumor cells. Lirilumab is licensed to Bristol-Myers Squibb Company. As part of the agreement between Innate Pharma and Bristol-Myers Squibb, Bristol-Myers Squibb holds exclusive worldwide rights to develop, manufacture and commercialize lirilumab and related compounds blocking KIR receptors, for all indications. Under the agreement, Innate Pharma conducts the development of lirilumab through Phase II in AML. Elotuzumab is a humanized IgG1 monoclonal antibody targeted against Signaling Lymphocyte Activation Molecule (SLAMF7, also called CS1), a glycoprotein expressed on myeloma and Natural Killer cells but not detectable in normal tissue. BMS is investigating whether through both direct activation and engagement of Natural Killer cells, elotuzumab may selectively target and kill SLAMF7 expressing myeloma cells. Elotuzumab is being studied as a monotherapy in smoldering myeloma and in combination with other therapies in first-line and relapsed or refractory multiple myeloma. A clinical development program for the agent is underway, including Phase 3 trials in first-line multiple myeloma (ELOQUENT-1) and relapsed or refractory multiple myeloma (ELOQUENT-2). Elotuzumab is also being investigated in a randomized Phase 2 study of bortezomib and dexamethasone in relapsed or refractory multiple myeloma. Elotuzumab is being co-developed with AbbVie, with Bristol-Myers Squibb leading the commercialization of the agent. In May 2014, the FDA has granted elotuzumab Breakthrough Therapy Designation for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received one or more prior therapies.
Disease: multiple myeloma
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On December 9, 2014, Innate Pharma, the innate immunity company developing first-in-class therapeutic antibodies for cancer and inflammatory diseases, announced that new preclinical data on lirilumab in combination with elotuzumab were presented at the 56th ASH Annual Meeting in San Francisco, CA. Elotuzumab can recruit and trigger natural killer (NK) cells to kill MM tumor cells, through a process called antibody-dependent cellular cytotoxicity (ADCC). This ADCC process is negatively regulated by KIR inhibitory receptors on NK cells. Thus, combination treatment with lirilumab, an anti-KIR antibody, and elotuzumab has strong scientific rationale. The two posters presented show that lirilumab enhances elotuzumab activity in vitro and in vivo and support the rationale for the ongoing Phase I clinical trial combining these agents in multiple myeloma.
• “Lirilumab Enhances Anti-Tumor Efficacy of Elotuzumab”. In an in vitro model of two multiple myeloma cell lines, activation of peripheral blood NK cells from healthy donors was significantly enhanced, in a dose-dependent manner, by both lirilumab and elotuzumab independently and further enhanced by the combination of both antibodies. The best combinatorial effect was observed in response to MM cells expressing low densities of CS1. These data suggest that lirilumab treatment may increase the therapeutic efficacy of elotuzumab. In double-transgenic mice engrafted with human multiple myeloma tumor cells and treated when high tumor volumes were reached, combination treatment with lirilumab and elotuzumab resulted in a significantly stronger anti-tumor effect and increased survival of the mice, when compared to either antibody treatment alone. In conclusion, blockade of KIR with lirilumab was able to augment elotuzumab mediated ADCC in vitro and synergized with elotuzumab to mediate potent anti-MM activity in vivo.
• “Effects of IL-21, KIR Blockade, and CD137 Agonism on the Non-Clinical Activity of Elotuzumab”. IL-21, agonist CD137 mAb and lirilumab were examined for their ability to augment elotuzumab activity in vitro and in vivo mouse models. Although IL-21 was able to increase elotuzumab mediated ADCC in vitro it showed little or no enhancement of elotuzumab activity in a xenograft tumor model. CD137 agonism showed minimal enhancement of elotuzumab ADCC in vitro but was able to synergize with elotuzumab in vivo to mediate potent anti-tumor activity in a xenograft tumor model. Blocking the inhibitory KIR pathway with lirilumab was able to augment elotuzumab mediated ADCC in vitro and synergized with elotuzumab in vivo, mediating potent anti-tumor activity in a
KIR2DL3 transgenic and RAG deficient mouse model.
