ABSTRACT
Over the last decade, various new therapies have been developed to promote anti-tumor immunity. Despite interesting clinical results in hematological malignancies, the development of bispecific killer-cell-engager antibody formats directed against tumor cells and stimulating anti-tumor T cell immunity has proved challenging, mostly due to toxicity problems. We report here the generation of trifunctional natural killer (NK) cell engagers (NKCEs), targeting two activating receptors, NKp46 and CD16, on NK cells and a tumor antigen on cancer cells. Trifunctional NKCEs were more potent in vitro than clinical therapeutic antibodies targeting the same tumor antigen. They had similar in vivo pharmacokinetics to full IgG antibodies and no off-target effects and efficiently controlled tumor growth in mouse models of solid and invasive tumors. Trifunctional NKCEs thus constitute a new generation of molecules for fighting cancer. VIDEO ABSTRACT.
Subject(s)
Antibodies, Bispecific , Antigens, Ly/immunology , Antineoplastic Agents, Immunological , Cytotoxicity, Immunologic/drug effects , Killer Cells, Natural/immunology , Natural Cytotoxicity Triggering Receptor 1/immunology , Neoplasms, Experimental , Animals , Antibodies, Bispecific/immunology , Antibodies, Bispecific/therapeutic use , Antineoplastic Agents, Immunological/immunology , Antineoplastic Agents, Immunological/pharmacology , Humans , Immunoglobulin G/immunology , Immunoglobulin G/pharmacology , Killer Cells, Natural/pathology , Mice , Neoplasms, Experimental/immunology , Neoplasms, Experimental/pathology , Neoplasms, Experimental/therapyABSTRACT
Harnessing innate immunity is emerging as a promising therapeutic approach in cancer. We report here the design of tetraspecific molecules engaging natural killer (NK) cell-activating receptors NKp46 and CD16a, the ß-chain of the interleukin-2 receptor (IL-2R), and a tumor-associated antigen (TAA). In vitro, these tetraspecific antibody-based natural killer cell engager therapeutics (ANKETs) induce a preferential activation and proliferation of NK cells, and the binding to the targeted TAA triggers NK cell cytotoxicity and cytokine and chemokine production. In vivo, tetraspecific ANKETs induce NK cell proliferation and their accumulation at the tumor bed, as well as the control of local and disseminated tumors. Treatment of non-human primates with CD20-directed tetraspecific ANKET leads to CD20+ circulating B cell depletion, with minimal systemic cytokine release and no sign of toxicity. Tetraspecific ANKETs, thus, constitute a technological platform for harnessing NK cells as next-generation cancer immunotherapies.