Tetraspecific ANKETs harnesses innate immunity in cancer therapies

Tetraspecific, artificial molecules that recognise both tumour antigens and natural killer cell receptors harness the innate immune response to tumours, both in vitro and in vivo, French investigators showed.

Natural killer (NK) cells are able to kill tumour cells directly and to stimulate anti-tumour T-cell responses indirectly. ANKETs (antibody-based NK cell Engager Therapeutics) are artificial molecules that recognise both tumour antigens and NK cell receptors. Previously, trispecific ANKETs were designed, recognising a tumour antigen as well as CD16 and NKp46, both NK-expressed antigens. Now, Prof. Eric Vivier (University Hospital Marseille, France) presented a tetraspecific ANKET [1]. In addition to NKp46 and CD16, the tetraspecific ANKET also binds to the IL-2 receptor on NK cells.

In vitro, this tetraspecific ANKET promoted IL-2R signalling preferentially in NK cells, inducing primary human NK cell proliferation and cytolytic activity, and the secretion of cytokines and chemokines only after binding to the tumour target. In mouse models of both invasive and solid tumours, the tetraspecific ANKET induced NK cell proliferation and accumulation at the tumour bed, and had a higher anti-tumour efficacy than approved therapeutic antibodies like obinutuzumab, targeting the same tumour antigen. In non-human primates, CD20-directed tetraspecific ANKETs resulted in sustained CD20-positive B-cell depletion with minimal systemic cytokine release and no clinical sign of toxicity.

“Tetraspecific ANKETs constitute a synthetic technological platform combining the induction of NK cell proliferation and effector functions without toxicity, supporting their clinical development for next-generation cancer immunotherapies,” concluded Prof. Vivier.

1. Vivier E, et al. Harnessing innate immunity in cancer therapies: The example of natural killer cell engagers. Abstract 1O. ESMO Congress 2021, 16–21 September.

 

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Posted on 19 November 2021