A novel bispecific antibody platform to direct complement activity for efficient lysis of target cells.

Autor: Cruz JW; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Damko E; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Modi B; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Tu N; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Meagher K; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Voronina V; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Gartner H; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Ehrlich G; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Rafique A; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Babb R; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Aneja P; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Potocky TB; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., D' Orvilliers A; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Coppi A; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., E SY; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Qiu H; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Williams CM; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Bennett BL; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Chen G; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Macdonald L; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Olson W; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Lin JC; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Stahl N; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Murphy AJ; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Kyratsous CA; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA., Prasad BC; Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA. brinda.prasad@regeneron.com.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2019 Aug 19; Vol. 9 (1), pp. 12031. Date of Electronic Publication: 2019 Aug 19.
DOI: 10.1038/s41598-019-48461-1
Abstrakt: Harnessing complement-mediated cytotoxicity by therapeutic antibodies has been limited because of dependency on size and density of antigen, structural constraints resulting from orientation of antibody binding, and blockade of complement activation by inhibitors expressed on target cells. We developed a modular bispecific antibody platform that directs the complement-initiating protein C1q to target cells, increases local complement deposition and induces cytotoxicity against target antigens with a wide-range of expression. The broad utility of this approach to eliminate both prokaryotic and eukaryotic cells was demonstrated by pairing a unique C1q-recruiting arm with multiple targeting arms specific for Staphylococcus aureus, Pseudomonas aeruginosa, B-cells and T-cells, indicating applicability for diverse indications ranging from infectious diseases to cancer. Generation of C1q humanized mice allowed for demonstration of the efficacy of this approach to clear disease-inducing cells in vivo. In summary, we present a novel, broadly applicable, and versatile therapeutic modality for targeted cell depletion.
Databáze: MEDLINE
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