Combination Therapy with Bispecific Antibodies and PD-1 Blockade Enhances the Antitumor Potency of T Cells.

Autor:	Chang CH; Immunomedics, Inc., Morris Plains, New Jersey. kchang@immunomedics.com.; IBC Pharmaceuticals, Inc., Morris Plains, New Jersey., Wang Y; Immunomedics, Inc., Morris Plains, New Jersey., Li R; Immunomedics, Inc., Morris Plains, New Jersey., Rossi DL; Immunomedics, Inc., Morris Plains, New Jersey., Liu D; Immunomedics, Inc., Morris Plains, New Jersey.; IBC Pharmaceuticals, Inc., Morris Plains, New Jersey., Rossi EA; Immunomedics, Inc., Morris Plains, New Jersey., Cardillo TM; Immunomedics, Inc., Morris Plains, New Jersey., Goldenberg DM; Immunomedics, Inc., Morris Plains, New Jersey.; IBC Pharmaceuticals, Inc., Morris Plains, New Jersey.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2017 Oct 01; Vol. 77 (19), pp. 5384-5394. Date of Electronic Publication: 2017 Aug 17.
DOI:	10.1158/0008-5472.CAN-16-3431
Abstrakt:	The DOCK-AND-LOCK (DNL) method is a platform technology that combines recombinant engineering and site-specific conjugation to create multispecific, multivalent antibodies of defined composition with retained bioactivity. We have applied DNL to generate a novel class of trivalent bispecific antibodies (bsAb), each comprising an anti-CD3 scFv covalently conjugated to a stabilized dimer of different antitumor Fabs. Here, we report the further characterization of two such constructs, (E1)-3s and (14)-3s, which activate T cells and target Trop-2- and CEACAM5-expressing cancer cells, respectively. (E1)-3s and (14)-3s, in the presence of human T cells, killed target cells grown as monolayers at subnanomolar concentrations, with a similar potency observed for drug-resistant cells. Antitumor efficacy was demonstrated for (E1)-3s coadministered with human peripheral blood mononuclear cells (PBMC) in NOD/SCID mice harboring xenografts of MDA-MB-231, a triple-negative breast cancer line constitutively expressing Trop-2 and PD-L1. Growth inhibition was observed following treatment with (E1)-3s or (14)-3s combined with human PBMC in 3D spheroids generated from target cell lines to mimic the in vivo behavior and microenvironment of these tumors. Moreover, addition of an antagonistic anti-PD-1 antibody increased cell death in 3D spheroids and extended survival of MDA-MB-231-bearing mice. These preclinical results emphasize the potential of combining T-cell-redirecting bsAbs with antagonists or agonists that mitigate T-cell inhibition within the tumor microenvironment to improve immunotherapy of solid cancers in patients. They also support the use of 3D spheroids as a predictive alternative to in vivo models for evaluating T-cell functions. Cancer Res; 77(19); 5384-94. ©2017 AACR . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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