CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

Abstract

A Hammond (2014) CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas, mAbs, 6:6, 1571-1584, DOI: 10.4161/19420862.2014 To link to this article: https://doi.org/10. 4161/19420862.2014 Individual or combinations of somatic mutations found in genes from colorectal cancers can redirect the effects of chemotherapy and targeted agents on cancer cell survival and, consequently, on clinical outcome. Novel therapeutics with mechanisms of action that are independent of mutational status would therefore fulfill a current unmet clinical need. Here the CEA and CD3 bispecific single-chain antibody MEDI-565 (also known as MT111 and AMG 211) was evaluated for its ability to activate T cells both in vitro and in vivo and to kill human tumor cell lines harboring various somatic mutations commonly found in colorectal cancers. MEDI-565 specifically bound to normal and malignant tissues in a CEA-specific manner, and only killed CEA positive cells. The BiTE Ò antibody construct mediated T cell-directed killing of CEA positive tumor cells within 6 hours, at low effector-to-target ratios which were independent of high concentrations of soluble CEA. The potency of in vitro lysis was dependent on CEA antigen density but independent of the mutational status in cancer cell lines. Importantly, individual or combinations of mutated KRAS and BRAF oncogenes, activating PI3KCA mutations, loss of PTEN expression, and loss-of-function mutations in TP53 did not reduce the activity in vitro. MEDI-565 also prevented growth of human xenograft tumors which harbored various mutations. These findings suggest that MEDI-565 represents a potential treatment option for patients with CEA positive tumors of diverse origin, including those with individual or combinations of somatic mutations that may be less responsive to chemotherapy and other targeted agents.

Immune and Stromal Classification of Colorectal Cancer Is Associated with Molecular Subtypes and Relevant for Precision Immunotherapy

“…3; Supplementary Table S6), and are thus most likely poorly immunogenic, which may explain the low tumor Tcell infiltration in these subgroups. The use of bispecific antibodies targeting a tumor-associated antigen (42), such as carcinoembryonic antigen (43), could enhance these tumors' immunogenicity.…”

A Novel Carcinoembryonic Antigen T-Cell Bispecific Antibody (CEA TCB) for the Treatment of Solid Tumors

“…CEA TCB is the only IgGbased CEA TCB antibody that entered clinical trials to date (NCT02324257) and is differentiated from previously described scFv or diabody-based TCB antibodies targeting CEA, including MEDI-565/AMG 211 (29,30) or others (31,32). CEA TCB molecule bears several technologic features, including (i) bivalent binding to CEA, (ii) head-to-tail fusion via a flexible linker of the CEA-and CD3e-binding Fab domains, (iii) an engineered, heterodimeric Fc region with completely abolished binding to FcgRs and complement component C1q, and (iv) a robust production process based on standard manufacturing steps enabled by the combination of CrossMAb and knob-intohole technologies (18,33).…”

A Novel Bispecific Antibody, S-Fab, Induces Potent Cancer Cell Killing

“…In vivo tumor growth assays were performed as described previously 16,25 with modifications. Briefly, LS174T human colon carcinoma cells were harvested from cell culture, washed once with PBS, resuspended in PBS, and mixed with PBMCs freshly isolated from healthy donors.…”