Mode of cytotoxic action of T cell-engaging BiTE antibody MT110

Haas, Cornelia; Krinner, Eva; Brischwein, Klaus; Hoffmann, Patrick; Lutterbüse, Ralf; Schlereth, Bernd; Kufer, Peter; Baeuerle, Patrick A.

doi:10.1016/j.imbio.2008.11.014

Cited by 162 publications

(128 citation statements)

References 35 publications

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“…Furthermore, a dose-dependent increase in TNF-α levels in the supernatant was observed only in the presence of C4-2 cells, indicating specific activation of T cells after the formation of a pseudoimmunological synapse between C4-2 and T cells (Fig. 3C) (37). The rosette morphology that is evident upon synapse formation was observed clearly only in the presence of the P-SMAC with C4-2 cells (Fig.…”

Section: Resultsmentioning

confidence: 87%

Bispecific small molecule–antibody conjugate targeting prostate cancer

Kim

Axup

Lawson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Bispecific antibodies, which simultaneously target CD3 on T cells and tumor-associated antigens to recruit cytotoxic T cells to cancer cells, are a promising new approach to the treatment of hormone-refractory prostate cancer. Here we report a site-specific, semisynthetic method for the production of bispecific antibodylike therapeutics in which a derivative of the prostate-specific membrane antigen-binding small molecule DUPA was selectively conjugated to a mutant αCD3 Fab containing the unnatural amino acid, p-acetylphenylalanine, at a defined site. Homogeneous conjugates were generated in excellent yields and had good solubility. The efficacy of the conjugate was optimized by modifying the linker structure, relative binding orientation, and stoichiometry of the ligand. The optimized conjugate showed potent and selective in vitro activity (EC 50 ∼100 pM), good serum half-life, and potent in vivo activity in prophylactic and treatment xenograft mouse models. This semisynthetic approach is likely to be applicable to the generation of additional bispecific agents using drug-like ligands selective for other cell-surface receptors.antibody engineering | immunotherapy

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Section: Resultsmentioning

confidence: 87%

Bispecific small molecule–antibody conjugate targeting prostate cancer

Kim

Axup

Lawson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The coefficient of determination (r 2 ), calculated from Pearson's correlation coefficient (r), was used to assess the correlation between MEDI-565 binding sites and EC 50 values for cytotoxicity assays using 6 cell lines with the same 3 independent T cell donors.…”

Section: Statistical Analysesmentioning

confidence: 99%

“…Clinical studies are ongoing in adult and pediatric patients with relapsed/refractory B-precursor ALL, adults with persistent minimal residual disease B-precursor ALL, and adults with relapsed diffuse large B cell lymphoma (DLBCL), (ClinicalTrials.gov identifiers NCT01471782, NCT01207388, NCT01466179, and NCT01741792). Solitomab targets EpCAM on both epithelial carcinomas as well as tumor-initiating cells, [50][51][52] and has entered a Phase I trial in patients with solid tumors that express EpCAM (ClinicalTrials.gov identifier NCT00635596). AMG 212 is being tested in a Phase I trial in patients with castration-resistant prostate adenocarcinoma (ClinicalTrials.gov identifier NCT01723475).…”

Section: Introductionmentioning

confidence: 99%

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

Oberst¹,

Fuhrmann²,

Mulgrew³

et al. 2014

mAbs

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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.

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“…The CD19xCD3 BiTE (blinatumomab or MT103) has been studied in phase I trials of lymphoma and leukemia (10), and in phase II trials for B-acute lymphoblastic leukemia (11). MT110, the EpCAM (epithelial cell adhesion molecule) antibody xCD3 BiTE (12), is currently undergoing a phase I study in various solid tumors, including lung, gastric, colorectal, breast, prostate, and ovarian cancers (ClinicalTrials.gov identifier NCT00635596).…”

Section: Introductionmentioning

confidence: 99%

Redirected T-Cell Killing of Solid Cancers Targeted with an Anti-CD3/Trop-2–Bispecific Antibody Is Enhanced in Combination with Interferon-α

Rossi

Chang

et al. 2014

Molecular Cancer Therapeutics

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Trop-2 has limited presence on normal tissues but is highly expressed in diverse epithelial cancers. (E1)-3s is a T-cell-redirecting trivalent bispecific antibody (bsAb), comprising an anti-CD3 scFv covalently linked to a stabilized dimer of a Trop-2-targeting Fab using Dock-and-Lock. We show for the first time that bsAbmediated bidirectional trogocytosis occurs between target and T cells and involves immunologic synapses. We studied the effects of interferon-a (INFa) on (E1)-3s-mediated T-cell killing of human gastric and pancreatic cancer cell lines. T-cell activation, cytokine induction, and cytotoxicity were evaluated ex vivo using peripheral blood mononuclear cells (PBMC) or T cells with NCI-N87 gastric cancer as target cells. In vivo activity was assayed with NCI-N87 and Capan-1 (pancreatic) xenografts. In the presence of target cells and PBMCs, (E1)-3s did not cause excess cytokine production. When combined with (E1)-3s, peginterferonalfa-2a-which alone did not increase T-cell activation or raise cytokine levels over baseline-increased CD69 expression but did not significantly increase cytokine induction. (E1) 3s mediated a highly potent T-cell lysis of NCI-N87 target cells in vitro. Inclusion of peginterferonalfa-2a or a more potent form of INFa, 20 Ã -2b, significantly potentiated the activity of (E1)-3s by more than 2.5-or 7-fold, respectively. In vivo, combining peginterferonalfa-2a with (E1)-3s delayed Capan-1 growth longer than each single agent. Similarly, combination therapy delayed tumor proliferation of NCI-N87 compared with (E1)-3s or peginterferonalfa-2a single-treatment groups. (E1)-3s effectively induced T-cell-mediated killing of Trop-2-expressing pancreatic and gastric cancers, which was enhanced with INFa.

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Mode of cytotoxic action of T cell-engaging BiTE antibody MT110

Cited by 162 publications

References 35 publications

Bispecific small molecule–antibody conjugate targeting prostate cancer

Bispecific small molecule–antibody conjugate targeting prostate cancer

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

Redirected T-Cell Killing of Solid Cancers Targeted with an Anti-CD3/Trop-2–Bispecific Antibody Is Enhanced in Combination with Interferon-α

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