Reference Detail

Ref Type

Journal Article

PMID

(26240273)

Authors

Nguyen M, Miyakawa S, Kato J, Mori T, Arai T, Armanini M, Gelmon K, Yerushalmi R, Leung S, Gao D, Landes G, Haak-Frendscho M, Elias K, Simmons AD

Title

Preclinical Efficacy and Safety Assessment of an Antibody-Drug Conjugate Targeting the c-RET Proto-Oncogene for Breast Carcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	21	24	2015 Dec 15	5552-62	Clin Cancer Res

URL

Abstract Text

The RET proto-oncogene has been implicated in breast cancer, and the studies herein describe the preclinical and safety assessment of an anti-RET antibody-drug conjugate (ADC) being developed for the treatment of breast cancer.RET protein expression was analyzed in breast tumor samples using tissue microarrays. The fully human anti-RET antibody (Y078) was conjugated to the DM1 and DM4 derivatives of the potent cytotoxic agent maytansine using thioether and disulfide linkers, respectively. The resulting compounds, designated Y078-DM1 and Y078-DM4, were evaluated for antitumor activity using human breast cancer cell lines and established tumor xenograft models. A single-dose, 28-day, safety study of Y078-DM1 was performed in cynomolgus monkeys.By immunohistochemistry, RET expression was detected in 57% of tumors (1,596 of 2,800 tumor sections) and was most common in HER2-positive and basal breast cancer subtypes. Potent in vitro cytotoxicity was achieved in human breast cancer cell lines that have expression levels comparable with those observed in breast cancer tissue samples. Dose-response studies in xenograft models demonstrated antitumor activity with both weekly and every-3-weeks dosing regimens. In cynomolgus monkeys, a single injection of Y078-DM1 demonstrated dose-dependent, reversible drug-mediated alterations in blood chemistry with evidence of on-target neuropathy.RET is broadly expressed in breast cancer specimens and thus represents a potential therapeutic target; Y078-DM1 and Y078-DM4 demonstrated antitumor activity in preclinical models. Optimization of the dosing schedule or an alternate cytotoxic agent with a different mechanism of action may reduce the potential risk of neuropathy. Clin Cancer Res; 21(24); 5552-62. ©2015 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Y078-DM1	Y078-DM1	1	0
Y078-DM4	Y078-DM4	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Y078-DM1			RET Inhibitor 52	Y078-DM1 is an antibody drug conjugate composed of a RET antibody (Y078) linked to a derivative of the cytotoxic agent maytansine, which may lead to increased cytotoxicity in RET-expressing tumors (PMID: 26240273).
Y078-DM4			RET Inhibitor 52	Y078-DM4 is an antibody-drug conjugate composed of a RET antibody (Y078) linked to a derivative of the cytotoxic agent maytansine, which may lead to increased cytotoxicity in RET-expressing tumors (PMID: 26240273).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET positive	thyroid gland medullary carcinoma	sensitive	Y078-DM4	Preclinical	Actionable	In a preclinical study, Y078-DM4 induced cytotoxicity in a RET-expressing medullary thyroid cell line in culture (PMID: 26240273).	26240273
RET over exp	breast cancer	sensitive	Y078-DM1	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Y078-DM1 induced cytotoxicity in a human breast cancer cell line with high levels of RET expression in culture and inhibited tumor growth in xenograft models (PMID: 26240273).	26240273
RET positive	breast cancer	sensitive	Y078-DM4	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Y078-DM4 induced cytotoxicity in RET-expressing human breast cancer cell lines in culture and inhibited tumor growth in xenograft models (PMID: 26240273).	26240273