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

Abstract

Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: 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. Ó2015 AACR.

An Anti-GDNF Family Receptor Alpha 1 (GFRA1) Antibody–Drug Conjugate for the Treatment of Hormone Receptor–Positive Breast Cancer

“…The GFRA1 transcript levels correlates well with protein expression in a luminal A breast cancer tissues, suggesting that a high-throughput RNA-based diagnostic assay might suffice for patient selection instead of a IHC. RET, a receptor in GDNF-signaling is also known to be overexpressed in the breast cancer tissues (5,22), but we found it inferior to GFRA1 at both the mRNA and protein level, with only 6/29 (20%) samples expressing RET at 2þ/3þ in line with previous reports (20). Our IHC analysis further confirmed that RET is overexpressed with IHC score of 2þ/3þ only in 20% (6 of 29) patients, while 28% (8 of 29) patients showed IHC score 1þ and 52% (15 of 29) luminal A breast cancer patients showed no expression.…”

RET Signaling in Prostate Cancer

“…Of course, pheochromocytoma and paraganglioma would be expected to express high levels of RET since their tissues of origin intrinsically express high levels of RET. It has also been shown that more than half of all breast cancers express RET by immunohistochemistry (27). …”

Preclinical Evaluation of MEDI0641, a Pyrrolobenzodiazepine-Conjugated Antibody–Drug Conjugate Targeting 5T4

“…To our knowledge, this is the first report where a headto-head comparison was made between two ADCs comprised of the same antibody but conjugated with payloads from different drug classes with different mechanisms of action: PBDs that form interstrand DNA cross-links and tubulysins that depolymerize microtubules. Others have reported comparing cleavable versus noncleavable drug linkers, but typically, these comparisons have included the same warhead class; for example, comparing conjugates with either cleavable mc-VC-PABC-MMAE or noncleavable mc-MMAF (45,46), or cleavable SPDB-DM4 versus noncleavable SMCC-DM1 (47,48). There have also been reports of comparing conjugates with auristatins and maytansinoids (49), but these are both inherently two classes of drugs with a similar mechanism of action, namely microtubule inhibition.…”