Abstract
Luminal A (hormone receptor-positive) breast cancer constitutes 70% of total breast cancer patients. In an attempt to develop a targeted therapeutic for this cancer indication, we have identified and characterized Glial cell line-Derived Neurotrophic Factor (GDNF) Family Receptor Alpha 1 (GFRA1) antibody-drug conjugates (ADC) using a cleavable valine-citrulline-MMAE (vcMMAE) linker-payload. RNAseq and IHC analysis confirmed the abundant expression of GFRA1 in luminal A breast cancer tissues, whereas minimal or no expression was observed in most normal tissues. Anti-GFRA-vcMMAE ADC internalized to the lysosomes and exhibited target-dependent killing of GFRA1-expressing cells both in vitro and in vivo The ADCs using humanized anti-GFRA1 antibodies displayed robust therapeutic activity in clinically relevant cell line-derived (MCF7 and KPL-1) tumor xenograft models. The lead anti-GFRA1 ADC cross-reacts with rodent and cynomolgus monkey GFRA1 antigen and showed optimal pharmacokinetic properties in both species. These properties subsequently enabled a target-dependent toxicity study in rats. Anti-GFRA1 ADC is well tolerated in rats, as seen with other vcMMAE linker-payload based ADCs. Overall, these data suggest that anti-GFRA1-vcMMAE ADC may provide a targeted therapeutic opportunity for luminal A breast cancer patients. Mol Cancer Ther; 17(3); 638-49. ©2017 AACR.
Highlights
Breast cancer is the most frequently diagnosed cancer in women
ERþ breast cancers, we assessed their suitability as antibody–drug conjugates (ADC) target antigens for luminal A breast cancers using expression from The Cancer Genome Atlas (TCGA)
These analyses confirmed that relative expression of GDNF Family Receptor Alpha 1 (GFRA1) is more abundant than RET, GFRA1 may be a superior ADC target
Summary
Breast cancer is the most frequently diagnosed cancer in women. In the year 2016, there were 246,660 women estimated to be diagnosed with breast cancer and over 40,450 reported deaths in the United States [1]. Breast cancer can be further classified into four molecular subtypes based on the presence or absence of hormone (estrogen or progesterone) receptors (HRþ/HRÀ) and excess levels of human epidermal growth factor receptor 2 (HER2þ/HER2À): Luminal A (HRþ/HER2À), Luminal B. Inc., 1 DNA Way, South San Francisco, California. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Kuijl: VU Medical Center, Amsterdam, the Netherlands; current address for R. Hudson Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia; current address for J.-A. Cellerant Therapeutics, Inc., 1561 Industrial Road, San Carlos, California
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