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

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.

• Authors: Sunil Bhakta, Lisa M Crocker, Yvonne Chen, Meredith Hazen, Melissa M Schutten, Dongwei Li, Coenraad Kuijl, Rachana Ohri, Fiona Zhong, Kirsten A Poon, Mary Ann T Go, Eric Cheng, Robert Piskol, Ron Firestein, Aimee Fourie-O'Donohue, Katherine R Kozak, Helga Raab, Jo-Anne Hongo, Deepak Sampath, Mark S Dennis, Richard H Scheller, Paul Polakis, Jagath R Junutula
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 17 Issue 3 Pg. 638-649 (03 2018) ISSN: 1538-8514 [Electronic] United States
• PMID: 29282299 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Antibodies
• Antineoplastic Agents
• Glial Cell Line-Derived Neurotrophic Factor Receptors
• Immunoconjugates
• Receptors, Steroid

Topics

• Animals
• Antibodies (chemistry, immunology, pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Glial Cell Line-Derived Neurotrophic Factor Receptors (antagonists & inhibitors, genetics, immunology)
• HEK293 Cells
• Humans
• Immunoconjugates (immunology, pharmacokinetics, pharmacology)
• MCF-7 Cells
• Macaca fascicularis
• Mice, Nude
• Mice, SCID
• Rats, Sprague-Dawley
• Receptors, Steroid (metabolism)
• Tumor Burden (drug effects, genetics)
• Xenograft Model Antitumor Assays