Development of ASG-15ME, a Novel Antibody-Drug Conjugate Targeting SLITRK6, a New Urothelial Cancer Biomarker.

Kendall Morrison,Pia M Challita-Eid,Alla Verlinsky,Dawn Ratay Lortie,Daniel S Pereira,Josh T Snyder,Ingrid B.J Joseph,Hector Aviña,Karen Morrison,Arthur Raitano,Fernando Doñate,Linnette Capo,Wendy Liu,Zili An,Joseph D Abad,David R Stover,Peng Yang

doi:10.1158/1535-7163.mct-15-0570

Abstract

SLITRK6 is a member of the SLITRK family of neuronal transmembrane proteins that was discovered as a bladder tumor antigen using suppressive subtractive hybridization. Extensive immunohistochemistry showed SLITRK6 to be expressed in multiple epithelial tumors, including bladder, lung, and breast cancer as well as in glioblastoma. To explore the possibility of using SLITRK6 as a target for an antibody-drug conjugate (ADC), we generated a panel of fully human mAbs specific for SLITRK6. ADCs showed potent in vitro and in vivo cytotoxic activity after conjugation to Monomethyl Auristatin E or Monomethyl Auristatin F. The most potent ADC, ASG-15ME, was selected as the development candidate and given the product name AGS15E. ASG-15ME is currently in phase I clinical trials for the treatment of metastatic urothelial cancer. This is the first report that SLITRK6 is a novel antigen in bladder cancer and also the first report of the development of ASG-15ME for the treatment of metastatic bladder cancer. Mol Cancer Ther; 15(6); 1301-10. ©2016 AACR.

Highlights

Recent advances in the antibody–drug conjugate (ADC) technology and two recently approved ADCs have brought this drug class to the forefront of drug development in oncology
SLITRK6 is highly expressed in bladder cancer TMAs A total of 509 cases of bladder cancer were investigated using
SLITRK6 expression was seen in 88% of the bladder cancer specimens of which 67% had strong to moderate expression

Summary

Introduction

Recent advances in the antibody–drug conjugate (ADC) technology and two recently approved ADCs have brought this drug class to the forefront of drug development in oncology. Poor prognosis and ineffective therapies for patients with advanced bladder cancer make the discovery of new drugs very important for the treatment of this common disease. The SLITRK family members are type I transmembrane proteins that share conserved leucine-rich repeat domains similar to those in the secreted axonal guidance molecule, SLIT. They show similarities to Ntrk neurotrophin receptors in their carboxy-termini, sharing a conserved tyrosine residue [13]. We report here the discovery that SLITRK6 is expressed at high levels in bladder cancer and to a lesser extent in other epithelial tumors (lung, breast, and glioblastoma). We discuss the preclinical development of ASG-15ME along with the rationale for developing it as a new treatment for advanced bladder cancer

Materials and Methods

Results

Discussion

Disclosure of Potential Conflicts of Interest