Abstract 1782: Discovery and activity of STRO-002, a novel ADC targeting folate receptor alpha for ovarian and endometrial cancer

Abstract

Folate receptor alpha (FolRα) is a glycosylphosphatidylinositol linked cell-surface glycoprotein that is widely expressed in serous and epithelial ovarian cancer, endometrial adenocarcinoma, non-small cell lung cancer and triple negative breast cancer. In contrast, FolRα expression is highly restricted on normal tissues, making it a highly promising target for cancer therapy using antibody drug conjugates (ADCs). We have designed a novel, FolRα-targeting ADC, STRO-002, with potent cytotoxic activity on FolRα expressing tumors in vitro and in vivo, including in cells with low expression levels (~0.2 million copies/cell) of FolRα. STRO-002 contains the anti-FolRa human IgG1 antibody (SP8166) conjugated to a proprietary cleavable drug-linker (SC239). SC239 contains a tubulin-targeting 3-aminophenyl hemiasterlin warhead, SC209, which has potent cytotoxic activity and is a weak substrate for efflux pumps. SP8166 was discovered and optimized using a Fab ribosome display selection and screening platform based on Sutro's Xpress CF+TM system. Four non-natural amino acid p-azidomethyl phenylalanine (pAMF) residues are incorporated into SP8166 at two defined sites on each heavy chain. These sites were selected based on optimal stability and activity in vitro and in vivo. The SC239 drug-linker is conjugated via a cleavable valine citrulline p-aminobenzyl carbamate linker functionalized with dibenzocyclooctyne (DBCO). The rapid and selective reaction of DBCO and pAMF results in a well-defined, homogeneous ADC with a drug-antibody ratio (DAR) of ~4. STRO-002 has potent cytotoxic activity (0.1-3 nM) on multiple FolRα-positive ovarian cancer cell lines in vitro and demonstrates strong anti-tumor response in KB, Igrov1 and OvCAR3 xenograft models in vivo. On Igrov1 xenografts, STRO-002 exhibits dose-dependent tumor growth inhibition starting at a single dose as low as 2.5 mg/kg. Evaluation of in vivo activity of STRO-002 in additional xenograft and PDX models, as well as in combination studies with chemotherapeutic agents is ongoing. Data from exploratory safety studies of STRO-002 in cynomolgus monkey and SC209 (active catabolite) in rats show a favorable safety profile. Our data suggests that STRO-002 is a promising clinical candidate for ovarian cancer, including tumors with low expression levels of FolRα, and IND enabling studies are currently being conducted. Citation Format: Xiaofan Li, Cristina Abrahams, Sihong Zhou, Stellanie Krimm, Robert Henningsen, Heather Stephenson, Jeffrey Hanson, Mary Rose Masikat, Krishna Bajjuri, Tyler Heibeck, Cuong Tran, Gang Yin, James Zawada, Ganapathy Sarma, Joy Chen, Maureen Bruhns, Willy Solis, Alexander Steiner, Adam Galan, Toni Kline, Ryan Stafford, Alice Yam, Venita I. De Almeida, Mark Lupher, Trevor Hallam. Discovery and activity of STRO-002, a novel ADC targeting folate receptor alpha for ovarian and endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1782.

Site-selective modification strategies in antibody–drug conjugates

“…11C). 174,[185][186][187] Ahn et al were also able to use this technology to introduce two DBCO-functionalised bifunctional chelators to trastuzumab, thus enabling the incorporation of radioisotopes for positron emission tomography. 188 A modified CFPS system enabled incorporation of 2, 4, 6, or 8 pAMF residues into an anti-HER2 antibody, which could then undergo conjugation to DBCO-maytansine to yield ADCs with DAR values of 1.77, 3.83, 5.82 and 7.43, respectively.…”

“…204 Two further ADCs currently in Phase I clinical trials, STRO-001 and STRO-002, have been developed by Sutro. 186,187 These ADCs were generated using a cell-free platform, XpressCF+t, which has an engineered RF1 mutant to facilitate efficient incorporation of pAMF at positions designated by a UGA codon. 174 In STRO-001, pAMF was incorporated into each heavy chain of an anti-CD74 antibody by replacing the codon corresponding to HC-F404 with an amber codon.…”

“…ADC composed of an anti-folate receptor alpha human IgG1 antibody conjugated to a cleavable drug-linker (SC239) containing the tubulin-targeting 3-aminophenyl hemiasterlin payload SC209. 186 To generate this ADC, four pAMF residues were incorporated into the antibody at two defined sites on each heavy chain. These sites were then conjugated to SC239 via a cleavable Val-Cit-PABC linker functionalised with DBCO.…”

Advances in Antibody–Drug Conjugate Design: Current Clinical Landscape and Future Innovations

“…Another UAA, p-azidomethylphenylalanine (pAMF), was genetically encoded in antibody sequences in order to obtain either a DAR2 for maytansinoid SC236 157 or a DAR4 for hemiasterlin SC239 ADC. 158 In these instances, antibodies were produced using a cell-free protein expression system and conjugation to pAMF was achieved using a copper-free azide-alkyne cycloaddition, with a dibenzocyclooctyne-bearing payload that provides a stable linkage. 156 Whatever the SSC technology used, ADCs resulting from careful selection of an SSC site-some SSC sites work far worse than stochastic conjugates-demonstrated either an improved tolerability in rodents and nonhuman primates or an increased efficacy in mice versus stochastic ADCs.…”

Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics

“…Indeed, STRO‐002, an ADC developed by Sutro Biopharm, uses the hemiasterlin analogue 3‐aminophenyl hemiasterlin as the payload. This ADC is currently undergoing a Phase I clinical trial for the treatment of ovarian and endometrial cancer (clinical trial number: NCT03748186) [24] …”