Abstract NT-090: PRECLINICAL ACTIVITY AND SAFETY OF STRO-002, A NOVEL ADC TARGETING FOLATE RECEPTOR ALPHA FOR OVARIAN AND ENDOMETRIAL CANCER

Abstract

OBJECTIVES: Folate receptor alpha (FolRα) is a cell-surface glycoprotein, highly expressed in ovarian and endometrial adenocarcinoma, and thus a promising target for cancer therapy using antibody drug conjugates (ADCs). Most ADCs currently in development are generated by random attachment of the cytotoxic payload to the antibody and result in a heterogeneous mixture, comprised of many different forms that are likely to vary in stability and activity, and therefore may be suboptimal therapeutic agents. We have employed an E. coli cell-free expression system (XpressCFTM) and site-specific conjugation technology, to generate STRO-002, a novel homogenous FolRα-targeting ADC. STRO-002 was optimized by selection of the antibody, drug-linker, conjugation site and drug-antibody ratio (DAR) that conferred the best pharmacological properties. We have conducted preclinical studies to evaluate the stability of STRO-002 and characterize the pharmacological properties of the cytotoxic metabolite SC209. In vitro cytotoxicity assays and in vivo efficacy studies were conducted to evaluate the activity of STRO-002 in multiple ovarian cancer cell lines and xenografts. IND enabling toxicology studies were conducted to determine the safety profiles for STRO-002 and its metabolite SC209 in cynomolgous monkeys and rats, respectively. RESULTS: Based on optimization studies, the anti-FolRα human IgG1 antibody (H01/SP8166) conjugated to a proprietary cleavable drug-linker (SC239) was selected for the lead ADC STRO-002. SC239 contains a tubulin-targeting 3-aminophenyl hemiasterlin warhead, SC209, which has potent cytotoxic activity. Based on most favorable anti-tumor activity, positions 180 and 404 on each heavy chain were selected for conjugation of SC239 to SP8166 to yield an ADC with DAR of ~ 4. The drug-linkage in STRO-002 is highly stable and the released warhead, SC209, is a very weak substrate for cellular drug-resistance efflux pumps and is cleared rapidly from plasma. STRO-002 has potent but highly specific cytotoxic activity (0.1-3 nM) on multiple FolRα-positive ovarian cancer cell lines in vitro and anti-tumor efficacy in ovarian xenograft models. STRO-002 exhibits dose-dependent tumor growth inhibition in Igrov-1 tumor xenografts at a single dose and complete regression is achieved in Igrov-1 and OVCAR-3 tumors with a single dose at 10 and 5 mg/kg, respectively. In addition, administration of STRO-002 in combination with carboplatin confers added benefit in efficacy in Igrov-1 tumors. Toxicology studies show favorable safety profiles for STRO-002 and SC209. The main toxicity finding in monkeys dosed up to 9 mg/kg consists of reversible hematopoietic/lymphoid tissue toxicity, which is considered antigen-independent and is consistent with the anti-proliferative effects of SC209 observed in single-dose toxicology studies in rats. No evidence of ocular toxicity due to SC209 were observed in either species. CONCLUSIONS: STRO-002 is a highly specific FolRα targeting ADC with minimal drug moiety release in circulation and the potential for an improved safety and activity profile, and a reduced risk of tumor drug resistance. Our data supports the advancement of STRO-002 to the clinic as a potential treatment of FolRα expressing malignancies such as ovarian cancer. Citation Format: Cristina Abrahams, Stellanie Krimm, Xiaofan Li, Sihong Zhou, Jeffrey Hanson, Mary Rose Masikat, Krishna Bajjuri, Tyler Heibeck, Dharti Kothari, Abigail Yu, Robert Henningsen, Cuong Tran, Gang Yin, James Zawada, Julie Hang, Maureen Bruhns, Willy Solis, Alexander Steiner, Adam Galan, Toni Kline, Ryan Stafford, Alice Yam, Venita I. De Almeida, Mark Lupher, Jr., Trevor Hallam. PRECLINICAL ACTIVITY AND SAFETY OF STRO-002, A NOVEL ADC TARGETING FOLATE RECEPTOR ALPHA FOR OVARIAN AND ENDOMETRIAL CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-090.

A review of recent advances on single use of antibody-drug conjugates or combination with tumor immunology therapy for gynecologic cancer

“…The two types of linkers are shown in the Table 1 . In addition, some ADCs such as DMUC4064A, XMT-1536, and stro-002, are being coupled by proprietary technologies ( Ohri et al, 2018 ; Abrahams et al, 2019 ; Yurkovetskiy et al, 2021 ).…”

“…STRO-002 is a novel FRα-targeting ADC that includes the tubulin-targeting 3-aminophenyl hemiasterlin warhead, SC209, joined to the antibody, SP8166. This drug is generated using a cell-free antibody production system (XpressCF™) and a site-specific conjugation (XpressCF+™) platform ( Abrahams et al, 2019 ). A phase I dose-escalation study of STRO-002 (NCT03748186) contained 39 platinum-resistant patients without requirement for FRα expression.…”

Natural Product Based Antibody Drug Conjugates: Clinical Status as of November 9, 2020

“…Three relatively simple marine-derived tripeptides are now in trials, one in phase I and two at the preclinical stage. The first is listed as SC209 in two AACR posters, the first in 2018 by Li et al 49 and the second in 2019 by Abrahams et al 50 Both posters define the warhead as a 3-aminophenyl hemiasterlin. However, according to the Sutro Biopharma site, the warhead is the hemiasterlin derivative HTI-286 (49) linked as shown to the mAb (50).…”

“…The first is listed as SC209 in two AACR posters, the first in 2018 by Li et al 49 and the second in 2019 by Abrahams et al 50 Both posters define the warhead as a 3-aminophenyl hemiasterlin. However, according to the Sutro Biopharma site, the warhead is the hemiasterlin derivative HTI-286 (49) linked as shown to the mAb (50). In the case of the other Sutro ADC (working with Merck Darmstadt), which is at the preclinical stage, the warhead/construct is known as M1231 is quoted as being a "hemiasterlin-related toxic warhead and a cleavable Val-Cit module".…”