Discovery of STRO-002, a Novel Homogeneous ADC Targeting Folate Receptor Alpha, for the Treatment of Ovarian and Endometrial Cancers

Abstract

STRO-002 is a novel homogeneous FolRα targeting antibody drug conjugate (ADC), currently being investigated in the clinic as a treatment for ovarian and endometrial cancers. Here we describe the discovery, optimization, and anti-tumor properties of STRO-002. STRO-002 was generated by conjugation of a novel cleavable 3-aminophenyl hemiasterlin linker-warhead (SC239) to the non-natural amino acid para-azidomethyl-L-phenylalanine (pAMF) incorporated at specific positions within a high affinity anti-FolRα antibody using Sutro’s XpressCF+™, which resulted in a homogeneous ADC with a drug-antibody ratio (DAR) of 4. STRO-002 binds to FolRα with high affinity, internalizes rapidly into target positive cells, and releases the tubulin-targeting cytotoxin 3-aminophenyl hemiasterlin (SC209). SC209 has reduced potential for drug efflux via P-gp drug pumps compared to other tubulin-targeting payloads. While STRO-002 lacks non-specific cytotoxicity toward FolRα-negative cell lines, bystander killing of target negative cells was observed when co-cultured with target positive cells. STRO-002 is stable in circulation with no change in DAR for up to 21 days and has a half-life of 6.4 days in mice. A single dose of STRO-002 induced significant tumor growth inhibition in FolRα expressing xenograft models and patient derived xenograft (PDX) models. In addition, combination treatment with carboplatin or Avastin further increased STRO-002 efficacy in xenograft models. The potent and specific pre-clinical efficacy of STRO-002 supports clinical development of STRO-002 for treating patients with FolRα-expressing cancers including ovarian, endometrial, and NSCLC. Phase I dose escalation for STRO-002 is in progress in ovarian cancer patients (NCT03748186).

An Integrated In Vivo/In Vitro Protein Production Platform for Site-Specific Antibody Drug Conjugates

“…ADC binding to the FcRn receport protects from degradation and has been demonstrated to be an important determinant of efficacy, safety, and pharmacokinetics (PK) [ 36 ]. aFolR ADCs were prepared by conjugating the SC239 DBCO-hemiasterlin drug linker to IgG produced in CFPS using either two-plasmid co-expression or PFLC [ 37 ]. Comparison of the BLI data ( Figure S6 ) and the resulting kinetic constants from fitting with a one-to-one model ( Table 3 ) demonstrate that binding to FcRn at pH 5.8, the physiologically relevant pH, is identical for proteins produced by CFPS, irrespective of the method of LC production.…”

Natural Products Derived from Marine Sponges with Antitumor Potential against Lung Cancer: A Systematic Review

“…STRO-002 is an ADC that contains taltobulin, a synthetic analog derived from hemiasterlin, originally sourced from the marine sponge Hemiasterella minor . Phase I clinical trial for STRO-002 is in progress in ovarian cancer and endometrial cancer patients (NCT03748186, NCT05200364, and NCT05870748) [ 65 ]. E7130, a novel antitumor agent inspired by the natural compound norhalichondrin B [ 66 ], is currently undergoing evaluation in phase I clinical trials of solid tumors (NCT03444701).…”

Folate Receptor Alpha—A Novel Approach to Cancer Therapy

“…One such novel ADC targeting FRα is STRO-002. In a study conducted by Li et al, STRO-002 was found to bind to FRα with increased affinity, leading to the avid internalization of the ADC into cells carrying FRα [ 18 ]. After this process occurs, a cytotoxin is released, specifically a tubulin-targeting cytotoxin called 3-aminophenol hemiasterlin, which was seen to significantly reduce tumor growth, particularly when it was combined with platinum- or Avastin-based treatments.…”