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

• Published in: Molecular cancer therapeutics 2023-02, Vol.22 (2), p.155-167
• Main Authors: Li, Xiaofan, Zhou, Sihong, Abrahams, Cristina L, Krimm, Stellanie, Smith, Jennifer, Bajjuri, Krishna, Stephenson, Heather T, Henningsen, Robert, Hanson, Jeffrey, Heibeck, Tyler H, Calarese, Daniel, Tran, Cuong, Yin, Gang, Stafford, Ryan L, Yam, Alice Y, Kline, Toni, De Almeida, Venita I, Sato, Aaron K, Lupher, Mark, Bedard, Kristin, Hallam, Trevor J
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Endometrial Neoplasms - drug therapy; Female; Folate Receptor 1; Humans; Immunoconjugates - chemistry; Lung Neoplasms; Mice; Tubulin - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-22-0322

STRO-002 is a novel homogeneous folate receptor alpha (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 antitumor properties of STRO-002. STRO-002 was generated by conjugation of a novel cleavable 3-aminophenyl hemiasterlin linker-warhead (SC239) to the nonnatural amino acid para-azidomethyl-L-phenylalanine 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-glycoprotein 1 drug pump compared with other tubulin-targeting payloads. While STRO-002 lacks nonspecific cytotoxicity toward FolRα-negative cell lines, bystander killing of target negative cells was observed when cocultured 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 models. In addition, combination treatment with carboplatin or Avastin further increased STRO-002 efficacy in xenograft models. The potent and specific preclinical efficacy of STRO-002 supports clinical development of STRO-002 for treating patients with FolRα-expressing cancers, including ovarian, endometrial, and non-small cell lung cancer. Phase I dose escalation for STRO-002 is in progress in ovarian cancer and endometrial cancer patients (NCT03748186 and NCT05200364).