Data presented at the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting II from June 22-24, 2020 of Sutro Biopharma‘s folate receptor alpha (FolRα) targeting antibody-drug conjugate STRO-002, suggests a potential synergy between the ADC and Immune Checkpoint Inhibitors. According to the investigators, this results in resulting in tumor regression and adaptive anti-tumor immunity.[1]

STRO-002 is an antibody-drug conjugate directed against FolRα, a membrane receptor glycoprotein, which is highly expressed in ovarian cancer and endometrial cancer and is composed of a FolRα antibody conjugated to a tubulin inhibitor hemiasterlin using a cleavable linker.

Hemiasterlin is a natural product derived from marine sponges. Like other structurally diverse peptide-like molecules, hemiasterlin bind to the Vinca-peptide site in tubulin and disrupts normal microtubule dynamics, and, at stoichiometric amounts, depolymerizes microtubules.[2]

The data presented during the AACR meeting demonstrates STRO-002’s immune-modulating properties and potentiation by PD-L1 blockade.

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Combination
In FolRα positive tumor cells, STRO-002 treatment induced hallmarks of immunogenic cell death, killing tumor cells while activating immune cells, including monocytes. When combined in mouse tumor models with avelumab (Bavencio®),  a fully human PD-L1 antibody developed by Merck KGaA and Pfizer, the combination treatment enhanced efficacy leading to more complete responses and increased killer T-cells, than either agent alone.

The data suggest that a single dose of STRO-002 when combined with a PD-1/PD-L1 blockade could provide an effective and protective anti-tumor immune response.

e-poster presentation based on 2250 presented by Trevor Hallam Ph.D., discusses immune-modulating properties and potentiates PD-L1 blockade of STRO-002, an anti-FolRα ADC. Click to download the poster. Image courtesy: © 2020 Sutro Biopharma.

“These data suggest that STRO-002 can drive immune-modulatory responses that can cause complete tumor regression, tumor-specific T-cell activation, and adaptive anti-tumor immunity,” noted Sutro’s Chief Scientific Officer, Trevor Hallam, Ph.D.

“The results here support the clinical evaluation of STRO-002 in combination with anti-PD1 or anti-PD-L1 agents. While we believe STRO-002 as a single agent may demonstrate clinical benefit in certain tumors resistant to checkpoint inhibitor monotherapies, we are excited at the prospect of evaluating potential additional positive impacts on cancer patients that may result from combination treatment regimens involving STRO-002 with other checkpoint inhibitors,” Hallam added.

“An important part of our STRO-002 clinical development strategy includes evaluating these data to determine an optimal combination regimen to take into clinical trials,” said Sutro Chief Medical Officer, Arturo Molina, M.D.

“We anticipate evaluating STRO-002 in combination studies in addition to our single-agent studies. We currently expect to initiate an STRO-002 combination clinical trial in 2021.”

Clinical development
A Phase I, open-label, multicenter, dose-escalation trial with dose expansion of STRO-002 is ongoing, designed to identify the maximum tolerated dose, the recommended Phase II clinical dose, and to evaluate the safety, tolerability, and preliminary anti-tumor activity of STRO-002 in adults with advanced epithelial ovarian cancer, including fallopian or primary peritoneal cancer, and endometrial cancer.

Sutro discovered, developed, and manufactures STRO-002 using its proprietary XpressCF+™ cell-free protein synthesis technology. The platform allows researchers at Sutro to accelerate the discovery and development of potential first-in-class and best-in-class molecules through a rapid and systematic evaluation of protein structure-activity relationships to create optimized homogeneous product candidates.

Clinical trials
Study of STRO-002, an Anti-Folate Receptor Alpha (FolRα) Antibody-drug Conjugate in Ovarian & Endometrial Cancers – NCT03748186

Reference
[1] Hallam T. STRO-002, an anti-FolRα ADC, demonstrates immune-modulating properties
and potentiates PD-L1 blockade; Abstract Number: 2250; AACR Virtual meeting II, June 22 – 24, 2020.
[2] Loganzo F, Discafani CM, Annable T, et al. HTI-286, a synthetic analogue of the tripeptide hemiasterlin, is a potent antimicrotubule agent that circumvents P-glycoprotein-mediated resistance in vitro and in vivo. Cancer Res. 2003;63(8):1838-1845.