American Association for Cancer Research (AACR) 2020 Virtual Meeting II – Poster Script
My name is Trevor Hallam and I am the Chief Scientific Officer of Sutro Biopharma. In the next few minutes I will describe the content of Poster #2250, entitled; STRO-002, an anti-FolRα ADC, demonstrates immune-modulating properties and potentiates PD-L1 blockade.
STRO-002 is an antibody drug conjugate directed against FolRα, which is highly expressed in ovarian cancer and endometrial cancer. STRO-002 is composed of an anti-FolRα antibody conjugated to a potent tubulin inhibitor, hemiasterlin, using a cleavable linker. It’s design was facilitated by Sutro’s proprietary cell-free protein production and manufacturing system that enables precise incorporation of conjugatable non-natural amino acids at any chosen position in an antibody as the method of site-specific conjugation. STRO-002 has been designed such that the cytotoxin is attached at specific chosen sites on the antibody heavy chain resulting in a well-defined, single molecule ADC product with consistent placement and drug-antibody ratio of 4. Compared with conventional ADCs that consist of a heterogeneous mixture of molecules in the drug product, the precision and efficient conjugation method that is a feature of STRO-002 confers superior specificity, stability and pharmacological properties preclinically, with promise of a better therapeutic index in the clinic.
We have previously shown that STRO-002 has potent efficacy in preclinical tumor models of ovarian and endometrial cancer. In this poster, we describe how STRO-002 demonstrates immune-modulating properties and potentiates PD-L1 blockade.
Several classes of cytotoxins have been shown to elicit immunogenic cell death resulting in increased sensitivity to immunomodulatory agents and our study aimed to evaluate immunogenic cell death as a component of the mechanism of action of STRO-002. We show here that treatment with STRO-002 (or it’s active catabolite, the hemiasterlin warhead alone) induced hallmarks of Immunogenic Cell Death in FolRα expressing tumor cell lines as well as monocyte activation in co-culture assays with PBMC. The STRO-002 responses were dependent on the cellular expression of FolRα, demonstrating that they were target-antigen specific.
Anti-tumor activity of STRO-002 was evaluated in combination with the PD1 pathway blocker, Avelumab, an anti-human PD-L1 monoclonal antibody that also blocks mouse PD-L1. We were able to study the combined effect of the two agents using a human FolRα expressing mouse MC38 tumor model in immune-competent mice. Combination treatment with a single dose of STRO-002 and avelumab administered simultaneously resulted in 6 out of 8 animals having complete tumor regression, considerably better than the only 1-2 of 8 Complete Responses in animals that received either single agent alone. When animals with Complete Responses were re-challenged with a second inoculation of the MC38- cells, 100% of the mice were resistant and no tumor growth was observed for up to 60 days in the absence of additional therapy. The resistance to tumor re-challenge suggests that a single dose of STRO-002 combined with Avelumab could provide a protective anti-tumor immune response. In line with the proposed mechanism of Immunogenic Cell Death, ImmunoHistoChemistry analysis showed an increase in the recruitment of CD8+ T cells in tumors treated with the combination of STRO-002 and Avelumab that was absent in mice treated with either single agent alone. In addition, STRO-002 induced upregulation of PD-1 expression and this may have further sensitized the MC38 tumors to the combination treatment.
Taken together, our data shows that STRO-002’s mechanism of action drives immuno-modulatory responses that can cause complete tumor regression and induce adaptive, protective anti-tumor immunity in concert with PD-1 pathway blockade. The safety and preliminary activity of STRO-002 is currently being assessed in a phase I clinical study in ovarian cancer that was initiated in March 2019. Our preclinical data supports clinical evaluation of STRO-002 in combination with anti-PD1 or anti-PD-L1 agents and supports the premise that combinations of STRO-002 and check point inhibitors may drive significant clinical benefitin tumors that are refractory to check point inhibitor monotherapy.
Finally, my thanks go to my co-authors and the many other Sutro colleagues that have enabled our unique platform.