STRO-001, an antibody-drug conjugate or ADC targeting the CD74 cell surface protein in hematologic B-cell malignancies, being developed by Sutro Biopharma, has shown to eradicate tumors in human xenograft models of non-Hodgkin lymphoma and multiple myeloma. Based on the available data, Sutro plans to evaluate STRO-001 for the treatment of non-Hodgkin lymphoma and multiple myeloma in a Phase I clinical trial planned for early 2018.
The research findings, which come as Sutro prepares to file an investigational new drug application (NDA) to begin the clinical testing, show that the investigational drug STRO-001 eliminated tumors or significantly delayed tumor growth in diffuse large B-cell lymphoma and mantle cell lymphoma xenograft models and prolonged survival in the disseminated Mino mantle cell lymphoma xenograft model compared to tumor models treated with vehicle, which developed advanced disease with palpable neck and abdominal tumors.
Sutra’s investigational ADC also suppressed tumor growth in a diffuse large B-cell lymphoma tumor model, SU-DHL-6, when administered with standard of care chemotherapy. In immunohistochemistry testing using the unconjugated antibody component of STRO-001 with a large number of human lymphoma tissue samples, researchers confirmed that CD74 is highly-expressed in diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma.
The data was presented during at the 14th International Conference on Malignant Lymphoma, June 14-16, 2017 in Lugano, Switzerland and at the 22nd Congress of the European Hematology Association, June 23, 2017 in Madrid, Spain.
Additionally, research on STRO-001 revealed potent antitumor activity in multiple myeloma xenograft models and potent in vitro cytotoxicity in multiple non-Hodgkin lymphoma cell lines.
Bioluminescence imaging with the luciferase MM.1S xenograft model showed that a single dose of Sutro’s ADC STRO-001 eradicated multiple myeloma at each post-treatment time point investigated, compared to animals treated with vehicle, which experienced diffuse replacement of bone marrow with malignant myeloma. The imaging enabled researchers to quantify tumor growth in response to treatment and vehicle more precisely than in earlier xenograft tumor models designed to assess survival.
“These results are the clearest, most compelling evidence that STRO-001 performs effectively in multiple malignant B-cell lines and xenograft tumor models,” Sutro CEO Bill Newell remarked.
Preventing the ‘Bystander Effect’
“STRO-001 was developed with Sutro’s proprietary cell-free protein synthesis and site-specific conjugation platforms, which facilitate multiple rounds of antibody and ADC optimization,” noted Arturo Molina, MD, MS, a medical oncologist and Sutro’s Chief Medical Officer.
“Sutro’s Xpress CF+™ platform enables us to produce novel ADCs that directly target cancer cells while minimizing a toxic ‘bystander effect‘ on adjacent healthy cells,” he added.
The chemotherapy-induced bystander effect perpetuates the cellular damage from drug-exposed cells to the unexposed ones and is being explored to improve the therapeutic response. However, the tumor microenvironment consists of a heterogeneous mass of malignant as well as nonmalignant cells. The nonmalignant cells include endothelial, fibroblast and immune cells that establish multitude of interactions among themselves and also with malignant cells. Hence, a toxic ‘bystander effect‘ on adjacent healthy – nonmalignant – cells may not necessarily be desirable.
Unlike conventional cell-based expression systems, Sutro’s technology isolates a cell’s protein production machinery into a cell-free extract, Xtract CF™, which includes all the necessary biochemical components for energy production, transcription and translation to generate aglycosylated homogeneous antibodies. The Xpress CF+™ platform allows the incorporation of non-natural amino acids into specific positions of the generated antibody, allowing for site-specific conjugation of cytotoxins and the creation of homogeneous ADCs. This process is capable of producing homogeneous proteins at large scale within 24 hours, unconstrained by cellular structures and their limitations.
Sutro’s manufacturing facility in San Carlos, California, is built to maximize the speed and efficiency of cell-free extract and protein production. The cell-free extract is manufactured by a multi-day continuous process producing extract for large scale Xpress CF™ and Xpress CF+™ reactions.