‘Building a better ADC’
SOUTH SAN FRANCISCO, Calif.—Sutro Biopharma has been busy, rolling out a pair of new antibody-drug conjugates (ADCs) targeting ovarian cancer, lymphoma and multiple myeloma. Clinical trials have recently begun on ADC STRO-001, which targets CD74, a protein highly expressed in B cell malignancies such as myeloma and lymphoma. Likewise, ADC STRO-002 targets the folate receptor alpha, a cell-surface protein highly expressed in ovarian cancer, and has shown effectiveness in targeting solid tumors while demonstrating a strong safety profile.
ADCs represent an innovative cancer therapy that allows for the targeting of diseased cells while sparing healthy tissue. ADCs effectively join an antibody with cytotoxic anticancer drugs that specifically target certain tumor markers. While the potential for ADCs is vast, first-generation ADCs are linked non-selectively to antibodies, resulting in a heterogenous mixture of ADCs. This approach leads to suboptimal safety and efficacy properties, and makes optimization of the biological, physical and pharmacological properties of an ADC challenging.
Sutro has developed a unique cell-free expression technology that allows for the development of next-generation ADCs by incorporating non-natural amino acids (nnAA) within the antibody structure. The site-specific incorporation of nnAAs generates a site for controlled and stable attachment of the drug, allowing for more homogenous ADCs, which can be delivered with more precise ratios. Sutro uses its XpressCF technology to design and develop therapeutic proteins that contain one or more non-natural amino acids in addition to natural amino acids and to discover drugs that feature such proteins.
“The XpressCF+ platform allows the incorporation of non-natural amino acids into specific positions on the generated antibody, allowing for site-specific conjugation of cytotoxins with a linker and warhead to enable consistent, stable, pinpoint placement of STRO-002’s toxic payload, resulting in highly efficient delivery of cytotoxin to tumor cells,” Sutro’s chief scientific officer, Dr. Trevor Hallam, said in a press release. “By contrast, earlier generations of ADCs result in products with unpredictable pharmacologic properties that result in relatively suboptimal stability, compromised efficacy and poor tolerability for patients.”
For the STRO-001 clinical trial now underway, Sutro expects to enroll up to 220 patients in the open-label, multicenter, dose escalation and dose expansion study across approximately 50 sites in the United States and Europe. The primary outcome measures are safety and tolerability of STRO-001 in dose escalation and preliminary antitumor activity in dose expansion.
“Based on preclinical research findings, we are hopeful that this Phase 1 study will demonstrate that STRO-001 has preliminary activity in patients with multiple myeloma and non-Hodgkin’s lymphoma with progressive disease following standard of care therapies,” said Sutro CEO Bill Newell. “Ultimately, we aim to demonstrate that STRO-001 can be an important new treatment option to address an unmet need for targeted therapies for patients who have multiple myeloma and non-Hodgkin’s lymphoma.”
Likewise, STRO-002 has shown potent in-vitro cytotoxicity in ovarian cancer cell lines and significantly inhibited tumor growth in multiple ovarian cancer xenograft models. Safety testing in non-human primates showed it to be well tolerated. While some ADCs have shown ocular toxicity, a common side effect that requires limiting one’s dose, STRO-002 was well tolerated at clinically relevant doses in non-human primates. Sutro will file an investigational new drug application for STRO-002 and hopes to initiate a Phase 1 clinical trial by the end of the year.
“While ocular toxicity has traditionally been dose-limiting in ADCs targeting cancer, Sutro’s research suggests that oncologists might be able to achieve clinically effective doses of STRO-002 before the development of ocular toxicity and other major side effects, because the drug directly targets cancer cells so efficiently,” explained Dr. Wendel Naumann, a professor and associate director at the Levine Cancer Institute in Charlotte, N.C.
STRO-001 and STRO-002 are two in a host of novel therapies in the pipeline at Sutro and its partners. There are a number of ADCs, bispecific antibodies and antibody-based therapeutics that target immune-oncology pathways in the investigational new drug stage.
“We are building a better ADC,” said Dr. Arturo Molina, a medical oncologist and Sutro’s chief medical officer. “[STRO-001 and STRO-002] are more milestones in Sutro’s evolution from a platform company to a clinical-stage company with products entering the clinic and in late preclinical testing.”