On April 10, 2021 Bolt Biotherapeutics, Inc. (Nasdaq: BOLT), a clinical-stage biotechnology company pioneering a new class of immuno-oncology agents that combine the targeting precision of antibodies with the power of both the innate and adaptive immune systems, reported that an online oral presentation with live Q&A and a Trial in Progress poster presentation for lead agent BDC-1001 are being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 being held virtually from April 10-15th (Press release, Bolt Biotherapeutics, APR 10, 2021, View Source [SID1234618697]).
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The oral presentation explores immunosuppression mediated by various cells in the tumor microenvironment (TME), as well as the tumor-supportive nature of antigen presenting cells (APCs) in the TME in preclinical models. Reawakening these immunosuppressed APCs may result in a productive and durable anti-tumor immune response. Bolt is utilizing its Boltbody platform to create immune-stimulating antibody conjugates (ISACs), such as BDC-1001, that invoke this mechanism and provided complete tumor regression in preclinical tumor models.
"In murine models we have seen efficacy in a variety of tumors that are immunologically cold and well-established. Furthermore, consistent with our proposed mechanism of action for ISACs, we see evidence of increased myeloid and T cell infiltration in the tumor microenvironment mediated by BDC-1001 surrogate ISACs," said David Dornan, Ph.D., Chief Scientific Officer at Bolt Biotherapeutics. "We’re excited to share our rationale for selecting the linker-payload for BDC-1001 to optimize anti-tumor activity while minimizing the potential for the formation of anti-drug antibodies."
BDC-1001 is comprised of a tumor antigen-targeting monoclonal antibody (mAb), a trastuzumab biosimilar and an immune-stimulating agent (a TLR7/8 agonist) conjugated to each other with a non-cleavable linker. In a series of preclinical studies with BDC-1001, Bolt demonstrated the mechanism of action for their HER2-targeted ISAC. BDC-1001 surrogate was able to eliminate established, treatment-resistant tumors through the engagement of both innate and adaptive immunity. There were no adverse findings in toxicology studies of BDC-1001.
A Trial in Progress poster is also being presented by Manish R. Sharma, M.D. of START Midwest, a principal investigator in Bolt’s ongoing BDC-1001 Phase 1/2 trial. The poster details the design of the study: a four-part study with two dose-escalation parts and two dose-expansion parts. The study is evaluating BDC-1001 administered intravenously with or without an immune checkpoint inhibitor targeting PD-1 in up to 390 patients with HER2-expressing or HER2-amplified advanced or metastatic solid tumors. The dose escalation parts will evaluate sequential doses of BDC-1001 as a monotherapy or in combination with a PD-1 checkpoint inhibitor in a 3+3 design, with the ability to backfill up to an additional 12 patients in each dose cohort. The dose expansion parts will evaluate the recommended Phase 2 dose as monotherapy or in combination with a PD-1 checkpoint inhibitor in four cohorts of patients.
The primary objective of the dose escalation portion of the study is to assess safety as measured by the incidence of adverse events and serious adverse events; dose-limiting toxicities within the 3+3 design; and potential immune-related toxicities and determine the recommended phase 2 dose. Secondary objectives will evaluate pharmacokinetic parameters and pharmacodynamic biomarkers in tumor tissue and in peripheral blood associated with drug exposure. These exploratory studies will help reinforce the ISAC mechanism of action in humans and seek to identify biomarkers associated with BDC-1001 biological activity with or without an immune checkpoint inhibitor.
In January, Bolt presented a preliminary clinical update on the first 20 patients that showed early signs of clinical activity, including stable disease in several patients and a confirmed partial response by RECIST, and acceptable safety with all 20 patients completing their dose-limiting toxicity (DLT) evaluation period without DLTs or drug-related serious adverse events. Treatment-emergent adverse events deemed to be related to BDC-1001 have been mild or moderate in severity, including mild infusion-related reactions without interruption to dosing. Bolt expects to provide an update on the trial sometime in the second half of 2021.
About Bolt Biotherapeutics’ Immune Stimulating Antibody Conjugate (ISAC) Platform Technology
The Boltbody ISAC platform technology harnesses the ability of innate immune agonists to convert cold tumors into immunologically hot tumors, thereby illuminating tumors to the immune system and allowing them to be invaded by tumor killing cells. Boltbody ISACs have demonstrated the ability to eliminate tumors following systemic administration as monotherapy in preclinical models and have also led to the development of immunological memory, which is predicted to translate into more durable clinical responses for patients.
About the Ongoing BDC-1001 Phase 1/2 Study in Patients with HER2-Expressing Solid Tumors
The Phase 1/2, multi-center, open-label study is evaluating the safety, pharmacokinetics, pharmacodynamics and proof of mechanism of BDC-1001 in patients with HER2-expressing solid tumors. The first portion of the study includes a monotherapy dose-escalation phase in which cohorts of patients will receive ascending intravenous doses of BDC-1001 to determine the maximum tolerated dose and/or the recommended dose to advance into expansion cohorts and Phase 2 based on safety and tolerability. The second portion of the study is a dose expansion phase in which patients will receive BDC-1001 monotherapy to further evaluate the safety, tolerability and clinical antitumor activity of the recommended Phase 2 dose. Please refer to www.clinicaltrials.gov NCT04278144 for additional clinical trial information.