Phase 2, Multi-Center, Randomized, Open-Label Trial of BDC-1001 as a Single Agent and in Combination With Pertuzumab in Subjects With HER2-Positive Metastatic Breast Cancer Previously Treated With Trastuzumab Deruxtecan

This is an open-label, Phase 2 study to evaluate preliminary anti-tumor activity, safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of BDC-1001 administered as a single agent and in combination with pertuzumab in subjects with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) previously treated with trastuzumab deruxtecan (Enhertu®).

Start Date30 Nov 2023

Sponsor / Collaborator

Bolt Biotherapeutics, Inc.

[+1]

NCT04278144

/ Active, not recruitingPhase 1/2

Phase 1/2 Study of BDC-1001 as a Single Agent and in Combination With Nivolumab in Patients With Advanced HER2-Expressing Solid Tumors

A first-in-human study using BDC-1001 as a single agent and in combination with nivolumab in HER2 expressing advanced malignancies

Start Date24 Feb 2020

Sponsor / Collaborator

Bolt Biotherapeutics, Inc.

[+1]

100 Clinical Results associated with HER2 x TLR7

100 Translational Medicine associated with HER2 x TLR7

0 Patents (Medical) associated with HER2 x TLR7

Literatures (Medical) associated with HER2 x TLR7

04 Nov 2024·Molecular Cancer Therapeutics

A DXd/TLR7-Agonist Dual-Conjugate Anti-HER2 ADC Exerts Robust Antitumor Activity Through Tumor Cell Killing and Immune Activation

Article

Author: Zeng, Qingzhong ; Wang, Xiyuan ; Geng, Meiyu ; Yue, Hangtian ; Li, Xiyuan ; Xu, Hui ; Yang, Biyu ; Ma, Lanping ; Li, Han ; Xie, Zuoquan ; Meng, Tao ; Zhang, Deqiang

AbstractThe emergence of trastuzumab deruxtecan (T-DXd), a new-generation antibody–drug conjugate (ADC), has profoundly altered the therapeutic paradigm for HER2-positive solid tumors, demonstrating remarkable clinical benefits. However, the combined outcomes of T-DXd with immunotherapy agents remain ambiguous. In this study, we introduce Tras-DXd-MTL1, an innovative HER2 targeting ADC that integrates the topoisomerase inhibitor DXd and a toll like receptor 7 (TLR7) agonist MTT5, linked to trastuzumab via a GGFG tetrapeptide linker. Mechanistically, Tras-DXd-MTL1 retains the DNA-damaging and cell-killing properties of topoisomerase inhibitors while simultaneously enhancing the immune response within the tumor microenvironment. This is achieved by promoting immune cell infiltration and activating dendritic cells and CD8+T cells via MTT5. In vivo evaluation of Tras-DXd-MTL1’s antitumor potency revealed a notably superior performance compared with the T-DXd (Tras-DXd) or Tras-MTL1 in immunocompetent mice with trastuzumab-resistant EMT6-HER2 tumor and immunodeficient mice with JIMT-1 tumor. This improved efficacy is primarily attributed to its dual functions of immune stimulation and cytotoxicity. Our findings highlight the potential of incorporating immunostimulatory agents into ADC design to potentiate antitumor effects and establish durable immune memory, thereby reducing tumor recurrence risks. Therefore, our study offers a novel strategy for the design of immune-activating ADCs and provides a potential approach for targeting solid tumors with different levels of HER2 expression.

15 Jul 2023·Bioorganic & medicinal chemistry letters

Generation and structure-activity relationships of novel imidazo-thienopyridine based TLR7 agonists: application as payloads for immunostimulatory antibody drug-conjugates.

Article

Author: Duan, Renee ; Guedia, Joy ; Barnscher, Stuart D ; Lasalle, Manuel ; Mendez-Campos, José ; Garnett, Graham A E ; Lawn, Samuel ; Winters, Geoffrey C ; Hirkala-Schaefer, Truman ; Petersen, Mark E ; Brant, Michael G

Pairing immunostimulatory small molecules with the targeting capability of an antibody has emerged as a novel therapeutic modality with the potential to treat a variety of solid tumors. A series of compounds based on an imidazo-thienopyridine scaffold were synthesized and tested for their ability to agonize the innate immune sensors toll-like receptor 7 and 8 (TLR7/8). Structure-activity relationship (SAR) studies revealed that certain simple amino-substituents could enable TLR7 agonism at low nanomolar concentrations. Drug-linkers containing either payload 1 or 20h were conjugated to the HER2-targeting antibody trastuzumab at the interchain disulfide cysteine residues using a cleavable valine-citrulline dipeptide linker and stochastic thiol-maleimide chemistry. In vitro, these immune-stimulating antibody drug-conjugates (ADCs) were found to induce cytokine release in a murine splenocyte assay when co-cultured with the HER2-high NCI-N87 cancer cell line. In vivo, tumor regression was observed with a single dose in an NCI-N87 gastric carcinoma xenograft model in BALB/c nude mice.

02 Dec 2022·Cancer Immunology Research

Preclinical Characterization and Phase I Study of an Anti–HER2-TLR7 Immune-Stimulator Antibody Conjugate in Patients with HER2+ Malignancies

Article

Author: Siena, Salvatore ; Cortez, Alex ; Lee, Lang Ho ; Mahling, Ping C. ; Iaconis, Lori A. ; Ajani, Jaffer A. ; Kuboki, Yasutoshi ; Amatu, Alessio ; Pelletier, Marc R. ; Schoenfeld, Heidi A. ; Subramanian, Kulandayan ; Doi, Toshihiko ; Han, Sae-Won ; Dranoff, Glenn ; Askoxylakis, Vasileios ; Cellitti, Susan E. ; Choi, Sarah M. ; Janku, Filip

AbstractImmune-stimulator antibody conjugates (ISAC) combining tumor-targeting monoclonal antibodies with immunostimulatory agents allow targeted delivery of immune activators into tumors. NJH395 is a novel, first-in-class ISAC comprising a Toll-like receptor 7 (TLR7) agonist conjugated to an anti-HER2 antibody via a noncleavable linker payload. Preclinical characterization showed ISAC-mediated activation of myeloid cells in the presence of antigen-expressing cancer cells, with antigen targeting and TLR7 agonism contributing to antitumor activity. Safety, efficacy, immunogenicity, pharmacokinetics, and pharmacodynamics were investigated in a phase I, multicenter, open-label study in patients with HER2+ non-breast advanced malignancies (NCT03696771). Data from 18 patients enrolled in single ascending dose escalation demonstrated delivery of the TLR7-agonist payload in HER2+ tumor cells and induction of type I IFN responses, which correlated with immune modulation in the tumor microenvironment. Cytokine release syndrome was a common, but manageable, drug-related adverse event. Antidrug antibodies and neuroinflammation at high doses represented significant clinical challenges. Data provide proof-of-mechanism and critical insights for novel immunotherapies.

News (Medical) associated with HER2 x TLR7

15 May 2024

·www.biopharmadive.com

Bolt Biotherapeutics to lay off staff, abandon lead ADC candidate

San Francisco-based Bolt Biotherapeutics on Tuesday said it is ending development of its lead cancer drug, laying off half its staff and changing up its leadership.Alongside announcing first quarter earnings, the biotechnology company revealed it will no longer advance its antibody-drug conjugate trastuzumab imbotolimod, or BDC-1001, after concluding the program was unlikely to meet its high bar for advancement.Instead, the company will focus on two earlier-stage candidates: BDC-3042, an agonist antibody now in Phase 1 testing, and BDC-4182, currently in preclinical evaluation. The latter is a product of Bolts immune-stimulating antibody conjugate, or ISAC, platform, which is meant to trigger anti-tumor immune responses. Its aimed at a protein called Claudin 18.2 thats becoming an increasingly popular target among cancer drug developers.The companys ISAC research will continue to be supported by collaborations with Genmab and Toray. The former is funding up to three ISAC candidates through early-stage development, while the latter is funding one ISAC candidate through Phase 1 testing.In a client note downgrading her rating on Bolts stock, Leerink Partners analyst Daina Graybosch described the two newly prioritized programs as at the high end of risk, given novelty and early nature of development. While Graybosch expressed confidence in the promise of Bolts platform, she expects multiple surprises and restarts to come.Bolt is laying off 50% of its workforce, or approximately 50 people, as part of its pipeline reprioritization. The company expects the cuts to extend its cash runway into the second half of 2026.Additionally, Willie Quinn, who was previously Bolts chief financial officer, has replaced Randal Schatzman as CEO. Chief Business Officer Grant Yonehiro will be promoted to chief operating officer, and Chief Medical Offier Edith Perez will move into an advisory role.Shares for Bolt fell around 34% in Wednesday morning trading. The company is now worth about $33 million. '

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