Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release

Autor: Laura Davison, Suhasini Iyer, Roland Buelow, Rong Deng, Alec Starzinski, Wenchao Sun, Preethi Sankaran, Serena S. Kwek, Starlynn Clarke, Yuping Li, Nathan D. Trinklein, Lawrence Fong, Aarti Balasubramani, Pranjali Dalvi, Ute Schellenberger, Ben Buelow, Wim Van Schooten, Giulia Castello, Duy Pham, Andrew Boudreau, Harshad Ugamraj, Katherine E. Harris, Kevin Dang
Rok vydání: 2021
Předmět:
Glutamate Carboxypeptidase II
Male
0301 basic medicine
Cancer Research
CD3 Complex
medicine.medical_treatment
prostatic neoplasms
Mice
Prostate cancer
0302 clinical medicine
Antibodies
Bispecific
Immunology and Allergy
Medicine
Cytotoxic T cell
RC254-282
T-lymphocytes
Clinical/Translational Cancer Immunotherapy
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Prostatic Neoplasms
Castration-Resistant
Cytokine release syndrome
medicine.anatomical_structure
Cytokine
Oncology
030220 oncology & carcinogenesis
Antigens
Surface
PC-3 Cells
Molecular Medicine
immunotherapy
Rats
Transgenic
Cell Survival
Regulatory T cell
T cell
Immunology
03 medical and health sciences
Cell Line
Tumor
Animals
Humans
Cell Proliferation
Pharmacology
Dose-Response Relationship
Drug
business.industry
Immunotherapy
medicine.disease
Xenograft Model Antitumor Assays
cytokines
Rats
Macaca fascicularis
030104 developmental biology
Immunoglobulin G
Cancer research
business
Ex vivo
Zdroj: Journal for Immunotherapy of Cancer
Journal for ImmunoTherapy of Cancer, Vol 9, Iss 6 (2021)
ISSN: 2051-1426
Popis: BackgroundTherapeutic options currently available for metastatic castration-resistant prostate cancer (mCRPC) do not extend median overall survival >6 months. Therefore, the development of novel and effective therapies for mCRPC represents an urgent medical need. T cell engagers (TCEs) have emerged as a promising approach for the treatment of mCRPC due to their targeted mechanism of action. However, challenges remain in the clinic due to the limited efficacy of TCEs observed thus far in solid tumors as well as the toxicities associated with cytokine release syndrome (CRS) due to the usage of high-affinity anti-CD3 moieties such as OKT3.MethodsUsing genetically engineered transgenic rats (UniRat and OmniFlic) that express fully human IgG antibodies together with an NGS-based antibody discovery pipeline, we developed TNB-585, an anti-CD3xPSMA TCE for the treatment of mCRPC. TNB-585 pairs a tumor-targeting anti-PSMA arm together with a unique, low-affinity anti-CD3 arm in bispecific format. We tested TNB-585 in T cell-redirected cytotoxicity assays against PSMA+ tumor cells in both two-dimensional (2D) cultures and three-dimensional (3D) spheroids as well as against patient-derived prostate tumor cells. Cytokines were measured in culture supernatants to assess the ability of TNB-585 to induce tumor killing with low cytokine release. TNB-585-mediated T cell activation, proliferation, and cytotoxic granule formation were measured to investigate the mechanism of action. Additionally, TNB-585 efficacy was evaluated in vivo against C4-2 tumor-bearing NCG mice.ResultsIn vitro, TNB-585 induced activation and proliferation of human T cells resulting in the killing of PSMA+ prostate tumor cells in both 2D cultures and 3D spheroids with minimal cytokine release and reduced regulatory T cell activation compared with a positive control antibody that contains the same anti-PSMA arm but a higher affinity anti-CD3 arm (comparable with OKT3). In addition, TNB-585 demonstrated potent efficacy against patient-derived prostate tumors ex vivo and induced immune cell infiltration and dose-dependent tumor regression in vivo.ConclusionsOur data suggest that TNB-585, with its low-affinity anti-CD3, may be efficacious while inducing a lower incidence and severity of CRS in patients with prostate cancer compared with TCEs that incorporate high-affinity anti-CD3 domains.
Databáze: OpenAIRE
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