Bispecific T-Cell Engagers Therapies in Solid Tumors: Focusing on Prostate Cancer

Simão, Diana; Zarrabi, Kevin; Mendes, José; Luz, Ricardo da; García, Jorge A.; Kelly, William Kevin; Barata, Pedro C.

doi:10.3390/cancers15051412

Cited by 20 publications

(10 citation statements)

References 108 publications

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“…It shall be noted that several PSMA-targeting BiTEs, including AMG-212, AMG-160, MOR-209, CC-1, and JNJ-081, have been tested in preclinical settings and/or entered clinical trials. − While these drugs showed positive effects in targeting PCa, (pre)clinical data also highlighted challenges and adverse effects that need to be addressed and mitigated to develop safe and efficacious immunotherapeutics against PCa. For example, the short half-life of BiTE constructs limits their overall therapeutic efficacy, requiring engineering of constructs with prolonged serum half-lives and increased stability that could be achieved, e.g., by incorporating an albumin-binding domain, Fc antibody fragments, or pasylation sequences. − Administration of BiTEs is also often accompanied by the development of anti-drug antibody (ADA) responses, leading to lower efficacy and unacceptable systemic toxicity.…”

Section: Discussionmentioning

confidence: 99%

Targeting Prostate Cancer Using Bispecific T-Cell Engagers against Prostate-Specific Membrane Antigen

Das,

Ptacek,

Havlinova

et al. 2023

ACS Pharmacol. Transl. Sci.

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Prostate cancer (PCa) tops the list of cancer-related deaths in men worldwide. Prostate-specific membrane antigen (PSMA) is currently the most prominent PCa biomarker, as its expression levels are robustly enhanced in advanced stages of PCa. As such, PSMA targeting is highly efficient in PCa imaging as well as therapy. For the latter, PSMA-positive tumors can be targeted directly by using small molecules or macromolecules with cytotoxic payloads or indirectly by engaging the immune system of the host. Here we describe the engineering, expression, purification, and biological characterization of bispecific T-cell engagers (BiTEs) that enable targeting PSMA-positive tumor cells by host T lymphocytes. To this end, we designed the 5D3-αCD3 BiTE as a fusion of single-chain fragments of PSMA-specific 5D3 and anti-CD3 antibodies. Detailed characterization of BiTE was performed by a combination of size-exclusion chromatography, differential scanning fluorimetry, and flow cytometry. Expressed in insect cells, BiTE was purified in monodisperse form and retained thermal stability of both functional parts and nanomolar affinity to respective antigens. 5D3-αCD3's efficiency and specificity were further evaluated in vitro using PCa-derived cell lines together with peripheral blood mononuclear cells isolated from human blood. Our data revealed that T-cells engaged via 5D3-αCD3 can efficiently eliminate tumor cells already at an 8 pM BiTE concentration in a highly specific manner. Overall, the data presented here demonstrate that the 5D3-αCD3 BiTE is a candidate molecule of high potential for further development of immunotherapeutic modalities for PCa treatment.

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Section: Discussionmentioning

confidence: 99%

Targeting Prostate Cancer Using Bispecific T-Cell Engagers against Prostate-Specific Membrane Antigen

Das,

Ptacek,

Havlinova

et al. 2023

ACS Pharmacol. Transl. Sci.

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“…There are over 45 registered clinical trials of T-cell engagers targeting a variety of other solid tumor-associated antigens. While most have preliminary evidence of efficacy, important limitations are the narrow therapeutic index due to on-target off-tumor toxic effects and the short half-life requiring continuous infusion for days [ 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ].…”

Section: Bispecific Antibodiesmentioning

confidence: 99%

Bispecific T-Cell Engagers and Chimeric Antigen Receptor T-Cell Therapies in Glioblastoma: An Update

Alsajjan,

Mason

2023

Current Oncology

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Glioblastoma is the most common malignant primary brain tumor in adults. The prognosis is extremely poor even with standard treatment of maximal safe resection, radiotherapy, and chemotherapy. Recurrence is inevitable within months, and treatment options are very limited. Chimeric antigen receptor T-cell therapy (CART) and bispecific T-cell engagers (TCEs) are two emerging immunotherapies that can redirect T-cells for tumor-specific killing and have shown remarkable success in hematological malignancies and been under extensive study for application in glioblastoma. While there have been multiple clinical trials showing preliminary evidence of safety and efficacy for CART, bispecific TCEs are still in the early stages of clinical testing, with preclinical studies showing very promising results. However, there are multiple shared challenges that need to be addressed in the future, including the route of delivery, antigen escape, the immunosuppressive tumor microenvironment, and toxicity resulting from the limited choice of tumor-specific antigens. Efforts are underway to optimize the design of both these treatments and find the ideal combination therapy to overcome these challenges. In this review, we describe the work that has been performed as well as novel approaches in glioblastoma and in other solid tumors that may be applicable in the future.

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“… 12 , 13 In recent years, T-cell engager immunotherapies including chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engager (BiTE) therapies have emerged as promising modalities for the treatment a variety of hematologic malignancies, and hold promise of demonstrating efficacy in patients with PCa. 14 , 15 In this review, we highlight novel BiTE therapies under development for patients with PCa, focusing on early reports of their efficacy and tolerability. We aim to share our perspective on BiTE successes and pitfalls, as well as to reflect on how BiTE therapies will shape the future of the treatment of mCRPC.…”

Section: Introductionmentioning

confidence: 99%

T-Cell redirecting bispecific antibodies: a review of a novel class of immuno-oncology for advanced prostate cancer

Palecki,

Bhasin,

Bernstein

et al. 2024

Cancer Biology & Therapy

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Novel T-cell immunotherapies such as bispecific T-cell engagers (BiTEs) are emerging as promising therapeutic strategies for prostate cancer. BiTEs are engineered bispecific antibodies containing two distinct binding domains that allow for concurrent binding to tumor-associated antigens (TAAs) as well as immune effector cells, thus promoting an immune response against cancer cells. Prostate cancer is rich in tumor associated antigens such as, but not limited to, PSMA, PSCA, hK2, and STEAP1 and there is strong biologic rationale for employment of T-cell redirecting BiTEs within the prostate cancer disease space. Early generation BiTE constructs employed in clinical study have demonstrated meaningful antitumor activity, but challenges related to drug delivery, immunogenicity, and treatment-associated adverse effects limited their success. The ongoing development of novel BiTE constructs continues to address these barriers and to yield promising results in terms of efficacy and safety. This review will highlight some of most recent developments of BiTE therapies for patients with advanced prostate cancer and the evolving data surrounding BiTE constructs undergoing clinical evaluation.

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Bispecific T-Cell Engagers Therapies in Solid Tumors: Focusing on Prostate Cancer

Cited by 20 publications

References 108 publications

Targeting Prostate Cancer Using Bispecific T-Cell Engagers against Prostate-Specific Membrane Antigen

Targeting Prostate Cancer Using Bispecific T-Cell Engagers against Prostate-Specific Membrane Antigen

Bispecific T-Cell Engagers and Chimeric Antigen Receptor T-Cell Therapies in Glioblastoma: An Update

T-Cell redirecting bispecific antibodies: a review of a novel class of immuno-oncology for advanced prostate cancer

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