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Published on: May 12, 2023
Novel tetravalent bispecific antibody, PSMA/TRAIL‑R2 REGULGENT™, induces selective tumor cell apoptosis without
Makoto Nakayama1, Sayaka Takagi-Maeda2, Yusuke Machino2
1Core Research Laboratories, Bio‑Pharmaceutical Center, Research Division, Kyowa Kirin Co., Ltd., Tokyo 194‑8533, Japan.
Abstract:
Tumor necrosis factor‑related apoptosis‑inducing ligand‑receptor 2 (TRAIL‑R2) can induce apoptosis in various tumors through the oligomerization of TRAIL. Several TRAIL‑R2 agonistic monoclonal antibodies have been tested in clinical trials but have failed owing to a lack of efficacy or severe hepatotoxicity. Although bispecific constructs have been developed to improve TRAIL‑R2 targeting and enhance efficacy against tumors while reducing adverse effects on hepatocytes, the risk of hepatotoxicity still persists. The present study used a TRAIL‑R2 antibody, E11, that does not trigger apoptosis in the absence of crosslinking and constructed a novel tetravalent bispecific IgG4‑based antibody, REGULGENT™, comprised of E11 and a clone that binds to prostate‑specific membrane antigen (PSMA), a specific marker for prostate tumors. PSMA/TRAIL‑R2 REGULGENT™ selectively induced death in PSMA/TRAIL‑R2 double‑positive cells but not in TRAIL‑R2 single‑positive cells in vitro and in vivo. By contrast, a bivalent bispecific antibody did not result in tumor cell death, indicating that tetravalent bispecific antibodies have an important role in inducing tumor cell apoptosis by binding to TRAIL‑R2 in a bivalent manner. Moreover, the present study demonstrated, for the first time to the best of the authors' knowledge, that PSMA/TRAIL‑R2 REGULGENT™ is not hepatotoxic in vitro (primary human hepatocytes) or in vivo (chimeric human hepatocyte‑transplanted PXB mouse model). This finding suggests that tetravalent bispecific therapeutics such as REGULGENT™ can be promising therapeutic agents for TRAIL‑R2‑positive tumors by exerting tumor‑specific activity while avoiding toxicity.
Insights
A novel tetravalent bispecific antibody, REGULGENT™, targets both prostate-specific membrane antigen (PSMA) and tumor necrosis factor-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2). It selectively kills double-positive cancer cells without causing hepatotoxicity, offering a promising new cancer therapy.
Area of Science:
- Oncology
- Immunology
- Drug Development
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) pathway is a target for cancer therapy.
- Previous TRAIL-R2 agonistic antibodies faced challenges with efficacy and severe hepatotoxicity.
- Bispecific antibodies aim to improve targeting and reduce side effects, but hepatotoxicity risks remain.
Purpose of the Study:
- To develop a novel tetravalent bispecific antibody for enhanced tumor targeting and reduced toxicity.
- To evaluate the efficacy and safety of the PSMA/TRAIL-R2 REGULGENT™ bispecific antibody.
- To investigate the role of tetravalency in TRAIL-R2-mediated apoptosis induction.
Main Methods:
- Constructed a tetravalent bispecific IgG4-based antibody (REGULGENT™) combining E11 (TRAIL-R2 binder) and a prostate-specific membrane antigen (PSMA) binder.
- Assessed selective induction of cancer cell death in vitro and in vivo using PSMA/TRAIL-R2 double-positive cells.
- Evaluated hepatotoxicity in vitro using primary human hepatocytes and in vivo using a PXB mouse model.
Main Results:
- PSMA/TRAIL-R2 REGULGENT™ selectively induced apoptosis in PSMA/TRAIL-R2 double-positive cells, sparing single-positive cells.
- A bivalent bispecific antibody failed to induce tumor cell death, highlighting the importance of tetravalency.
- REGULGENT™ demonstrated no significant hepatotoxicity in vitro or in vivo models.
Conclusions:
- Tetravalent bispecific antibodies are crucial for effective TRAIL-R2-mediated tumor apoptosis.
- PSMA/TRAIL-R2 REGULGENT™ shows promising tumor-specific efficacy and a favorable safety profile.
- REGULGENT™ represents a potential new therapeutic strategy for TRAIL-R2-positive tumors, avoiding common toxicities.
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