Bispecific TRAILR2-CDH17 Antibody for Selective Cancer Cell Apoptosis
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing TRAIL-receptor agonist molecules face challenges in selectively inducing apoptosis in cancer cells while minimizing toxicity to non-cancerous cells, particularly due to liver hepatocytes' susceptibility to TRAIL-induced apoptosis, and anchor targets like CEA, CRIPTO, FAP, MCSP, ROBO4, LTβR, and TENASCIN C pose risks of unwanted side effects or limited efficacy.
Innovation Solution
Development of a bispecific and tetravalent binding molecule that specifically targets TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) and cadherin-17 (CDH17) to promote apoptosis only in cells expressing both receptors, using a modified immunoglobulin molecule with antigen binding sites fused to the Ig molecule via peptide linkers, ensuring selective activation in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TRAIL-receptor agonist molecules are used to induce apoptosis in cancer cells, then anticancer activity is improved, but toxicity to non-cancerous cells (particularly liver hepatocytes) increases
Solution Approach 1:
The patent applies local quality by creating a bispecific antibody with differential binding characteristics: the antibody exhibits high affinity binding to TRAILR2 on cancer cells (expressing both CDH17 and TRAILR2) while showing reduced binding/activation on normal hepatocytes (expressing TRAILR2 but lacking CDH17). This spatially differentiated interaction pattern enables selective apoptosis induction in tumor cells while sparing healthy liver tissue, resolving the contradiction between anticancer efficacy and hepatotoxicity
Solution Approach 2:
The patent introduces cadherin-17 (CDH17) as an intermediary anchor target that mediates selective localization of the bispecific antibody to cancer cells. The antibody requires simultaneous binding to both CDH17 and TRAILR2 for effective apoptosis induction. Since CDH17 is overexpressed on cancer cell surfaces but absent on normal hepatocytes, it acts as a gatekeeping intermediary that directs the therapeutic effect specifically to tumor cells while protecting healthy tissue from off-target toxicity
2Productivity
If strongly activating TRAIL-receptor molecules are used, then apoptosis induction efficiency is improved, but side effects increase due to activation in non-cancerous cells
Solution Approach 1:
The bispecific antibody implements local quality by creating a context-dependent activation profile: strong apoptotic activation occurs locally at cancer cell sites where both CDH17 and TRAILR2 are co-expressed, while minimal activation occurs at normal tissue sites (particularly liver) where CDH17 is absent. This localized differential activation achieves high productivity in tumors while minimizing harmful side effects in healthy organs
Solution Approach 2:
The patent applies partial action by requiring dual binding events (CDH17 + TRAILR2) for full apoptotic activation. This two-step recognition mechanism ensures that the antibody exerts its full potent cytotoxic effect only under the specific condition of dual antigen co-expression on cancer cells, while exerting minimal or no effect on cells expressing only TRAILR2 without CDH17, thereby achieving selective potency with reduced off-target side effects
3Reliability
If anchor targets like CEA, CRIPTO, FAP, MCSP, ROBO4, LTβR, and TENASCIN C are used, then cancer cell targeting is improved, but unwanted side effects or limited efficacy occur
Solution Approach 1:
The patent employs a copy strategy by selecting cadherin-17 as an anchor target that replicates the ideal characteristics needed for selective cancer targeting: high overexpression on epithelial cancer cell surfaces, absence on normal hepatocytes, and stable membrane localization. This copying of optimal target properties from the ideal profile enables the bispecific antibody to achieve superior selective targeting of cancer cells while avoiding the side effects associated with previously used anchor targets
Data Source
Figure 1a
Figure 1b
Figure 2
AI summary
This invention relates to binding molecules that bind specifically to TNF-related apoptosis- inducing ligand receptor 2 (TRAILR2) and cadherin-17 (CDH17) and their use in medicine, pharmaceutical compositions comprising the same, and methods of using the same as agents for treatment and/or prevention of cancer.