Multispecific Polypeptides for 5T4 and 4-1BB Binding
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Solution Overview
Problem
Current therapeutics targeting 5T4 and 4-1BB face challenges such as liver and skin toxicities, and there is a need for safer and more effective methods to activate 4-1BB for cancer treatment, as well as a lack of FDA-approved therapeutics specifically binding to 5T4.
Innovation Solution
Development of multispecific polypeptides that specifically bind to both 5T4 and 4-1BB, comprising immunoglobulin heavy and light chain variable regions with specific amino acid sequences, designed to enhance effector cell activation and cytotoxicity by cross-linking 5T4-expressing cells and 4-1BB on effector cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapeutics targeting 5T4 and 4-1BB are used, then cancer treatment is achieved, but liver and skin toxicities occur
Solution Approach 1:
The therapeutic is divided into two separate binding domains: a first binding domain that specifically binds to 5T4 on tumor cells, and a second binding domain that specifically binds to 4-1BB on effector cells. This segmentation allows each domain to be optimized for its specific target, reducing off-target effects and toxicities while maintaining treatment effectiveness.
Solution Approach 2:
Each binding domain is designed with specific amino acid sequences tailored to recognize and bind to its particular target antigen with high specificity. The first binding domain has amino acid sequences optimized for 5T4 recognition, while the second binding domain has sequences optimized for 4-1BB recognition, ensuring localized and specific therapeutic action.
2Productivity
If 4-1BB activation is used for cancer treatment, then effector cell activation is enhanced, but adverse events and toxicities increase
Solution Approach 1:
The multispecific polypeptide acts as an intermediary that bridges tumor cells (via 5T4 binding) and effector cells (via 4-1BB binding). This intermediary function enables selective activation of effector cells against tumor cells while controlling the magnitude and specificity of the immune response, thereby reducing adverse events.
Solution Approach 2:
The invention modifies the binding parameters of the therapeutic by using specific amino acid sequences in each binding domain. The first binding domain uses sequences with high affinity for 5T4, while the second binding domain uses sequences with appropriate affinity for 4-1BB, optimizing the activation parameters to enhance effector cell function while minimizing toxicity.
3Productivity
If multisspecific polypeptides binding to both 5T4 and 4-1BB are developed, then effector cell activation and cytotoxicity are enhanced, but device complexity increases
Solution Approach 1:
The invention merges two separate binding functions into a single multispecific polypeptide molecule. The first binding domain and second binding domain are combined in one polypeptide chain, allowing simultaneous binding to 5T4 on tumor cells and 4-1BB on effector cells, thereby enhancing cytotoxicity while managing structural complexity through integrated design.
Solution Approach 2:
The multisspecific polypeptide performs multiple functions: it binds to 5T4 on tumor cells, binds to 4-1BB on effector cells, and mediates effector cell activation and cytotoxicity. This multi-functionality is achieved through the integration of two specialized binding domains in a single molecular entity, optimizing therapeutic effectiveness.
Data Source
AI summary
The present disclosure relates to protein molecules that specifically bind to 5T4 and/or 4-1BB. The molecules may have at least one humanized 5T4-binding or 4-1BB-binding domain. Such molecules are useful for the treatment of cancer. The protein molecule binding to 5T4 or 4-1BB may have a second binding domain that binds to another target. The molecules may bind both 5T4-expressing cells and a cell-surface molecule expressed by an effector cell to enhance effector cell activation, proliferation, survival and/or effector-cell mediated cytotoxicity. The disclosure also provides pharmaceutical compositions comprising the 5T4-binding or 4-1BB-binding polypeptide or protein molecules, nucleic acid molecules encoding these polypeptides and methods of making and using these molecules.