Multimeric CD40L-4-1BBL Bispecific Proteins for TIL Expansion
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Solution Overview
Problem
Existing CD40 agonists in cancer immunotherapy have moderate antitumor effects and are associated with adverse events such as cytokine storms and hepatotoxicity, necessitating improved efficacy and safety.
Innovation Solution
Development of multimeric costimulatory agonists comprising CD40 and 4-1BB constructs, including specific CD40L monomers and 4-1BBL, connected via leucine zipper, FOLDON motif, or IgG2A Fc domain, forming trimers or tetramers to enhance immune activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD40 agonists are used for cancer immunotherapy, then antitumor effects are observed, but the effects are moderate and adverse events occur
Solution Approach 1:
The patent combines CD40 agonist and 4-1BB agonist into a single bispecific protein molecule, creating a dual-costimulation therapy that simultaneously activates two immune pathways. This merging approach enhances antitumor efficacy while allowing for controlled dosing of both activities through a single agent, potentially reducing adverse events associated with separate administrations.
Solution Approach 2:
The bispecific protein is divided into distinct functional domains: a CD40-binding domain and a 4-1BB-binding domain, each capable of independent interaction with their respective targets. This segmentation allows the molecule to engage multiple immune receptors simultaneously, amplifying the immune response while maintaining structural organization that can be optimized for reduced toxicity.
2Reliability
If multimeric constructs are formed to enhance immune activation, then TIL expansion is improved, but molecular complexity increases
Solution Approach 1:
The bisspecific protein employs nested domain structures where the CD40L and 4-1BBL functional domains are embedded within a multimeric framework formed by Fc regions or trimerization motifs. This nesting allows complex multimeric structures to self-assemble from simpler modular components, enhancing immune activation through increased valency while simplifying production and characterization.
Solution Approach 2:
The patent utilizes universal multimerization strategies such as Fc domains from IgG antibodies or standardized trimerization motifs that can be applied to both the CD40L and 4-1BBL portions of the bispecific protein. These universal elements provide predictable self-assembly behavior and controlled multimer formation, reducing the need for complex, protein-specific engineering while achieving enhanced immune activation.
Data Source
AI summary
In one aspect, disclosed herein are novel multimeric costimulatory agonistic constructs comprising said monomers for expanding tumor infiltrating lymphocytes (TILs) in vitro or ex vivo said methods comprising obtaining TILs and culturing the TILs in media comprising one or more multimeric costimulatory agonists.