WT1 Antigen-Binding Proteins for MHC Class II Cancer Targeting
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Solution Overview
Problem
Current T cell therapies targeting HLA-class I-restricted cancer cells face limitations in specificity and risk of on- and off-target toxicities, while HLA-class II-restricted approaches could offer broader applicability across diverse cancer patients but require effective targeting strategies.
Innovation Solution
Development of antigen-binding molecules, such as antibodies and chimeric antigen receptors, that specifically bind peptide fragments of Wilms' tumor protein (WT1) presented by MHC class II molecules, allowing for targeted cancer therapy with reduced off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If HLA-class I-restricted T cell therapies are used, then therapeutic efficacy against cancer cells is achieved, but the risk of on- and off-target toxicities increases
Solution Approach 1:
The patent extracts the peptide fragment from the full-length tumor antigen and presents it separately on MHC class II molecules. This allows T cells to recognize and bind specifically to the extracted peptide fragment-MHC class II complex, achieving targeted therapy while reducing off-target effects. The peptide fragment acts as an isolated target that can be recognized without affecting other cellular components.
Solution Approach 2:
MHC class II molecules serve as intermediaries between the tumor antigen peptide fragments and T cell receptors. The patent utilizes this intermediary mechanism to enable specific recognition of tumor cells while avoiding direct binding to other cellular structures, thereby reducing off-target toxicities. The MHC class II-peptide complex acts as a mediator that presents the antigen in a controlled manner.
2Adaptability or versatility
If HLA-class II-restricted approaches are used, then applicability across diverse cancer patients is improved, but effective targeting strategies are required
Solution Approach 1:
The patent employs MHC class II molecules that can present multiple different tumor antigen peptide fragments from various cancer types. This universal presentation mechanism allows a single T cell therapy approach to be applicable across diverse cancer patients with different tumor antigens, as long as their tumor cells express MHC class II molecules and present the relevant peptide fragments.
Solution Approach 2:
The patent changes the target parameter from full-length tumor antigens to specific peptide fragments of 10-20 amino acids. This parameter change enables the immune system to recognize and respond to conserved epitopes across different tumor antigens, thereby improving versatility across diverse cancer patients while simplifying the targeting strategy through focused peptide recognition.
Data Source
AI summary
The present disclosure is directed to antigen-binding molecules that specifically bind peptide fragments of tumor antigens, wherein the peptide fragment is capable of being presented by more than one type of major histocompatibility complex (MHC) class II molecule. In some aspects, the tumor antigen is a WT1 polypeptide. Other aspects are directed to antibodies, multispecific antibodies, and chimeric antigen receptors, and nucleotides encoding the same. Other aspects are directed to methods of administering the same to a subject in need thereof.