HLA-Restricted PRAME Binding Proteins for Selective pMHC Targeting
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Solution Overview
Problem
Existing immunotherapies targeting PRAME peptide-MHC complexes face challenges such as low target affinity, biophysical properties, and potential cross-reactivity, leading to undesired side-effects and limited population coverage due to HLA gene polymorphism.
Innovation Solution
Development of antigen binding proteins with high affinity and avidity for MHC-displayed PRAME peptide SLLQHLIGL, optimized for low immunogenicity and stability, which are incorporated into CARs or ADCs for potent and selective tumor cell killing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If soluble TCRs are used to target PRAME peptide-MHC complexes, then T-cell mediated cancer cell killing can be achieved, but target affinity is low and biophysical properties are compromised
Solution Approach 1:
The patent changes the binding parameters by engineering the TCR into a soluble antibody format with optimized CDR sequences that achieve nanomolar affinity for the PRAME peptide-MHC complex, transforming the low affinity TCR interaction into a high affinity antibody-like binding interaction
Solution Approach 2:
The invention creates a composite molecular structure combining TCR-derived variable regions with antibody constant regions, forming a chimeric protein that integrates the specificity of TCRs with the biophysical properties and manufacturability of antibodies
2Reliability
If TCR-like antibodies are developed to target pMHC complexes, then high affinity binding can be achieved, but cross-reactivity with similar peptides occurs leading to undesired side-effects
Solution Approach 1:
The patent applies local quality by carefully designing the CDR regions to recognize specific structural features of the PRAME peptide-MHC complex that are unique to this target, while using conserved framework regions to maintain stability, thereby achieving high affinity binding without cross-reactivity
Solution Approach 2:
Instead of trying to eliminate cross-reactivity by excluding similar peptides (the traditional approach), the invention inverts the strategy by designing the antibody to positively discriminate against non-target peptides through precise CDR sequences that only bind the specific PRAME-MHC complex
3Measurement precision
If naturally occurring cancer reactive TCRs are used, then specificity to pMHC target can be maintained, but binding affinities are low requiring substantial engineering efforts
Solution Approach 1:
The patent changes the affinity parameter by transferring the TCR variable regions into a soluble antibody format with optimized CDR sequences, transforming the micro-millimolar affinity of natural TCRs into nanomolar affinity while preserving the high specificity established by thymic selection
4Adaptability or versatility
If HLA gene polymorphism is considered, then diverse pMHCs can be targeted, but population coverage is limited due to high level of polymorphism
Solution Approach 1:
The patent applies universality by designing the antibody to recognize a conserved structural feature of the PRAME peptide-MHC complex that is preserved across different HLA alleles, allowing a single antibody to target multiple HLA-restricted presentations of the same peptide, thereby expanding population coverage
Data Source
AI summary
Described herein are antigen binding proteins targeting PRAME derived peptide-MHCs (pMHCs). Also described are multispecific antigen binding proteins comprising an antigen binding domain with specificity to CD3, and at least one target peptide binding domain, in particular bispecific antigen binding proteins targeting both CD3 and PRAME. Methods of treatment with the same are also described.