Glycosylated BTLA Antibodies for Selective Cancer Immunotherapy
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Solution Overview
Problem
Current cancer treatments that modulate the immune system to overcome immune evasion by cancer cells, such as anti-CTLA-4 and anti-PD1 antibodies, have limitations in safely and effectively targeting cancer cells, necessitating the development of new therapeutics that can selectively target specific immune regulatory molecules.
Innovation Solution
Development of isolated monoclonal antibodies that selectively bind to glycosylated B- and T-lymphocyte attenuator (BTLA) at specific positions (N75, N94, and N110) with enhanced affinity, potentially inhibiting HVEM binding and modulating immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional anti-CTLA-4 and anti-PD1 antibodies are used to modulate the immune system, then immune evasion by cancer cells can be overcome, but the treatment lacks sufficient selectivity and safety
Solution Approach 1:
The antibody is engineered to recognize a specific local feature (N-linked glycosylation at positions N75, N94, and/or N110) on the BTLA protein. This localized recognition confers selective binding to glycosylated BTLA while avoiding unglycosylated forms, thereby improving treatment safety through enhanced targeting precision without requiring broad immune modulation
Solution Approach 2:
The invention exploits a post-translational modification parameter (N-linked glycosylation) to create antibody specificity. By designing the antibody to bind specifically to the glycosylated form of BTLA, the treatment achieves higher selectivity for cancer-associated immune regulation pathways while sparing normal physiological functions mediated by unglycosylated BTLA
2Adaptability or versatility
If new therapeutics targeting specific immune regulatory molecules are developed, then treatment selectivity can be improved, but the complexity of identifying and targeting specific glycosylation sites increases
Solution Approach 1:
The invention extracts and isolates the critical distinguishing feature (N-linked glycosylation at specific positions) from the overall BTLA protein structure. By focusing the antibody recognition solely on this extracted glycosylation motif rather than the entire protein, the therapeutic achieves high selectivity while simplifying the target identification process to focus on identifiable glycosylation sites
Solution Approach 2:
The N-linked glycosylation acts as an intermediary marker that bridges the antibody and the BTLA protein. This glycosylation motif serves as a recognizable intermediate structure that simplifies antibody design and development, as glycosylation patterns are conserved and can be targeted using standard glyco-specific antibody engineering approaches
Data Source
AI summary
Provided herein are molecules, such as antibodies, that selectively bind to glycosylated BTLA (B- and T-lymphocyte attenuator) relative to unglycosylated BTLA. Methods for making and using such molecules are also provided, including methods for treating or diagnosing cancer. In some embodiments, the anti-glycosylated BTLA antibodies provided herein can immunospecifically bind to glycosylated wild-type BTLA (WT). In some embodiments, the anti-glycosylated BTLA antibodies provided herein can immunospecifically bind to one or more BTLA double mutants that retain only a single glycosylation site at BTLA N75, N94 or N110. In some embodiments, the anti-glycosylated BTLA antibodies provided herein show only background binding, if any, to a BTLA triple mutant, that retains none of BTLA's N75, N94, or N110 0-glycosylation sites.