Human PD-L1 Antibody CDR Engineering for Binding Specificity
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Solution Overview
Problem
Tumors evade immune surveillance by upregulating PD-L1, leading to immune suppression and unchecked growth, and existing antibodies targeting PD-L1 have limited specificity and potential off-target effects.
Innovation Solution
Development of human antibodies with specific clone-paired heavy and light chain CDR sequences, engineered for enhanced binding to PD-L1, capable of blocking PD-L1/PD-1 interaction and delivering therapeutic payloads to cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing antibodies targeting PD-L1 are used, then some anti-tumor activity is achieved, but binding specificity is limited and off-target effects occur
Solution Approach 1:
The patent applies parameter changes by modifying the antibody sequences through mutagenesis to alter binding characteristics. Specifically, the patent describes creating humanized antibodies with modified complementarity-determining regions (CDRs) that enhance specificity for PD-L1 while reducing off-target effects. The sequences provided in the patent represent engineered variants with optimized binding parameters compared to existing antibodies.
Solution Approach 2:
The patent uses copying by creating humanized versions of existing antibody structures. The patent describes taking mouse or other animal antibody frameworks and copying/grafting human CDR sequences onto them, or creating entirely new human antibody sequences that replicate the functional binding characteristics of existing effective antibodies while improving specificity and reducing off-target effects.
2Reliability
If PD-L1 expression is tightly regulated in normal cells, then off-target reactivity is reduced, but therapeutic intervention becomes more challenging
Solution Approach 1:
The patent applies preliminary action by pre-characterizing and pre-engineering antibody sequences with optimized binding properties before clinical application. The patent provides specific sequence information and structural data that allow for the pre-development of antibodies with enhanced affinity and specificity, enabling more effective therapeutic intervention despite the tightly regulated expression of PD-L1 in normal cells.
Solution Approach 2:
The patent uses parameter changes to optimize antibody binding characteristics specifically for PD-L1 targets. By modifying sequence parameters, affinity, and specificity through engineered mutations, the patent creates antibodies that can effectively bind to PD-L1 even when it is tightly regulated, thereby facilitating successful therapeutic intervention without causing off-target effects.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The antibodies effectively block PD-L1/PD-1 binding, enhance anti-tumor immunity, and can be conjugated with therapeutic agents to target and treat various cancer types, including metastatic and drug-resistant cancers.
Implementation Method 1
an antibody or antibody fragment having clone-paired heavy and light chain CDR sequences from Tables 3 and 4, respectively
Data Source
AI summary
The present disclosure is directed to antibodies binding to PD-L1 and methods of using such antibodies to treat cancers, such as those that express or overexpress PD-L1.