pH-Dependent Anti-PD-L1 Antibody Engineering
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Solution Overview
Problem
Current anti-PD-L1 antibodies have limited efficacy due to rapid internalization and degradation by PD-L1 expressing cells, requiring continuous high doses for sustained inhibition of tumor growth, leading to high costs and limited complete response rates.
Innovation Solution
Development of novel monoclonal anti-PD-L1 antibodies with specific heavy and light chain complementarity-determining regions (CDRs) and framework sequences that exhibit reduced binding at acidic pH, allowing for lower dosing and prolonged receptor occupancy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current anti-PD-L1 antibodies are used to inhibit tumor growth, then tumor growth inhibition is achieved, but the antibodies are rapidly internalized and degraded by PD-L1 expressing cells, requiring continuous high doses to maintain therapeutic effect
Solution Approach 1:
The patent modifies the antibody structure by engineering specific CDR sequences (HCDR1: TYWX1H, HCDR2: MIQPNSGGTKYNX2X3FKX4, HCDR3: GAGTVDYFDY, LCDR1: RASESVDIYGNSFMH, LCDR2: RASNLES, LCDR3: X5QSX6X7DPYT) to alter the binding characteristics. This structural parameter change reduces internalization by PD-L1 expressing cells while maintaining blocking activity, thereby extending antibody half-life and reducing the quantity needed for sustained therapeutic effect
Solution Approach 2:
The invention creates an antibody with dynamic binding behavior that is pH-dependent. The antibody binds PD-L1 at neutral pH (physiological conditions) but has reduced binding at acidic pH (endosomal/lysosomal conditions), preventing internalization and degradation. This dynamic response to environmental conditions allows the antibody to remain active at lower doses for longer periods
2Reliability
If continuous infusion of large amounts of antibodies is administered to sustain tumor growth inhibition, then tumor growth inhibition is maintained, but treatment cost increases significantly
Solution Approach 1:
By changing the structural parameters of the antibody (CDR sequences) to reduce internalization and extend half-life, the patent decreases the frequency and amount of dosing required. This structural modification directly reduces the total quantity of antibody needed over time, thereby reducing treatment cost while maintaining reliable tumor growth inhibition
Solution Approach 2:
The engineered antibody provides self-sustaining therapeutic activity through its extended half-life and reduced clearance. The antibody maintains effective concentrations for longer periods without requiring frequent external replenishment, reducing the ongoing resource input (cost) needed to maintain therapeutic effect
3Reliability
If high concentrations of antibodies are maintained in the tumor site to block PD-L1 activity, then complete response rate improves, but the rapid degradation of antibodies limits the ability to achieve and maintain complete response
Solution Approach 1:
The patent engineers specific CDR sequences that change the kinetic parameters of antibody-PD-L1 interaction. The modified antibody has reduced internalization rate and extended half-life, allowing it to maintain effective concentrations at the tumor site for longer periods. This parameter change enables sustained blocking of PD-L1 activity necessary for complete response without requiring continuously high doses
Solution Approach 2:
The antibody exhibits dynamic pH-dependent binding behavior that enhances its persistence at the tumor site. By binding at neutral pH and releasing at acidic pH, the antibody avoids degradation in endosomes and lysosomes, extending its functional half-life and enabling sustained complete response at lower overall doses
Data Source
AI summary
The present disclosure relates to an isolated PD-L1 antibody whose binding to PD-L1 at acidic pH is substantially lower than its binding to PD-L1 at neutral pH at the same assay setting and an isolated PD-L1 antibody that is not pH dependent in binding to PD-L1. Also provided is the pharmaceutical composition of the antibody, encoding polynucleotide and expression vector, isolated host cell thereof as well as a kit comprising the PD-L1 antibody. Also provided herein are methods of treating a PD-L1 associated condition using the PD-L1 antibody.