PD-L1 Binding Polypeptide Structure and Design

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

There is limited structural information on how antibodies block the interaction between PD-1 and PD-L1, hindering the development of effective treatments for immune checkpoint blockade in cancer therapy.

Innovation Solution

A high-resolution crystal structure of a PD-L1-blocking heavy-chain single-domain antibody KN035 binding with PD-L1 is provided, along with methods to produce PD-L1 binding polypeptides that can interact with PD-L1 and additional targets, such as tumor antigens, by modifying or grafting CDR loops, enabling the development of novel therapeutic agents.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Loss of information

If high-resolution crystal structure of PD-L1-blocking antibody is determined, then understanding of binding mechanism is improved, but time and resource investment increases

Engineering Contradiction:

Improvestructural information on antibody binding mechanismVSAvoidtime for crystal structure determination

Core Design Contradiction:

Loss of informationVSLoss of time

Solution Approach 1:

The patent performs preliminary crystal structure determination of the PD-L1/KN035 complex before full therapeutic development, establishing the binding mechanism upfront to guide subsequent drug design and reduce overall development time

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent uses the determined crystal structure as a template to design and develop novel PD-L1 binding polypeptides with similar or improved binding characteristics, avoiding the need to determine structures for each new candidate

Inventive Principle:

Principle #26Copying

2Adaptability or versatility

If CDR loops are modified or grafted to create novel polypeptides, then binding specificity and affinity are improved, but structural stability may be compromised

Engineering Contradiction:

Improvebinding specificity to PD-L1 and additional targetsVSAvoidstructural stability of polypeptide

Core Design Contradiction:

Adaptability or versatilityVSStability of the object's composition

Solution Approach 1:

The patent modifies only the CDR loops (local regions) while preserving the stable framework structure, allowing enhanced binding specificity without compromising overall structural stability

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent creates composite polypeptide structures by grafting CDR loops from different sources onto a stable framework, combining the stability of the framework with the enhanced binding properties of the grafted CDRs

Inventive Principle:

Principle #40Composite materials

3Adaptability or versatility

If polypeptides are designed to bind multiple targets including tumor antigens, then therapeutic effectiveness is improved, but complexity of polypeptide structure increases

Engineering Contradiction:

Improveability to bind PD-L1 and additional targetsVSAvoidcomplexity of polypeptide structure

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent designs polypeptides with multi-functional CDR loops that can simultaneously or sequentially bind to multiple targets including PD-L1 and tumor antigens, enabling a single agent to perform multiple therapeutic functions

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent divides the binding function into separate CDR loops, where different CDRs can independently recognize different epitopes or targets, allowing modular design of multi-specific polypeptides

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS11377497B2PD-L1 binding polypeptide or composite

Publication Date: 2022.07.05 SUZHOU ALPHAMAB CO LTD

AI summary

The present invention relates to the field of medical biology, and discloses a high-resolution crystal structure of a complex of PD-L1-blocking heavy-chain single-domain antibody KN035 binding with PD-L1, and the use of the crystal structure. The invention also relates to novel PD-L1 binding polypeptides or compounds developed based on the crystal structure and uses thereof.