LPAR1-Binding Polypeptides for Selective Allosteric Inhibition

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Solution Overview

Problem

There is a need for new LPAR1 inhibitors due to the poor drug selectivity of the previously leading small molecule drug, BMS-986020, which failed in Phase II clinical trials.

Innovation Solution

Development of polypeptides, such as antibodies or fragments thereof, that bind to functionally active LPAR1 on the surface of live cells, utilizing specific sequences with at least 80% identity to SEQ ID NOs for HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, and comprising VH and VL regions, for allosteric inhibition and inverse agonism of LPAR1.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If small molecule drugs like BMS-986020 are used to inhibit LPAR1, then LPAR1 inhibition is achieved, but drug selectivity is poor leading to failure in clinical trials

Engineering Contradiction:

Improvedrug selectivityVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent changes the molecular size and structural parameters from small molecules to polypeptides/antibodies, which have different binding characteristics and selectivity profiles. This parameter change enables achieving high drug selectivity while maintaining LPAR1 inhibition activity, resolving the contradiction between inhibition efficacy and selectivity.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If polypeptides binding to functionally active LPAR1 are developed, then binding affinity and selectivity are improved, but development complexity increases

Engineering Contradiction:

Improvebinding affinityVSAvoidpolypeptide sequence complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent segments the polypeptide into functional regions including variable regions (VH, VL) and constant regions, with further segmentation into CDRs (CDR1, CDR2, CDR3) and LCDRs. This segmentation allows systematic design and optimization of binding affinity while managing sequence complexity through modular architecture.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The polypeptide structure is designed to be universally applicable across different LPAR1 isoforms and species through conserved binding interfaces, while allowing customization of specific regions for different therapeutic applications. This multi-functionality reduces development complexity by creating a platform approach.

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Reliability

If polypeptides are designed to bind functionally active LPAR1 on live cells, then therapeutic efficacy is improved, but manufacturing precision requirements increase

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidprotein folding and assembly precision

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The polypeptide structure is designed to self-assemble into functional conformations through intrinsic folding mechanisms, where the amino acid sequence automatically adopts the correct three-dimensional structure without requiring complex external assistance. This self-service approach reduces manufacturing precision requirements while maintaining therapeutic efficacy.

Inventive Principle:

Principle #25Self-service

Data Source

PatentUS20250319150A1polypeptides

Publication Date: 2025.10.16 DJS ANTIBODIES LTD

AI summary

There is provided inter alia polypeptides such as antibodies or fragments thereof which bind to LPAR1.