Multivalent 41BB-PDL1 Fusion Proteins for TNFRSF Agonism

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Conventional antibodies targeting members of the TNF receptor superfamily require exogenous crosslinking to achieve sufficient agonist activity, limiting their therapeutic efficacy in activating TNFRSF members for treating neoplasms and inflammatory conditions.

Innovation Solution

Development of multivalent and multispecific TNF receptor superfamily binding fusion proteins that incorporate multiple TNFRSF binding domains to enhance clustering and signaling, including fusion proteins that target 41BB and PDL1, allowing for enhanced TNFRSF-dependent signaling without the need for exogenous crosslinking.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional bivalent antibodies are used to target TNFRSF members, then the antibody structure is simple and easy to manufacture, but the agonist activity is insufficient and requires exogenous crosslinking

Engineering Contradiction:

Improveagonist activityVSAvoidantibody structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The antibody is divided into multiple binding domains (e.g., scFv units) that can independently bind to TNFRSF members. These segmented binding domains are then reassembled in multivalent configurations (e.g., tandem scFv, diabody, or higher-order multimers) to achieve the necessary clustering and agonist activity without requiring exogenous crosslinking agents.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

Multiple binding domains are merged into a single polypeptide chain or complex, creating multivalent constructs that can simultaneously engage multiple TNFRSF receptors. This merging of binding functions into one molecule eliminates the need for separate crosslinking steps while achieving the required receptor clustering for potent agonist activity.

Inventive Principle:

Principle #5Merging (Combining)

2Reliability

If multivalent and multispecific fusion proteins are developed to enhance clustering and signaling, then the agonist activity is improved, but the manufacturing complexity increases

Engineering Contradiction:

Improveagonist activityVSAvoidprotein production

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The fusion proteins are designed with modular binding domains that can target multiple TNFRSF members or combine different functional domains (e.g., 41BB-binding and PDL1-binding domains). This multi-functionality allows a single platform to address multiple therapeutic targets and mechanisms, streamlining the manufacturing process by using common production methodologies for diverse therapeutic candidates.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The valency and specificity of the fusion proteins are optimized by adjusting parameters such as the number and arrangement of binding domains, linker lengths and sequences, and domain orientation. These parameter optimizations enable the proteins to achieve desired clustering and signaling properties while maintaining manufacturability through standardized expression systems and purification protocols.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS12187804B2Multivalent and multispecific 41BB-binding proteins

Publication Date: 2025.01.07 INHIBRX BIOSCIENCES INC

AI summary

This invention relates generally to molecules that specifically engage 41BB, a member of the TNF receptor superfamily (TNFRSF). More specifically, this invention relates to multivalent and multispecific molecules that bind at least 41BB.