Hexameric Antigen Binding Complexes for Enhanced Agonistic Activity

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Solution Overview

Problem

There is a need for improved methods to identify and utilize functional antibodies, particularly those with agonistic activity, from candidate molecule pools, as existing methods are inefficient in isolating such antibodies effectively.

Innovation Solution

Development of hexameric antigen binding complexes comprising six subunits with antigen binding polypeptides that include modified Fc regions for enhanced hexamer formation and agonistic activity, specifically designed to bind to cell surface receptors like OX40, DR5, CD27, and Tie2, with modifications to diminish C1q binding and Complement Dependent Cytotoxicity (CDC).

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional antibody formats are used, then ease of manufacture is maintained, but agonistic activity and therapeutic efficacy are insufficient

Engineering Contradiction:

Improveagonistic activityVSAvoidcomplex structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The antibody is divided into six identical subunits that assemble to form a hexamer, with each subunit containing an antigen-binding fragment (scFv) and an Fc region. This segmentation allows each subunit to independently bind to the same antigen, creating a multivalent binding system that enhances agonistic activity while maintaining manufacturability through modular design

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention combines different antibody components (scFv antigen-binding regions and Fc effector regions) into a hybrid hexameric structure. This composite design integrates the antigen-specific binding capability of scFv with the effector function and hexamer formation capability of the Fc region, achieving enhanced agonistic activity through multivalent binding

Inventive Principle:

Principle #40Composite materials

2Reliability

If effector function is enhanced, then therapeutic efficacy is improved, but harmful immune responses increase

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidimmune response

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The Fc region is locally modified with specific amino acid substitutions (P247A, I253L, S254L, Q311L, E345R, D356R, T359R, E382R, G385R, Q386R, E430R, N434R, Y436R, Q438R, K439R, S440R, K447R) that differentially affect various effector functions. These localized modifications selectively enhance agonistic activity and ADCC while reducing CDC and C1q binding, achieving therapeutic efficacy with minimized harmful immune responses

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS10865248B2Antigen binding complex having agonistic activity and methods of use

Publication Date: 2020.12.15 GENENTECH INC

AI summary

Provided herein are antigen binding polypeptides and complexes thereof having agonist activity. Also provided are methods for screening for complexes or polypeptides having agonist activity, enhancing the agonist activity of a polypeptide, and for agonizing a cell surface receptor using the complexes and polypeptide described herein.