Modified IgM Constant Regions for Reduced Complement Activity

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Solution Overview

Problem

There is a need to identify mutations in the IgM heavy chain constant region that reduce or eliminate complement-dependent cytotoxicity (CDC) activity in human IgM antibodies, as intact CDC activity can counteract agonist activity on targets like tumor cells, where multimerization is used for downstream signaling.

Innovation Solution

A modified human IgM constant region with specific amino acid substitutions in the Cμ3 domain, such as at positions L310, P311, P313, and K315, is developed to reduce CDC activity, allowing for targeted antigen binding with decreased cytotoxicity compared to wild-type IgM antibodies.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Object-affected harmful factors

If IgM antibody complement fixation activity is retained, then CDC activity is enhanced, but agonist activity on target cells is counteracted

Engineering Contradiction:

ImproveCDC activityVSAvoidagonist activity

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent extracts the complement fixation function from the IgM antibody by introducing mutations in the Cμ3 domain that specifically reduce C1q binding while preserving antigen binding and T-cell activation capabilities. This separates the harmful CDC effect from the desired agonist activity.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent applies local quality changes by making specific amino acid substitutions at targeted positions (L310, P311, P313, K315) in the Cμ3 domain while leaving the rest of the antibody structure intact. This localized modification selectively reduces complement fixation without affecting other functional regions.

Inventive Principle:

Principle #3Local quality

2Object-affected harmful factors

If mutations are introduced to reduce CDC activity, then cell killing is minimized, but antibody structure and function may be affected

Engineering Contradiction:

ImprovecytotoxicityVSAvoidantibody structure

Core Design Contradiction:

Object-affected harmful factorsVSStability of the object's composition

Solution Approach 1:

The patent changes specific parameters (amino acid residues) at targeted positions in the Cμ3 domain to achieve the desired reduction in CDC activity. The mutations L310, P311, P313, and K315 are carefully selected to modify complement binding parameters without disrupting overall antibody stability or antigen binding parameters.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If IgM multimerization is used for T-cell activation, then agonist activity is enhanced, but complement fixation is also enhanced

Engineering Contradiction:

Improveagonist activityVSAvoidcomplement fixation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent segments the functional effects of IgM multimerization by introducing mutations that specifically decouple complement fixation from antigen binding and T-cell activation. The mutated IgM can still multimerize and activate T-cells through CD40 engagement, but the complement fixation pathway is selectively inhibited.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS11401337B2Modified human IgM constant regions for modulation of complement-dependent cytolysis effector function

Publication Date: 2022.08.02 IGM BIOSCIENCES INC

AI summary

The disclosure provides modified human IgM heavy chain constant regions that include one or more amino acid substitutions, e.g., in the Cμ3 domain, where a modified human IgM antibody comprising the modified IgM constant region and a heavy chain variable region specific for a target antigen exhibits reduced complement-dependent cytotoxicity (CDC) of cells expressing the target antigen relative to a corresponding wild-type human IgM antibody.