Antibody Variant Combinations for Reduced Toxicity
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Solution Overview
Problem
Current antibody combination therapies may still exhibit residual activity against healthy cells that express only one of the target antigens, leading to undesired toxicity and a limited therapeutic window.
Innovation Solution
Engineering antibodies with specific Fc region modifications, such as substitutions at positions E430, E345, K248E, T437R, K439E, and S440K, and removing N-linked glycosylation at position N297, to enhance hetero-oligomerization while reducing self-oligomerization and maintaining efficacy on cells expressing both antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If Fc region modifications are introduced to enhance hetero-oligomerization between two antibodies, then selectivity for cells co-expressing both antigens is improved, but self-oligomerization of individual antibodies may still occur leading to residual toxicity against healthy cells
Solution Approach 1:
The patent introduces asymmetric Fc region modifications where the first antibody contains a modification at position E430 (e.g., E430G) while the second antibody contains a modification at position E345 (e.g., E345R). This asymmetric design creates complementary Fc regions that preferentially hetero-oligomerize with each other rather than self-oligomerize, thereby reducing residual toxicity to healthy cells while maintaining selectivity for target cells co-expressing both antigens.
Solution Approach 2:
The patent applies local quality by introducing specific point mutations at defined positions (E430, E345, K248, T437, K439, S440) within the Fc region to create localized changes in oligomerization propensity. These localized modifications at specific amino acid positions enable differential oligomerization behavior without affecting the overall antibody structure or antigen binding capabilities.
2Object-affected harmful factors
If N-linked glycosylation at position N297 is removed to reduce effector functions, then toxicity is reduced, but antibody stability and half-life may be affected
Solution Approach 1:
The patent removes the N-linked glycosylation at position N297 from the Fc region of the antibodies. This extraction of the glycan moiety eliminates the primary site for effector function mediation, thereby reducing toxicity to healthy cells. The patent compensates for potential stability and half-life issues through the asymmetric Fc region modifications that enhance hetero-oligomerization, providing an alternative mechanism for therapeutic efficacy.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach significantly reduces toxicity to healthy cells while maintaining potent activity against target cells co-expressing both antigens, thereby improving the therapeutic window of antibody treatments.
Implementation Method 1
The hexamerization is mediated through intermolecular non-covalent Fc-Fc interactions, and Fc-Fc interactions can be enhanced by point mutations in the CH3 domain, including E345R and E430G.
Implementation Method 2
C1q is a multimeric protein consisting of six globular binding heads attached to a stalk. The individual globular binding heads have low affinity for IgG, and C1q must gain avidity by binding multiple IgG1 molecules on a cell surface to trigger the classical complement pathway.
Implementation Method 3
ADCC and ADCP are initiated by binding of the IgG Fc region to Fcγ receptors (FcγR) on effector cells.
Implementation Method 4
The employment of effector functions by IgG antibodies is dependent on glycosylation status. The Fc region of IgG antibodies contains a highly conserved N-glycosylation site at amino acid position N297.
Data Source
AI summary
The invention relates to combination therapy involving two or more antibodies, wherein the Fc regions of the two antibodies have been modified such that hetero-oligomerization between the antibodies is strongly favored over self-oligomerization when antibodies are bound to their corresponding target antigens and such that hetero-oligomerization-independent effector functions of one or both antibodies are eliminated or strongly reduced. The invention also relates to antibodies, compositions, and kits suitable for use in the combination therapy of the invention.