Engineered IgG1 Antibodies for FcRn Binding Modulation

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Solution Overview

Problem

Current technologies face challenges in modulating the serum persistence and transport of immunoglobulin G (IgG) molecules, particularly in maintaining constant serum levels and efficiently delivering antibodies across cellular barriers, due to limitations in understanding and manipulating the interaction between IgG and the major histocompatibility complex-related receptor FcRn.

Innovation Solution

Engineered IgG1 molecules with specific amino acid modifications, such as Lys433, Phe434, and Tyr436, and additional mutations like Tyr252, Thr254, and Glu256, are developed to enhance binding affinity to FcRn, altering serum half-life and transport properties, allowing for increased persistence or rapid clearance of IgGs.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If amino acid mutations are introduced to increase FcRn binding affinity, then serum persistence is improved, but manufacturing precision becomes more difficult

Engineering Contradiction:

Improveserum persistenceVSAvoidmanufacturing precision

Core Design Contradiction:

Duration of action of moving objectVSManufacturing precision

Solution Approach 1:

The patent applies parameter changes by systematically mutating specific amino acid residues (I253, H310, H435, H436) in the Fc domain to alter the binding affinity parameters with FcRn. This enables precise control of serum persistence through defined sequence modifications while maintaining manufacturing feasibility through standardized mutagenesis protocols.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent implements local quality by introducing mutations only at specific critical positions within the FcRn interaction site rather than throughout the entire IgG molecule. This localized approach allows selective optimization of binding affinity while preserving the overall structural integrity and manufacturability of the antibody.

Inventive Principle:

Principle #3Local quality

2Duration of action of moving object

If amino acid mutations are introduced to increase FcRn binding affinity, then serum persistence is improved, but the complexity of the molecular structure increases

Engineering Contradiction:

Improveserum persistenceVSAvoidmolecular structure complexity

Core Design Contradiction:

Duration of action of moving objectVSDevice complexity

Solution Approach 1:

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent applies partial action by focusing mutagenesis efforts on the four most critical residues (I253, H310, H435, H436) that constitute the core FcRn interaction interface. This partial approach achieves significant improvements in serum persistence without the need for comprehensive mutagenesis of the entire Fc domain, thereby limiting structural complexity increases.

Inventive Principle:

Principle #16Partial or excessive action

3Productivity

If pH dependence of Fc-FcRn interaction is reduced through mutations, then transport efficiency is improved, but binding affinity at physiological pH becomes less selective

Engineering Contradiction:

Improvetransport efficiencyVSAvoidbinding selectivity

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies parameter changes by mutating histidine residues (H310, H435, H436) that are responsible for pH-dependent binding. These mutations alter the pKa values of the interaction interface, reducing pH dependence and enabling more consistent binding across different pH conditions, thereby improving transport efficiency while maintaining selectivity through the specific combination of mutated residues.

Inventive Principle:

Principle #35Parameter changes

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

These engineered IgG1 molecules demonstrate improved binding affinity and reduced pH dependence to FcRn, leading to enhanced serum persistence, efficient transport across cellular barriers, and increased clearance rates, offering therapeutic benefits in autoimmune diseases and infectious diseases by modulating IgG levels and delivery.

Implementation Method 1

the marked pH-dependence (binding at pH 6.0, release at pH 7.2-7.4) of the Fc-FcRn interaction... as the pKa of one of the imidazole protons lies in this pH range

Methodology Applied

Scientific EffectpH-dependent binding:

Implementation Method 2

FcRn is also involved in the transport of IgGs across epithelial and endothelial cell barriers of diverse origin

Methodology Applied

Scientific Effecttranscytosis:

Implementation Method 3

FcRn is involved in the homeostasis of serum IgGs... this receptor most likely acts as a salvage receptor

Methodology Applied

Scientific Effectsalvage receptor mechanism:

Data Source

PatentEP1896503B1IgG1 ANTIBODIES WITH MUTATED Fc PORTION FOR INCREASED BINDING TO FcRn RECEPTOR AND USES TEHEREOF

Publication Date: 2014.10.29 BOARD OF RGT THE UNIV OF TEXAS SYST

Figure 1A~1B
Figure 2
Figure 3A~3F

AI summary

The present invention provides for IgGl molecules with improved characteristics. In particular, substitution mutations are provided that, in combination, facilitate improved placental transfer, improved serum half-life and improved FcRn binding. Substitution mutations are also provided, that in combination, can be used to block FcRn function and thereby increase the clearance rates of other (endogenous or exogenous) IgGs, block placental transport of IgGs and have increased affinity/reduced pH dependence for FcRn binding.