Chimeric Llama-Human Polypeptides for Native Epitope Mapping

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Solution Overview

Problem

Current methods for generating antibodies against defined epitopes, particularly conformational epitopes, are often unsuccessful, as they rely on short peptides that fail to induce antibodies binding to antigens in their native, three-dimensional form.

Innovation Solution

Development of chimeric polypeptides comprising a camelid and a non-camelid polypeptide portion, specifically designed to produce antibodies that recognize and bind to specific regions of non-camelid proteins in their native conformation, allowing for precise epitope mapping and antibody selection.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If short peptides are used as immunogens to generate antibodies against defined epitopes, then the specificity to target epitope is improved, but the ability to generate antibodies against conformational epitopes deteriorates

Engineering Contradiction:

Improveepitope specificityVSAvoidconformational epitope recognition

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The patent changes the physical and structural parameters of the immunogen from short linear peptides to chimeric polypeptides that maintain the native three-dimensional conformation of the target antigen. This parameter change allows the immunogen to present conformational epitopes while retaining epitope specificity, thereby resolving the contradiction between specificity and conformational recognition capability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs chimeric polypeptides composed of camelid and human polypeptide portions as composite immunogens. These composite structures combine the advantages of both species-specific sequences while maintaining the native conformational structure, enabling simultaneous achievement of epitope specificity and conformational epitope recognition

Inventive Principle:

Principle #40Composite materials

2Quantity of substance

If camelids are immunized with camelid self-proteins, then the immune response to self-antigens is improved, but the production of camelid antibodies deteriorates

Engineering Contradiction:

Improveimmune response magnitudeVSAvoidself-tolerance suppression

Core Design Contradiction:

Quantity of substanceVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by creating chimeric polypeptides where only specific portions (human homologous regions) differ from the camelid self-protein while other portions remain identical. This localized differentiation is sufficient to break self-tolerance and induce antibody production without triggering a complete immune rejection, thereby resolving the contradiction between immune response magnitude and self-tolerance

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

Instead of immunizing with pure camelid self-proteins (which fail to induce antibodies due to self-tolerance), the patent inverts the approach by introducing human polypeptide portions into the camelid protein framework. This inversion creates a semi-allogeneic antigen that escapes self-tolerance recognition while maintaining sufficient similarity to elicit a controlled immune response

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentUS9926364B2Chimeric human-llama antigens and methods of use

Publication Date: 2018.03.27 ARGENX BVBA(BE)

AI summary

Provided are chimeric, camelid-human (e.g., llama-human) polypeptides comprising a first antigenic polypeptide portion and a second antigenic polypeptide portion wherein the first antigenic portion is a derived from a first portion of a camelid (e.g., llama) and the second antigenic portion is a human polypeptide homolog of a second portion of the camedid antigen. The chimeric polypeptides are useful inter alia for epitope mapping and generation of antibodies that bind to a desired region of human antigen.