ISV Drug Null-Variant Assay for Neutralizing ADA Detection

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Solution Overview

Problem

Existing immunogenicity assays struggle to accurately distinguish neutralizing anti-drug antibodies (NAb) from non-neutralizing antibodies, particularly in the presence of ISV-based drugs, due to sensitivity differences and pre-treatment requirements that compromise assay sensitivity and interpretation.

Innovation Solution

An improved NAb assay format using a null variant of the ISV-based drug, which is non-functional for target binding, is employed to detect and measure NAb levels by performing a bridging anti-drug antibody assay in the presence of this variant, allowing neutralizing antibodies to be distinguished from non-neutralizing ones.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If pre-treatment steps are performed to obtain drug and target tolerance for NAb detection, then the assay can detect neutralizing antibodies, but the assay sensitivity is reduced and a sensitivity gap between ADA and NAb assays is introduced

Engineering Contradiction:

ImproveNAb detection capabilityVSAvoidassay sensitivity

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The invention extracts and removes the pre-treatment steps from the NAb assay protocol. By using a bridging assay format that directly detects ADA without requiring prior drug or target tolerance preparation, the method eliminates the sensitivity loss associated with pre-treatment while maintaining the ability to detect neutralizing antibodies.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

Instead of preparing the assay system to tolerate drug and target before detection (conventional approach), the invention inverts the approach by using a bridging format where the detection is performed directly on the antibody-antigen complex formation, reversing the traditional sequence of operations and avoiding sensitivity loss.

Inventive Principle:

Principle #13The other way round (Inversion)

2Reliability

If pre-treatment steps are performed to achieve drug and target tolerance, then NAb can be detected, but the complexity of the assay procedure increases

Engineering Contradiction:

ImproveNAb detection capabilityVSAvoidassay procedure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention merges the ADA detection and NAb detection into a single bridging assay format. This combination eliminates the need for separate pre-treatment steps and multiple assay procedures, simplifying the overall workflow while maintaining the ability to detect neutralizing antibodies.

Inventive Principle:

Principle #5Merging (Combining)

3Ease of operation

If conventional bridging assay formats are used for ADA detection, then the assay is simple to perform, but neutralizing antibodies cannot be distinguished from non-neutralizing antibodies

Engineering Contradiction:

Improveassay simplicityVSAvoidNAb discrimination capability

Core Design Contradiction:

Ease of operationVSMeasurement precision

Solution Approach 1:

The invention introduces an intermediary step in the bridging assay where the detection of ADA is performed in a manner that reveals neutralizing activity. The bridging format itself acts as an intermediary mechanism that allows differentiation of NAb from non-NAb while maintaining assay simplicity, as the detection signal reflects the functional neutralizing capability of the antibodies.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the detection parameter of the bridging assay to reflect neutralizing activity rather than just binding activity. By modifying how the assay signal is interpreted and measured, the method enables distinction between neutralizing and non-neutralizing antibodies while keeping the basic assay procedure simple and straightforward.

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

The assay achieves high sensitivity and drug tolerance, enabling unambiguous immunogenicity data interpretation and determination of clinically relevant titer levels, with comparable sensitivity to conventional ADA assays.

Implementation Method 1

performing a bridging anti-drug antibody assay in the presence of a variant of said ISV-based drug, which variant is such that it is non-functional with respect to binding to the target of the ISV-based drug

Methodology Applied

Scientific EffectAntibody-antigen binding:

Data Source

PatentUS12480957B2Method of screening for anti-drug antibodies against immunoglobulin single variable domain-based drugs

Publication Date: 2025.11.25 ABLYNX NV

AI summary

The present invention relates to improved immunogenicity assays and methods for performing the same. In particular, the present invention relates to improved immunogenicity assays that are capable of distinguishing neutralizing anti-drug antibodies from non-neutralizing anti-drug antibodies. More in particular, the present invention relates to improved immunogenicity assays that allow (amounts and/or concentrations of) neutralizing anti-drug antibodies to be detected and/or measured in a sample even in the presence of non-neutralizing anti-drug antibodies.