Anti-CD38 Single-Domain Antibodies Prevent Antigen Internalization

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Solution Overview

Problem

Current anti-CD38 antibodies, such as daratumumab, cause internalization of the CD38 antigen-antibody complex, leading to downregulation of CD38 expression on cell surfaces, which hampers effective imaging and therapeutic targeting of neoplastic diseases.

Innovation Solution

Development of anti-CD38 single-domain antibodies (sdAbs) with specific amino acid sequences (CDR1: YTDSDYI, CDR2: TIYIGGTYIH, CDR3: AATKWRPFISTRAAEYNY) that minimize internalization of the CD38 antigen-antibody complex, allowing preserved surface expression and concurrent use with daratumumab for combined imaging and therapeutic applications.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional anti-CD38 antibodies (e.g., daratumumab) are used for therapeutic targeting, then therapeutic efficacy is improved, but CD38 surface expression is downregulated due to internalization

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidCD38 surface expression

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent divides the antibody functionality into two distinct components: a therapeutic component (daratumumab or similar anti-CD38 mAbs that induce internalization and cell killing) and a diagnostic component (the non-internalizing sdAb that maintains surface expression for imaging). This segmentation allows both therapeutic efficacy and sustained surface expression to coexist.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The non-internalizing sdAb acts as an intermediary that binds to CD38 without triggering internalization, thereby preserving surface expression levels. This intermediary molecule enables continued targeting for both therapy and imaging without the harmful side effect of downregulation caused by conventional antibodies.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Measurement precision

If conventional anti-CD38 antibodies are used for imaging, then initial targeting is achieved, but subsequent imaging is hampered by downregulation of CD38 expression

Engineering Contradiction:

Improveimaging accuracyVSAvoidsustained surface expression

Core Design Contradiction:

Measurement precisionVSDuration of action of stationary object

Solution Approach 1:

Instead of using antibodies that internalize and remove the target antigen (conventional approach), the patent employs sdAbs that specifically avoid internalization, thereby inverting the typical antibody-antigen interaction outcome. This inversion preserves the target antigen on the cell surface for prolonged imaging periods.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent changes the binding parameters of the anti-CD38 antibody by using sdAbs with different epitope specificities and binding characteristics that do not trigger internalization. This parameter change (from internalizing to non-internalizing binding) enables sustained surface expression for repeated imaging.

Inventive Principle:

Principle #35Parameter changes

3Quantity of substance

If sdAbs are designed to minimize internalization, then surface expression is preserved, but binding to daratumumab epitope is reduced

Engineering Contradiction:

Improvesurface expressionVSAvoidepitope binding flexibility

Core Design Contradiction:

Quantity of substanceVSAdaptability or versatility

Solution Approach 1:

The sdAbs are designed with specific local quality in their binding characteristics - they target specific epitopes on CD38 that are distinct from the daratumumab epitope. This localized epitope selection allows non-internalization while maintaining therapeutic utility through combination approaches.

Inventive Principle:

Principle #3Local quality

4Adaptability or versatility

If combination therapy with daratumumab and sdAbs is implemented, then therapeutic and diagnostic capabilities are enhanced, but complexity of treatment increases

Engineering Contradiction:

Improvecombined imaging and therapyVSAvoidtreatment complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The sdAbs serve multiple functions simultaneously: they act as diagnostic agents for imaging, as therapeutic agents when conjugated to toxins or radionuclides, and as surface expression maintainers that enable continued daratumumab binding. This multi-functionality reduces the need for separate agents and simplifies the overall treatment approach.

Inventive Principle:

Principle #6Universality (Multi-functionality)

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 anti-CD38 sdAbs enable reliable detection and targeting of CD38+ cells without competing with daratumumab, facilitating enhanced imaging and therapeutic strategies for neoplastic diseases by maintaining CD38 surface expression and allowing concomitant binding with daratumumab.

Implementation Method 1

the present anti-CD38 sdAbs bind to CD38 epitopes other than the epitope recognised by daratumumab

Methodology Applied

Scientific EffectAntigen-antibody binding:

Data Source

PatentUS20230190968A1Anti-CD38 single-domain antibodies in disease monitoring and treatment

Publication Date: 2023.06.22 KTH HLDG AG

AI summary

The present invention relates to medical imaging, disease monitoring and theranostic approaches in neoplastic diseases of certain anti-CD38 single-domain antibodies (sdAb).