Adenosine A2A Receptor Antibody Libraries for Unstable GPCR Targets

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Solution Overview

Problem

Raising antibodies to G protein-coupled receptors (GPCRs), such as adenosine receptors, is difficult due to their low expression levels and instability during purification, hindering effective therapeutic intervention.

Innovation Solution

Development of nucleic acid and protein libraries encoding for adenosine A2A receptor antibodies or fragments, utilizing a single domain antibody (VHH) with diverse CDR sequences, capable of binding with high affinity (KD < 100 nM) through a combination of phage display and in-silico library design.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If traditional antibody generation methods are used to target GPCRs, then therapeutic intervention can be achieved, but the process is hindered by low expression levels and instability of GPCRs during purification

Engineering Contradiction:

Improvetherapeutic intervention effectivenessVSAvoidantibody generation difficulty

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent uses a GPCR dimer as an intermediary structure to stabilize the target antigen. By forming a dimeric structure, the GPCR becomes more stable during purification and antibody generation, solving the instability problem while maintaining therapeutic effectiveness

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent performs preliminary stabilization of the GPCR by creating a dimer structure before antibody generation. This preliminary action ensures the GPCR maintains its structural integrity throughout the antibody production process, overcoming the low expression and instability issues

Inventive Principle:

Principle #10Preliminary action

2Ease of manufacture

If GPCRs are purified for antibody generation, then antibodies can be raised, but the GPCRs are very unstable during purification

Engineering Contradiction:

Improveantibody production feasibilityVSAvoidGPCR stability during purification

Core Design Contradiction:

Ease of manufactureVSStability of the object's composition

Solution Approach 1:

The GPCR dimer acts as a stable intermediary form that can be purified and used for antibody generation. The dimeric structure provides the necessary stability during purification while still allowing antibody production to proceed effectively

Inventive Principle:

Principle #24Intermediary (Mediator)

3Quantity of substance

If GPCRs are used as antigens for antibody generation, then therapeutic agents can be developed, but GPCRs are expressed at low levels in cells

Engineering Contradiction:

Improveavailable antigen quantityVSAvoidtherapeutic agent development

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent merges two GPCR molecules into a dimer structure, effectively doubling the available antigen quantity from a single expression source. This merging approach increases the amount of stable antigen available for antibody generation while maintaining therapeutic development reliability

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS12570750B2Antibodies that bind adenosine A2A receptors and methods of use thereof to treat cancer and neurological diseases

Publication Date: 2026.03.10 TWIST BIOSCIENCE CORP

AI summary

Provided herein are methods and compositions relating to adenosine A2A receptor libraries having nucleic acids encoding for a scaffold comprising an adenosine A2A binding domain. adenosine A2A receptor libraries described herein encode for immunoglobulins including antibodies and single domain antibodies. Libraries described herein include variegated libraries comprising nucleic acids each encoding for a predetermined variant of at least one predetermined reference nucleic acid sequence. Further described herein are protein libraries generated when the nucleic acid libraries are translated. Further described herein are cell libraries expressing variegated nucleic acid libraries described herein.