Degrader-Antibody Conjugates for the Treatment of Autoimmune Diseases

OVERVIEW

The Seeker for this Innocentive Challenge is looking for novel antibody drug conjugates (ADCs) for the treatment of human autoimmune diseases, using targeted protein degraders (TPDs) as warheads instead of conventional cytotoxic agents.

Degrader-antibody conjugates (DACs) are an emerging, cutting-edge technology for the treatment of human diseases involving pathogenic proteins. By combining the high specificity of antibodies with the catalytic mechanism of targeted protein degradation, this technology offers several benefits over traditional approaches.

So far, the DAC approach has been applied predominantly to the treatment of cancers. The objective of this Challenge is to identify DACs that can be used to treat human autoimmune diseases (AID), such as lupus and psoriasis, or inflammatory bowel diseases (IBD) with similar pathological mechanisms, Crohn’s disease and ulcerative colitis.

A successful solution to this Challenge will identify 1) an intracellular target to be degraded by the DAC warhead that has the potential for positive therapeutic outcomes for AID and IBD patients, 2) an extracellular target antigen to which the antibody portion of the DAC can bind and internalize into the cell, and 3) a target indication with high unmet need that the DAC can be used to treat. The solution should also justify why a DAC approach would be beneficial over more conventional therapies (e.g., small oral molecules, existing monoclonal antibodies, etc.).

By taking part in and submitting to this Prize Challenge you are granting the Seeker a right to use (but not own) your submitted information, provided that the Seeker pays the threshold of at least $10,000 in awards and decides the award winners within 45 days from the start of evaluation, otherwise the Seeker retains the right to use only Awarded solutions.

This Challenge requires a written proposal to be submitted and the best solution(s) have the opportunity to win awards from $2,500 to $20,000 for meeting enough of the requirements criteria. There is no assignment of IP Rights with this Challenge, absent further agreement between the Seeker and the Solver.

Solvers may:

• Submit ideas of their own
• Submit third-party information that they have the right to use and further, the authority to convey to the Seeker this right with the right to use and develop derivative works
• Submit information considered in the public domain without any limitations on use.

Submissions to this Challenge must be received by 11:59 PM (US Eastern Time) on August 06th, 2025.

Please review the later Participation Guidance section before submitting a proposal.

- Login or register your interest to start solving.

THE CHALLENGE

Background

Degrader-Antibody Conjugates (DACs) are an emerging, cutting-edge technology allowing to trigger, in a sustained and catalytic manner, degradation of any intracellular protein essential for cell function, leading, therefore, to cell death. By combining the high specificity of antibodies with the catalytic mechanism of targeted protein degradation, this technology offers several benefits over traditional approaches:

1. By harnessing the catalytic nature of protein degraders, DACs can induce the complete and sustained elimination of oncogenic or other pathogenic proteins, which may be particularly useful when the target is considered “undruggable” by classical inhibition strategies.
2. Antibody-mediated cell targeting allows for improved cell-specific delivery and internalization, which can lead to reduced systemic toxicity. This approach helps DACs overcome some limitations of traditional small-molecule degraders (such as poor bioavailability and pharmacokinetics properties).
3. DAC technology may also help overcome issues associated with resistance mechanisms as degraders can eliminate rather than merely inhibit targeted proteins, potentially offering longer-lasting responses in patients.

DACs are composed of two major components: a monoclonal antibody specific to the intended extracellular target and a chemically linked small-molecule protein degrader. The degrader component often includes a ubiquitin E3 ligase binding group (E3LB) and a target protein binding group (PB) that, together, recruit the cellular ubiquitination machinery to label a target protein for proteasomal degradation. Another option is to use the so-called molecular glue, a small molecule that enhances protein-protein interactions, effectively "gluing" the molecular glue entity and the target protein together.

Once the antibody binds its specific cell-surface antigen, the entire conjugate is internalized into the cell where the degrader is released and then drives the elimination of the protein of interest.

To learn more about DACs and their design, read here. If you have any problems following this link, a PDF is available as an attachment, after you have registered for the challenge.

The Challenge

The objective of this Challenge is to identify DACs that can be used to treat human autoimmune diseases (AID) and inflammatory bowel diseases (IBD). We’re especially interested in two “classic” AIDs, lupus and psoriasis, and two IBDs with similar pathological mechanisms: Crohn’s disease and ulcerative colitis.

Important! Although our primary focus is on the four diseases mentioned above, exceptionally promising DACs applicable to other AIDs, including but not limited to type 1 diabetes and rheumatoid arthritis, will be considered.

We envision that a successful solution to this Challenge will begin with identifying at least one molecular target whose destruction (or strong inhibition) will lead to positive therapeutic outcomes for patients with AID. The choice of the target must be thoroughly justified by published data (articles, clinical trial reports, etc.). Solutions appropriate for more than one target indication will be given preferential consideration.

Important! An “ideal” target will have biomarkers that can be assessed in non-human primates.

The Solvers should then proceed to describe at least one potential combination of a monoclonal antibody specific to the target cell and a chemically linked small-molecule degrader that can be used to treat at least one of the four conditions mentioned above.

To be effective, monoclonal antibodies must meet the following criteria to ensure precise delivery, intracellular release, and therapeutic efficacy:

• High antigen specificity and affinity. The antibody must bind selectively to a cell-surface antigen expressed on target cells with high affinity (low nM or pM range).
• High level of internalization. The antigen-antibody complex must trigger rapid receptor-mediated endocytosis to transport the DAC into the cell.

• Favorable pharmacokinetics and safety profile, such as long circulation half-life, low immunogenicity. That means that humanized or fully human antibodies are preferred, and antigen expression is restricted to diseased cells to limit systemic degrader release.
• The antibody should be cynomolgus monkey cross-reactive; mouse cross-reactive preferred.

We are particularly interested in degrader warheads, and both PROTAC and molecular glue degraders will be considered for this Challenge. To ensure the efficacy of DACs, the PROTACs or molecular glue degraders must meet the following requirements:

• Target protein specificity. The molecular glue should be able to exploit short peptide motifs (degrons) on the target protein to ensure selective degradation.
• Chemical stability and solubility. Ideally, the suggested molecules would have a cLogP less than 3.
• Catalytic potency. The molecular glues should ideally have high potency (low nM IC50) to be able to degrade multiple target proteins per conjugate.

There may be instances when a degrader material is not available for a solution build. In these cases, solutions where pathway inhibitors are available will be considered as long as there is ample literature validation of the importance of the pathway (e.g., exemplified by CRISPR or knock-out data). If the proposed degrader target and antibody combination is sufficiently compelling, the Seeker will consider the use of inhibitors to validate the solution and determine the feasibility for developing degraders.

Important! We’re not interested in just a random list of targets, antibodies and potential degraders. Every choice of a target or a DAC component must be thoroughly justified by available data (academic publications, industry reports, clinical trial data, etc.). At the very least, the choice of every molecular entity must be supported by in vitro or in vivo data. Solutions presenting molecular entities supported by available clinical data will be given preferential consideration.

To reiterate: molecular entities that are not supported by at least in vitro and in vivo data will not be considered.

At the same time, there should be a strong rationale for putting the degrader molecule onto an antibody for targeted cellular delivery, e.g., improved safety profile, better stability, and longer half-life. We will not accept solutions that propose degrader/inhibitor moieties that are already maximally efficacious as single-agents, or that do not offer differentiation from their component materials.

SOLUTION REQUIREMENTS

We’re open to any combination of degraders and antibodies as long as the submitted solutions meet the following Solution Requirements:

1. The destruction or strong inhibition of the proposed molecular targets has the potential for positive therapeutic outcomes for patients with lupus, psoriasis, Crohn’s disease, or ulcerative colitis.

2. Ideally, the proposed molecular target will have biomarkers that can be assessed in non-human primates.

3. The proposed antibody will have the following characteristics:

• High antigen specificity and affinity to the molecular target.
• High level of internalization.
• Favorable pharmacokinetics and safety profile.

4. The proposed degrader/inhibitor moiety will have the following characteristics:

• High target protein specificity
• Ideally, high chemical stability in circulation and during intracellular trafficking.
• Ideally, the proposed degrader/inhibitor should have a cLogP less than 3.
• High catalytic potency (ideally, low nM IC50) and the ability to degrade multiple target proteins per conjugate.

Important! We’re not interested in just a random list of targets, antibodies and potential degraders. Every choice of a target or a DAC component must be thoroughly justified by available data (academic publications, industry reports, clinical trial data, etc.). At the very least, the choice of every molecular entity must be supported by in vitro or in vivo data. Solutions presenting molecular entities supported by available clinical data will be given preferential consideration.

At the same time, we will not accept solutions that:

• Propose molecular entities that are not supported by at least in vitro and in vivo data.
• Propose degrader/inhibitor moieties that are already effective and safe as single agents.

Solutions with Technology Readiness Levels (TRLs) 1-3 are invited.

This Prize Challenge has the following features:

1. By taking part and submitting you are granting the Seeker a right to use (but not own) your submitted information, provided that the Seeker pays the threshold of at least $10,000 in awards and decides the award winners within 45 days from the start of evaluation, otherwise the Seeker retains the right to use only Awarded solutions. You will receive notification about the status of your proposal.

2. The Challenge requires a written proposal to be submitted and the best solution(s) have the opportunity to win awards from $2,500 to $20,000 for meeting enough of the requirements criteria. There is no assignment of IP Rights with this challenge absent further agreement between the Seeker and Solver.

3. The award distribution will be determined after theoretical evaluation of the proposals by the Seeker.

4. Solvers may:

• Submit ideas of their own
• Submit third-party information that they have the right to use and further, the authority to convey to the Seeker this right with the right to use and develop derivative works
• Submit information considered in the public domain without any limitations on use

5. The Seeker may also issue “Honourable Mention” recognitions for notable submissions that are not selected for monetary awards.

6. The Seeker may wish to partner with the Solver at the conclusion of the Challenge. Please indicate your interest in partnering.

YOUR SUBMISSION

The submitted proposals must be written in English and can include:

1. Participation type – you will first be asked to inform us how you are participating in this challenge, as a Solver (Individual) or Solver (Organization).

2. Solution Level - the Technology Readiness Level (TRL) of your solution.

3. Partnering - there may be an opportunity to partner at the conclusion of this Challenge. Please indicate if partnering is of interest to you.

4. Problem & Opportunity - highlight the innovation in your approach to the Problem, its point of difference, and the specific advantages/benefits this brings (up to 500 words).

5. Solution Overview - detail the features of your solution and how they address the SOLUTION REQUIREMENTS (500 words, there is space to add more in the summary field, and attach supporting data, diagrams, etc.).

6. Solution Justification – Every choice of a target or DAC component must be thoroughly justified by available data (academic publications, industry reports, clinical trial data, etc.) as to why this would be beneficial over more conventional therapies, to help the Seeker evaluate and validate the feasibility of the solution (up to 500 words).

7. Experience - Expertise, use cases and skills you or your organization have in relation to your proposed solution (up to 500 words).

8. Solution Risks - any risks you see with your solution and how you would plan for this (up to 500 words).

9. Timeline, capability and costs - describe what you think is required to deliver the solution, estimated time and cost (up to 500 words).

10. Online References - provide links to any publications, articles or press releases of relevance (up to 500 words).

PARTICIPATION GUIDANCE

1. Submission Close Date: Submissions to this Challenge must be received by 11:59 PM (US Eastern Time) on August 06th, 2025.
2. Late submissions: Late submissions will not be considered.
3. Multiple submissions, 3 Maximum: In case of multiple submissions by the same Solver, only 3 submissions – the final 3 submitted – will be considered. Any other submissions will be deleted prior to evaluation.
4. Submission form and attachments: Your submission will be evaluated by the evaluation team first reviewing the information and content you have submitted at the submission form, with attachments used as additional context to your form submission. Submissions relying solely on attachments will receive less attention from the evaluation team.
5. Evaluation notification steps: After the Challenge submission close date, the Seeker will review and select the winning ideas/solutions according to the timeline in the Challenge header. Everyone who submits a proposal will be notified about the status of their submissions.
6. Use of AI: Please note that any submissions produced solely with generative AI are not of interest.
7. Learn more: Find out more about participation in Innocentive Challenges.