The convergence of Antibody-Drug Conjugates and Targeted Protein Degraders creates Degrader-Antibody Conjugates: an emerging novel drug modality

STUTTGART, Germany I September 04, 2024 I La Merie Publishing released its newest report with a landscape description and analysis of degrader-antibody conjugate (DAC) stakeholders, platform technologies, development and discovery pipelines and partnering deals from an industry perspective as of September 2024:

Degrader-Antibody Conjugates 2024: A Landscape Analysis of Stakeholders, Technologies, Pipeline and Partnering from an Industry Perspective

The emerging novel drug modality of degrader-antibody conjugates represents the convergence of the existing technologies of antibody-drug conjugation and targeted protein degradation with the goal of combining the strengths and avoiding the limitations of both technologies. DACs combine the specificity of antibodies with the efficiency of degraders of difficult-to-drug protein targets. Degrader-antibody conjugates provide plenty of opportunities for ADC companies to use a novel payload to improve efficacy and the therapeutic window and for targeted protein degradation (TPD) companies to improve cell-specificity, half-life and drug-like properties.

The report brings you up-to-date with information about and analysis of:

• Stakeholders in the field, by company profiles of DAC activities at pharmaceutical and TPD technology companies;
• DAC technologies using PROTAC and molecular glue for proteasomal degradation for intracellular TPD;
• Proteins-of-interest for intracellular degradation;
• E3 ligases used for intracellular degradation;
• DAC technologies using broadly acting degraders for extracellular TPD; and
• DAC technologies with lysosomal pathway degraders;
• Clinical and non-clinical development pipeline of DACs;
• Profiles of clinical stage DACs;
• DAC discovery pipeline;
• Preclinical proof-of-concept of DAC conjugate technologies and constructs;
• Partnering activities (acquisition, licensing, collaborations)

The original concept of degrader-antibody conjugates defines DACs as tumor-targeted antibodies chemically conjugated to proteolysis-targeting chimera (PROTACs). PROTACs are large heterobifunctional small molecules with one part binding to the intracellular protein of interest (PoI), e.g. Bruton’s Tyrosine Kinase (BTK), via a linker to a second part which binds to an E3 ligase that ubiquitylates the PoI, resulting in proteasomal degradation in the cytosol. The majority of DAC discovery programs rely on this concept, but DAC using a molecular glue instead of a PROTAC are also being pursued and even are the first in clinical evaluation. Molecular glue-type small molecules act as an glue that enhances the interaction between an E3 ligase and a PoI, leading to its ubiquitylation and proteasomal degradation. PROTACs are easier to design than glues given their independent binding sites to the E3 ligase and the PoI. However, they are generally large molecules that can be challenging to develop, whereas glues are typically smaller and more “drug-like”.

The scope of degrader-antibody conjugates is currently being expanded into the extracellular space for degradation of membrane bound and soluble proteins. Extracellular targeted protein degradation involves bispecific biologics or small molecules that recruit the PoI, either membrane-bound or secreted (soluble), to a degradation machinery. Degradation may occur through a transmembrane E3 ligase, or a cytokine receptor or via a membrane bound recycling receptor for transport of the PoI to the lysosome, which is the typical pathway for the degradation of extracellular proteins.

The report “Degrader-Antibody Conjugates 2024: A Landscape Analysis of Stakeholders, Technologies, Pipeline and Partnering from an Industry Perspective” can be acquired at La Merie Publishing’s online store: https://lamerie.com/report/degrader-antibody-conjugates-2024-a-landscape-analysis-of-stakeholders-technologies-pipeline-and-partnering-from-an-industry-perspective/

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SOURCE: La Merie Publishing