What kind of sparks can occur when protein degradation meets antibody coupling?

Degrader-antibody conjugates (DACs) are a new molecular pattern that couples targeted protein degraders and monoclonal antibodies through certain chemical linke.

Recently, scientists from the Genentech Discovery Chemistry Division published a review in Chemical Society Reviews, summarizing the latest advances in this field and introducing various strategies for efficient construction of DA.

Advantages of Antibody Conjugated Degraders

Targeted protein degraders represented by PROTAC molecules are a hot spot in the field of new drug developme.

One strategy to improve the in vivo delivery of chimeric degraders is to conjugate them with monoclonal antibodi.

The basic mechanism of action of antibody-drug conjugates

A traditional ADC consists of three parts, a monoclonal antibody targeting a specific antigen, a cytotoxic payload, and a chemical linker that connects the t.

At present, the antibody conjugation technology has undergone multiple iterations, allowing researchers not only to precisely control the drug-to-antibody ratio (DAR), but also to precisely locate the site where the load is coupled to the antibody by introducing unnatural amino acids into the antibo.

Factors to consider when designing antibody-conjugated degraders

While some strategies for making traditional ADCs can be used to make and deliver antibody-conjugated degraders, the design of antibody-conjugated degraders often requires overcoming additional challeng.

For example, the toxic payload of traditional ADCs is broadly toxic to many cells, whereas targeted protein degraders (DACs) typically target targets associated with specific cancers or tissue typ.

Chimeric degraders typically show less potency in in vitro assays than cytotoxic drugs, meaning that more degraders (DARs over 4) may need to be conjugated per mAb to achieve the desired effect effica.

Moreover, the molecular properties of the chimeric degraders may result in the final DACs being larger and more lipophilic than conventional AD.

Design strategies for antibody-conjugated degraders

One of the first DACs to be published in a peer-reviewed scientific journal is a potent DAC (GNE) that uses a cleavable linker containing a disulfide bond to link a BRD4-targeting degrader to a CLL1-targeting monoclonal antibo.

▲ Illustration of GNE-987 (Image source: Reference [1])

This DAC exhibited potent dose-dependent in vivo activity in a xenograft model of acute myeloid leukemia (AML), whereas neither antibody targeting CLL1 nor an unconjugated protein degrader showed in vivo activi.

In some cases, the protein degrader molecule does not have a group suitable for conjugation with the monoclonal antibody, and it may be necessary to add a group that can form a covalent bond to the degrader molecu.

▲Generate DAC by modifying protein degrader molecules (Image source: Reference [1])

DACs targeting STEAP1 optimized based on this strategy exhibited lower toxicity than unconjugated protein degraders in vitro, suggesting that the use of antibody-conjugated technology may improve the therapeutic index of chimeric protein degrade.

In addition to targeted degradation of BRD4, antibody-conjugated degraders have also been used to degrade targets such as estrogen receptor alpha (ERα), TGFβR2, and B.

▲Antibody-conjugated degraders listed in the review (Image source: Reference [1], click to see a larger image)

Conclusion and Outlook

Several biotech companies are already optimizing this technology in an effort to develop innovative treatmen.

▲ORM-5029 showed in vivo activity in a HER2 low expression model (Image source: Orum Therapeutics official website)

The review authors state that the field of antibody-conjugated degraders is still in its infancy, but several antibody-conjugated degraders have demonstrated in vitro and in vivo activity, demonstrating that this therapeutic modality enables targeted delivery of protein degradation payloads to specific tumors or cells .

Based on these promising preliminary results, antibody-conjugated degraders are expected to be further developed and appli.

However, challenges remain in determining which protein-degrading molecules are suitable for conjugation, and how conjugation techniques can best preserve and even enhance the biological activity of degrade.

We look forward to further proof-of-concept of this technology in more studies that are more closely related to the disea.

References:

[1] Dragovi.

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Degrader-antibody conjugates, Chemical Society Reviews, DOI: 11039/d2cs00141a