Degrader-antibody conjugates (DACs) have emerged as an innovative approach for the targeted delivery of chemotherapeutics, offering the potential for more efficient and precise cancer treatment. Clinical trials for DACs have recently begun, signaling advancement in this therapeutic field. One notable development is ORM-6151, a CD33-antibody enabled proteolysis targeting chimera (PROTAC) degrader designed for acute myeloid leukemia (AML). It has shown potent activity against CD33-expressing cell lines and primary relapsed/refractory AML patient blasts, as well as robust efficacy in vivo.

 

Antibody-PROTAC Conjugates Demonstrate Precise Protein Degradation

A cell-targeted approach using an antibody-PROTAC conjugate demonstrated selective degradation of receptor-interacting serine/threonine-protein kinase 2 (RIPK2) in human epidermal growth factor receptor 2 positive (HER2+) cell lines, while HER2- cell lines were not affected. This selective degradation suggests the specificity and potential of such conjugates in targeted cancer therapy. Another study highlighted the discovery of a DAC that, by improving the pharmacokinetic properties of a chimeric protein degrader, resulted in antigen-specific tumor regressions in vivo.

 

ORM-5029: Promising Antibody Neodegrader Conjugate (AnDC) for HER2+ Cancer

The concept of combining the catalytic approach of protein degradation with the precision of tumor-targeting antibodies is further exemplified by ORM-5029. This therapy is aimed at HER2-expressing breast cancer cells and represents a first-in-class targeted protein degradation approach using an antibody neodegrader conjugate (AnDC). ORM-5029 is also being evaluated in a phase 1 study for its safety and efficacy in patients with HER2-expressing advanced solid tumors.

 

DACs Achieve Tissue-Specific Protein Degradation for Targeted Therapy

In terms of targeted tissue specificity, an antibody–PROTAC conjugate selectively induced degradation of bromodomain-containing protein 4 (BRD4) only in HER2 positive breast cancer cell lines, showing a proof-of-concept for tissue-specific degradation. The process of creating DACs involves combining a PROTAC payload with a monoclonal antibody through a chemical linker, and despite challenges in construction, some biologically-active DACs have been successfully prepared using diverse PROTAC payloads and E3 ligases.

 

Expanding ADC Strategies: bsADCs and BTK Degrader Approaches

Exploring novel approaches such as the SORT1×HER2 bispecific antibody-drug conjugate (bsADC), aimed at improving the efficacy of HER2-targeted treatment in tumors with low HER2 expression, further illustrates the versatility of ADC-based strategies. Moreover, CD79b ADCs that deliver a Bruton’s tyrosine kinase (BTK) degrader have shown promising results in vitro and in vivo, indicating a potential new approach for treating B-cell malignancies.

 

Hybrid T-PBA and PARC Innovations Show Promise in Cancer Treatment

An innovative hybrid molecular degrader-antibody conjugate called T-PBA has demonstrated a strong cytotoxic effect on Her2-positive cancer cells in vitro, adding to the arsenal of potential treatments in the ongoing battle against cancer. Additionally, a photoresponsive antibody-siRNA conjugate (PARC) has been developed for tumor-specific and photoinducible siRNA delivery, targeting intracellular PD-L1 mRNA for immunogene therapy of cancer. Other studies have focused on using an Endo180 ADC for treating sarcoma, showing specific cell death in Endo180-expressing sarcoma cell lines and impacting metastatic colonization.

 

Understanding ADC/PDC Pharmacokinetics: Improving Drug Distribution

Lastly, the pharmacokinetics of ADCs and PDCs are essential for understanding drug distribution in vivo. A study suggested a simple mathematical pharmacokinetic equation to provide rough estimations of drug distribution during animal testing, which could serve as a basis for further refinements.

Source:
https://www.geneonline.com/targeted-cancer-therapy-breakthrough-degrader-antibody-conjugates-dacs-advance-to-clinical-trials/
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