Degrader-Antibody Conjugation (DAC)

As a leading CRO in the field of drug development, BOC Sciences has been supporting customers at the forefront of drug conjugation. Degrader-antibody conjugates are a new type of molecular pattern that combine targeted protein degraders to monoclonal antibodies. We provide comprehensive services from the synthesis route design of complex degrader to the biological and pharmacological activity test of final generated antibody degrader conjugate. Based on a one-stop service platform covering preclinical development and commercial production, we have the capability to perform medicine chemical synthesis, chemical analysis and purification, kilogram-scale amplification, bioconjugation, and corresponding bioactivity testing services.

Degrader-Antibody Conjugates

Degrader-antibody conjugates (DACs) are a novel molecular paradigm that links target protein degraders with monoclonal antibodies through a chemical linker. In recent years, Targeted Protein Degradation (TPD) technology, a hot topic in the field of drug development, has rapidly evolved, with numerous degraders discovered for over 70 disease targets. Targeted protein degraders can bind to target proteins while also binding to E3 ligases, directing the target proteins for degradation within the cell's proteasome. Additionally, lysosome-mediated TPD technologies (e.g., LYTAC) have been introduced as supplemental methods for regulating protein homeostasis inside cells.

Fig. 1 Diagram of the antibody degrader conjugate¹

However, these degrader molecules often exhibit poor drug metabolism and pharmacokinetics (DMPK) characteristics, such as low oral bioavailability and rapid clearance in the body. An approach to enhance the in vivo delivery of degraders is to conjugate them with monoclonal antibodies. Antibody-drug conjugation (ADC) technology has received clinical validation in delivering cytotoxic payloads. Compared to unconjugated degrader molecules, antibody degrader conjugates may offer the following advantages:

• The ability to target specific antigens using monoclonal antibodies for the delivery of degrader molecules to particular tumors or tissues.
• Enhanced in vivo delivery of degrader molecules with unfavorable physicochemical or DMPK characteristics.
• Avoiding the need for complex and non-standard formulations to improve the in vivo bioavailability of unconjugated degraders.

Design of Antibody Degrader Conjugate

Compared to ADC production, the design of degrader-antibody conjugates typically involves overcoming more challenges.

• Target Selection

Traditional ADC payloads have broad toxicity to many cells, whereas DACs are usually directed toward targets associated with specific cancers or tissue types. We will carefully consider selecting antigens highly expressed on tissues or cells with antigens highly expressed sensitive to degrader payloads during target screening.

• DAR Control

Compared to cytotoxic drugs, DACs may exhibit lower potency in in vitro assays, meaning that more degrader molecules (DAR exceeding 4) may be required to achieve the desired efficacy on each monoclonal antibody. We can customize DACs with a specific degrader/antibody ratio based on the client's requirements.

• Linker Optimization

The molecular properties of DACs may lead to larger final molecules than traditional ADCs and possess increased lipophilicity, which may enhance molecular aggregation and affect pharmacokinetics. With our comprehensive bioconjugation platform and unique purification techniques, we provide linker design and conjugation method development services.

Conjugation of Antibody to Degraders

BOC Sciences is committed to solving all drug conjugation-related issues for our clients and selects the optimal conjugation methods based on different project objectives. For antibody degrader conjugates, we have the capability to innovate more efficient conjugation methods and provide optimized conjugate design strategies.

• Peptide Linker

In some cases, protein degraders may lack functional groups suitable for conjugation with monoclonal antibodies, requiring the introduction of groups into the degrader molecule that can generate covalent bonds. For example, introducing amine or aryl-amine groups into the degrader molecule provides sites for covalent linkage through a peptide linker on the targeted antibody, resulting in the formation of the desired molecule DAC.

• Disulfide Bond

We can use cleavable linkers containing disulfide bonds to connect targeted degraders with monoclonal antibodies, forming potent DACs. By introducing them at specific positions on the antibody using engineered cysteine residues, we can control DAR values through site-specific conjugation.

Our Advantages

• Small molecule degreder development and small molecule screening
• Comprehensive technology platform for drug screening and monoclonal antibody preparation
• Multiple site-specific conjugation techniques
• In vitro and in vivo experimental testing and animal lab validation of targeting efficiency
• Advanced instruments such as HPLC, Prep-Chromatography, LCMS/MS, GC/MS, IC