Molecular Glue–Antibody Conjugate

In the rapidly advancing world of biotechnology, Molecular Glue–Antibody Conjugates (MACs) are emerging as a groundbreaking approach to enhance the precision and efficacy of targeted therapies. By combining the specificity of antibodies with the unique properties of molecular glues, MACs offer a revolutionary platform for addressing complex diseases such as cancer, neurodegenerative conditions, and autoimmune disorders. As a professional biotech company, BOC Sciences offers comprehensive molecular glue-antibody conjugates services.

What is Molecular Glue–Antibody Conjugate (MAC)?

Molecular glue-antibody conjugate (MAC) is a new type of antibody-drug conjugate (ADC). Instead of the cytotoxic drugs in traditional ADCs, MAC uses molecular glue as the payload to induce small molecules that form a tight protein-protein interaction between the target protein and E3 ubiquitin ligase, thereby achieving ubiquitination degradation.

Molecular glue-antibody conjugate (MAC) (Poudel, Yam B., 2024)

MAC mechanism of action

The mechanism of action of molecular glue-antibody conjugates (DAC) is similar to that of traditional ADCs. The target antigen is recognized by the antibody, and after internalization, the linker can be cleaved and released by enzyme cleavage to exert its effect. However, the cytotoxic drug is replaced by PROTAC or molecular glue.

The molecular glue binds to the E3 ligase and generates a hot surface, which then interacts with the second target protein to form a stable protein-molecular glue-protein ternary complex. According to specific needs, the molecular glue can inhibit the interaction of proteins, destroy stability, and modify the structure.

General mechanism of the molecular glue−antibody conjugate (MAC).(Poudel, Yam B., 2024)

Advantages of Molecular Glue–Antibody Conjugates

• The payload in traditional ADC is usually widely cytotoxic, while MAC improves targeting by using molecular glue;
• Compared with PROTAC, molecular glue has a smaller molecular weight, simpler structure, higher membrane permeability and solubility, and solves the problem of cross-biomembrane and oral bioavailability.
• Molecular glue is usually easier to process comprehensively to quickly develop structure-activity relationship (SAR);
• In addition to promoting degradation, molecular glue can also regulate the function of protein or enhance its activity, making it flexible in a variety of treatments, such as autoimmune diseases, infections, etc.;
• Molecular glue often exhibits better physicochemical and ADME properties and higher drugability.

Challenges of Molecular Glue–Antibody Conjugates

• Due to the need to induce protein-protein interaction, the process often involves conformational changes in proteins, which makes the early discovery of molecular glue drugs usually have a low hit rate;
• Molecular glues are generally less potent than cytotoxic drugs, so a high drug loading (DAR is generally greater than 4) is required. This high drug loading is bound to cause aggregation problems and have a negative impact on the drug's metabolic kinetics;
• MAC is usually more lipophilic than the payload of ADC, so new linker designs and coupling methods need to be developed to overcome this problem;
• Linker optimization to keep it stable in the blood circulation, but after reaching the tumor cells, the linker needs to be able to be effectively cut in the lysosome;
• The stability of molecular glue in the lysosomal system, the ability of the degrader payload to effectively escape the lysosomal compartment, and the bystander effect tendency of the payload, etc.

Our MAC services

Selection of Suitable Molecular Glue: First, a suitable molecular glue is chosen based on the target protein and intended application. Molecular glues are molecules that can enhance specific protein-protein interactions, acting as a "bridge" to regulate protein function. Common examples include E3 ligase ligands like CRBN and VHL.

Chemical Modification of Molecular Glue: The stability and activity of the molecular glue degrader are essential. Chemical modifications can be made to enhance its stability while maintaining or improving its ability to induce protein degradation. Additionally, structure-activity relationship (SAR) studies can be conducted to optimize the pharmacological properties of the molecular glue. To enable binding to the antibody, molecular glues often require chemical modification. Active groups on the molecular glue, such as hydroxyl or amino groups, can be used for further conjugation.

Optimize Antibody Selection: Selecting antibodies with high specificity and strong affinity can enhance the tumor-targeting capability of MACs. Additionally, consider the antibody's immune-effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as these may help improve the therapeutic efficacy of MACs.

Enhance Linker Design: The linker should be stable in the bloodstream to prevent premature drug release before reaching the tumor. Once at the tumor site, however, the linker needs to be cleavable in lysosomes to release the molecular glue degrader. Using pH-sensitive, enzyme-sensitive, or reducible linkers can ensure specific release within tumor cells.

Optimize Conjugation Chemistry: Properly designing the conjugation site and method ensures that linking the drug to the antibody does not impair the antibody's biological function while also ensuring efficient drug release. Site-specific conjugation techniques can be considered to control the drug-to-antibody ratio (DAR) and conjugation site.

• Click Chemistry: Introducing complementary alkyne and azide groups on the molecular glue and antibody to perform a copper-catalyzed reaction.
• Thiol-Maleimide Conjugation: Thiols and maleimides introduced on the molecular glue and antibody can form stable covalent bonds through thiol conjugation.
• Peptide Bond Formation: Carboxyl or amino groups on the molecular glue and antibody are linked through amide bonds.

Optimize Biodistribution and Pharmacokinetics: By adjusting the molecular weight of MACs, applying surface modifications (e.g., PEGylation), or utilizing nanotechnology, it is possible to improve biodistribution and pharmacokinetics, increase tumor tissue concentration, and reduce nonspecific distribution and toxicity.

Purification: After conjugation, purification is performed to remove unreacted molecular glue, antibody, and by-products. Common methods include:

• Dialysis: To remove small molecular impurities.
• Chromatography: Techniques such as affinity chromatography or size-exclusion chromatography help isolate the target conjugate.

Our technical advantages

Cutting-Edge Bioconjugation Expertise: Our company has advanced expertise in bioconjugation, enabling us to precisely engineer molecular glue–antibody conjugates that maintain high stability, activity, and specificity. This expertise allows us to produce MGACs with optimal binding and degradation properties, setting us apart as a leader in next-generation therapeutic development.

Comprehensive Target Discovery and Validation: Our team utilizes state-of-the-art technologies for target discovery and validation, allowing us to identify and evaluate disease-relevant targets suitable for MGAC intervention. This capability ensures that our MGAC products are based on validated targets, increasing their potential efficacy and therapeutic impact.

Customized Solutions and Flexible Development: We offer custom MGAC development tailored to our clients' specific needs, from target selection to final conjugate. Our flexible approach supports clients in the pharmaceutical and biotechnology sectors with proprietary MGAC solutions that align with their therapeutic objectives, ensuring adaptable and collaborative partnerships.

Integrated Production and Quality Control: Our company boasts an integrated production pipeline, including conjugate synthesis, purification, and rigorous quality control protocols. This ensures high-quality, reproducible MGACs that meet stringent industry standards. Our advanced analytical tools allow us to confirm purity, activity, and stability, fostering client confidence in our product quality.

Diverse Therapeutic Applications: We are pioneering MGAC technology across various disease areas, including oncology, autoimmune disorders, and neurodegenerative diseases. Our versatile technology platform makes us well-suited for developing MGACs targeting a wide range of conditions, which expands our market reach and addresses significant unmet medical needs.

Proven Track Record in Protein Degradation Technologies: With an established track record in protein degradation technologies, our company is well-positioned as a trusted leader in targeted protein degradation. Our experience with various degradation pathways and molecular glue compounds enables us to design highly effective MGACs, distinguishing us from competitors in the bioconjugation and targeted therapy fields.