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Creative BioLabs is a contract research organization based in New York that specializes in antibody discovery and engineering. ADCs (antibody-drug conjugates) are chemotherapeutic agents designed to selectively deliver cytotoxic drugs to tumor cells. The effectiveness of ADCs depends on the drug antibody ratio (DAR), with an optimal range of 3 to 4. Highly potent anti-tumor agents have shown clinical efficacy in ADC format. Physicochemical properties and linker stability are important in ADC design. Strategies for high DAR ADCs include PEG-based bioconjugation technology and hydrophilic polymer-based linkers. Biodegradable polyacetyl drug carriers and antibody-targeted nanotherapeutics are also promising approaches. These technologies have the potential to enhance therapeutic response in cancer treatment. Welcome to Creative BioLabs, 100% of the effort, 100% of the service. As a dynamic contract research organization, we are based in New York and serve the whole world. Our seasoned scientists are skilled in antibody discovery, antibody engineering, and biomanufacturing solutions. Hello, today I am very glad to have you to share the knowledge of HIDAR ADCs. Can you give us a brief review about ADCs and the mechanism of action when ADCs work in vivo? Thank you for having me here today. ADCs for oncology applications are chemotherapeutic agents designed to selectively deliver cytotoxic drug payloads to neoplastic tissues. Its main components include antibodies, linkers, and small molecule cytotoxic drugs. These agents target cells that are characterized by surface presentation of tumor-associated antigens that are recognized by the antigen-specific domains of antibodies. Then these agents could selectively kill tumor cells with the cytotoxic drug payloads. According to recent research publications, it seems that lots of chemotherapeutic agents can be evaluated as payloads for ADC therapeutics, is that right? Not exactly. Although a variety of clinically validated chemotherapeutic agents with different biological mechanisms of action have been evaluated as payloads for ADC therapeutics, such as venblastine, methotrexate, doxorubicin, only a few classes of highly potent anti-tumor agents have shown clinical efficacy in an ADC format. Well, that is really a bad news. What do you think are some of the reasons that prevent some chemotherapeutic agents to be effective in an ADC form? There are many reasons. For example, the efficacy of ADC therapeutics depend on their physicochemical properties, which directly relates to drug antibody ratio, or DAR. If the DAR is too low, the antibody carrying efficiency is low. If the DAR is too high, the body will recognize it as a foreign body and remove it quickly. This is a complex regulatory process which could result in unintended toxicity or lead to lower therapeutic index. There are many restrictions on the choice of chemotherapeutic agents, and we need high-potency ADC payloads. So DAR is a key parameter in the design of ADCs, isn't it? Yes, maximum therapeutic index can be achieved by decreasing antibody drug loading. An average DAR of 3 to 4 was accepted as an optimal range for achieving maximum therapeutic index, and this became a key feature for these ADC classes independent of bioconjugation strategies or linker design. When payloads have ultra-high potency, the ADC DAR is typically limited to 2. The level of cytotoxic activity for majority of the validated small-molecule chemotherapeutic agents, including targeted agents used in the clinic to treat a variety of neoplastic malignancies, is significantly lower than the activity of ADC payloads. Can these agents be considered for ADC applications? To our delight, over the last few years, continuous improvements in drug linker selection, bioconjugation chemistry, and site-specific antibody engineering have dramatically changed the approaches of ADC design, and have created new opportunities for ADCs with high drug load. Growing evidence from both animal oncology models and clinical studies suggests that a new generation of ADCs with high drug load that combine moderately active chemotherapeutic agents with novel hydrophilic linkers may be a means of addressing this problem. Are there some strategies for high drug antibody ratio ADCs? Of course, I see new opportunities with designing ADCs with high drug load, such as recent progress in ADC and better understanding of the relationships between ADC drug load, drug linker stability, hydrophilicity, size, and in vivo properties, such as PARC and tissue disposition, as well as better understanding of the interaction with biological targets and reticular endothelial system. Careful selection of drug linker and payload is a good strategy that can result in ADC therapeutics with improved physical chemical and PARC properties. In addition, antibody-targeted nanotherapeutics, a growing and diverse class of anti-cancer agents are specifically designed for delivery of significant amounts of drug payload. All these strategies applied to the next generation of antibody-targeted agents could potentially expand the range of drug payloads, introduce new mechanisms of action, and improve the therapeutic index of ADCs for cancer treatment. When it comes to the strategy of drug linker, what techniques can be used for high DAR ADCs? For best therapeutic activity, a moderately stable linker with an intermediate drug release rate in serum can be specifically selected over more stable linkers. PEG-based bioconjugation technology and hydrophilic polymer-based linkers are useful for high DAR ADCs. Why is PEG-based bioconjugation technology useful for high DAR ADCs? PEG protein conjugates are regarded as immunologically safe and non-toxic. The highly hydrophilic nature of PEGs makes them very amenable for ADC applications, because they reduce the hydrophobicity of linkers and cytotoxic payloads. For example, in the company Immunomedics' high-loaded ADC technology, the hydrophobicity of the highly insoluble payload SN38, a DNA toposomerase I inhibitor, is reduced with adding a short PEG moiety in the drug linker. The drug payload is stabilized by attaching the drug linker to the 20-hydroxy position of SN38, thereby preventing the lactone ring from opening to the less active carboxylic acid form under physiological conditions. Why is hydrophilic polymer-based linker useful for high DAR ADCs? So about three decades ago, water-soluble polymer drug conjugates were recognized as an attractive drug delivery platform for active drug targeting by antibodies. Water-soluble stealth polymer carriers allow for an increase in ADC drug payload, from DARs of 2 to 4 to DARs of 10 to 20, and provide a significant increase in ADC anti-tumor activity without losing PARC properties. Are there other strategies for high DAR ADCs development? Sure. According to some research, biodegradable polyacetyl drug carriers have been used for high DAR ADCs development, such as Flexamer platform, Dolaflexin platform and HPMA drug conjugate-based ADCs. Biodegradable polyacetyl polymer carrier poly-1-hydroxymethylethylene hydroxymethylformyl, also known as Flexamer, was used to create high drug load ADCs. The high hydrophilic nature and polyvalency properties of the Flexamer polymer can reduce the hydrophobicity associated with high DAR ADCs, and thus overcome the limitations of direct ADCs by permitting high drug loading, with a variety of payloads without compromising the physicochemical and PARC properties of the ADC. The polymer backbone has several hydroxy groups suitable for further modification, and can be used to accommodate a high drug load. This allows for a significant increase in the ADC drug load, even when a limited number of bioconjugation sites are available on the antibody.Break time equals 20 milliseconds, greater than. Then we move to Dolaflexin. It consists of the Flexamer polymer conjugated to 4-5 molecules of Oristatin FHPA. It was designed to create high loaded ADCs with Oristatin FHPA which is a novel, synthetic analog of the natural product Dolastatin-10. A conventional conjugation approach was using cysteine residues, which can move up the DAR to 12-15. Then finally, HPMA-based ADCs were developed for the treatment of B-cell non-Hodgkin's lymphomas and tested in preclinical models. Epirubatai is a clinically validated chemotherapeutic agent with sub-micromolar potency. It was incorporated onto HPMA polymer carrier by a controlled living polymerization technique, resulting in a well-defined, high-loaded, polymer drug conjugate functionalized with terminally malamedo groups for cysteine conjugation. Sounds exciting. These biodegradable polyacetyl drug carriers are very useful for delivering more payload. Is antibody-targeted nanotherapeutic a very attractive targeted delivery carriers for small molecule cytotoxic drugs? Definitely. Antibody-targeted nanotherapeutics are a diverse class of therapeutic agents that combine active tumor targeting with antibodies, antibody fragments, or alternative protein-based recognition scaffolds. These therapies can use a wide range of drug delivery systems or nanocarriers, such as liposomes, water-soluble polymer drug conjugates, polymeric nanoparticles, polymeric macheles, carbon nanotubes, just to list a few. Targeted nanocarriers have been developed for delivery of a variety of macromolecular agents, such as proteins, oligonucleotides, serna, mRNA, and other emerging gene therapy products. So nanotherapeutics can also carry significant amounts of payload, a few to dozens, of molecules per construct, in the case of water-soluble polymer drug conjugates, and hundreds of thousands of drug molecules per nanoparticle in the case of liposomes. Several non-targeted nanotherapeutics were approved for cancer treatment and include the seven liposomal formulations. Thank you for sharing these insightful knowledge. At the end, could you summarize for us high DA or ADCs? Yeah. Emerging technologies and innovative approaches to create a new generation of high drug-loaded ADCs are transforming the current ADC playing field. New generation, high-loaded ADCs have demonstrated good physicochemical properties, excellent PARC profiles, superior efficacy in low-target expressing tumors, and acceptable tolerability. Several high drug-loaded ADCs based on distinct technologies are currently in clinical studies, and a few more are in the late stages of preclinical development. There is a high potential for these new generation ADCs to enhance therapeutic response. I believe there will be more breakthroughs in the future.
