New Progress Made to Accelerate Development of Antibody-drug Conjugates

The severe side effects of conventional chemotherapeutic treatments can’t be ignored since in most cases, the valid drug dose that can remove the tumor are too toxic for patients. To solve the limitations, the antibody drug conjugates (ADCs) have emerged consisting of tumor-selective antibody-linked drugs, with the potential to significantly broaden the therapeutic range.

Antibody-drug conjugates (ADCs), the focus of tumor treatment in recent years, are complexes composed of monoclonal antibodies, linkers, and payloads, in which monoclonal antibodies have high selectivity, stability and pharmacokinetics while the payloads are characterized by the powerful anti-tumor ability. ADC drugs have the characteristics of both small molecule cytotoxic drugs and macromolecular antibody drugs, and the toxicity of both small molecule drugs and macromolecular antibodies should be concerned in toxicological tests. The type of payloads, the conjugation site, the polymerization and cleavage caused by the combination of antibody and small molecule are all important factors affecting the toxicity.

Although there are currently 4 ADC drugs approved for marketing since the launch of the first ADC drug, multiple limitations from conjugation technology, targeting ability and effectiveness hinder the ADC development. Most payloads are lost on the way to target cancer cells, which, once released into the bloodstream, can lead to severe side effects. Hence, a stable link that between the drug and antibody is the mainstay of long-term efficacy.

A recently innovative technology is developed to achieve a more selective and effective treatment of cancer, which converts proteins and antibodies into stable, powerful drug transporters that more accurately detect and kill tumor cells, making ADCs safer and more effective. The biggest achievement of the new method is that the combination is stable even in the blood circulation process, which can’t be completed by previous ADCs.

The researchers discovered the outstanding properties of unsaturated phosphorus compounds in linking antibodies to chemical drugs, phosphonamidates connecting desired modifications. For example, they can specifically target cysteines in proteins or antibodies, extremely rare and naturally occurring amino acids that can effectively control the number of modifications per protein, which is critical for constructing drug conjugates, and furthermore, phosphonamidates can be easily incorporated into complex compounds. To test the applicability of targeted drug delivery, the investigators compared their technique with the ADC drug Adcetris, which has been approved by the FDA, using the same antibody and active agent to reconstitute the drug as precisely as possible, where the only difference is that the new technique applies the innovative phosphonate amide bond, and when applied to serum, the investigators observed that their modified ADC had significantly less active ingredient over time. In addition, this new technology was also used in mice experiments to combat Hodgkin lymphoma, showing more efficacy than conventional drugs.

What can be concluded from the research is that drug transporters associated with acid amides could be administered at lower doses, thereby further reducing the side effects in the ADC development. The novel technology demonstrates enormous potential for the development of a more effective and safer ADC, expected to take place the conventional method and revolutionize the field of immunotherapy.

Creative Biolabs was founded by scientists who are dedicated to conquering cancer, optimizing the drug development process, leveraging accessible resources.