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ADCs – From Lab to Clinical Development

Antibody-drug conjugates (ADCs) are a family of targeted therapeutic agents for the treatment of cancer. Compared to traditional small-molecule approaches, ADCs offer enhanced targeting of cancer cells along with reduced toxic side effects, making them an attractive prospect for the field of oncology. An antibody-drug conjugate (ADC) is typically composed of a monoclonal antibody (mAbs) covalently attached to a cytotoxic drug via a chemical linker. As all these components affect the ADC performance in equal measure, their optimisation is essential for the development of successful conjugates.

It has taken a while for this field to take off, but to date, over 100 ADCs are under clinical development. Since December 2021, after several decades of efforts to optimise their key components, a total of 14 ADC drugs have received marketing approval in different countries worldwide. Coincidently, half of the approved ADCs are mainly used against haematological malignancies, the rest being prescribed by and large for solid tumours. Medicilon is an integrated contract research organisation (CRO) providing comprehensive one-step new drug R&D for pharmaceutical companies and scientific research institutions around the world. Since May 2022, Medicilon has successfully assisted no less than ten ADC drugs on their path to approval for clinical use, and it’s committed to continuously improving the research capabilities of ADC drugs. As a matter of fact, half of these drugs target the protein HER2 (human epidermal growth factor receptor 2), a member of the HER family of membrane tyrosine kinases, developed for many years as an important target in breast cancer treatment.

The design idea of the ADC drugs is to couple antibodies with cytotoxic drugs, to simultaneously exert the high specificity of antibodies and the high toxicity of cytotoxic small molecules. The emergence of ADC drugs fills the gap between antibody drugs and traditional chemotherapeutic drugs, increasing the specificity of drugs and improving the therapeutic window.

Mechanism of Action of ADCs

When designing an ideal ADC, it’s essential to understand the mechanism of action, for the purpose of identifying the desired features of each of its three components: monoclonal antibody, linker, and cytotoxic small molecule drug (small molecule drugs are linked to monoclonal antibodies through coupling chains).

An ideal ADC is one that retains the selectivity and killing capacity of a mAb while still being able to release the cytotoxic drug in quantities large enough to kill tumour cells. However, each of the steps involved in the mechanism of action is associated with unique challenges that complicate the design of ADCs. The mAb binds to cell-surface antigens expressed on target cells, is internalised via endocytosis, and then transported to the lysosome, where proteases degrade the ADC. Subsequently, the payload is released and diffuses into the cytoplasm, resulting in cell death. Compared with traditional tumour treatment methods (radiotherapy and chemotherapy), ADC drugs have fewer side effects and stronger effects on tumour cells. Limited by the high specificity of the ADC drug antigen and the comprehensive factors that satisfy the effect of the ADC drug, the target must not only exist on the surface of tumour cells but also ensure that it can trigger endocytosis after binding to the antibody to facilitate the transport of cytotoxins into tumour cells. Therefore, the selection of targets is challenging and extremely important.

With more than 18 years of experience in new drug R&D, Medicilon specialises in the development and validation of analytical methods for different targets and can effectively analyse the expression level and accessibility of targets according to specific needs, providing constructive suggestions for target selection.

Essential to the efficacy of ADCs, the selection of highly specific antibodies can greatly reduce the off-target effects of ADC drugs, avoiding the binding of antibodies to the free antigens in the circulation, leading to systemic toxicity, and as a result improving the efficacy and safety of drugs.