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The majority of the ADCs currently under development or in clinical trials are for oncological and hematological indications. This is primarily driven by the availability of monoclonal antibodies targeting various types of cancer. However, some drug developers are also looking to expanding the application of ADCs beyond oncology and hematology to other important disease areas.

With the development and requirement of homogeneous ADCs, site-specific antibodies have been obtained via the technology of interchain cysteine cross-linking, besides the recombinant approaches. In recent years, some novel cysteine-reactive functionalities have been developed to yield site-specific antibody fragments or full antibodies via the insertion of specially designed chemical molecules or groups into native disulfide bonds, such as pyridazinedione, dibromopyridazinedione, dibromomaleimide, and bis-alkylating bis-sulfone groups. Compared to analogous heterogeneous ADCs, the homogeneous ADCs prepared from site-specific antibodies exhibit reduced toxicity and superior efficacy in vivo.

 

What's the ADCs?

Antibody Drug Conjugates (ADCs) are a rapidly expanding area in the pharmaceutical industry. They comprise of a desirable monoclonal antibody, an active cytotoxic drug and an appropriate linker. There are over 30 ADCs currently in pre-clinical or clinical development, and further improvements may be required to enhance the therapeutic potential of these ADCs. Monoclonal antibodies (mAbs) are of great use in many applications ranging from basic research to treatment of disease. The Drug-Linker Conjugates can expand the utility of mAbs and improve their potency and effectiveness; the antibodies are thus used as a means to target and delivery a toxic payload to the selected diseased tissue. The site-specific conjugations of Drug-Linker to an antibody may involve genetic engineering of the mAb to introduce discrete, available cysteines or non-natural amino acids with an orthogonally-reactive functional group handle such as an aldehyde, ketone, azido, or alkynyl tag. These site-specific approaches not only increase the homogeneity of ADCs but also enable novel bio-orthogonal chemistries that utilize reactive moieties other than thiol or amine. The cytotoxic drug, monomethyl auristatin E (MMAE), is conjugated to the three trastuzumab variants using a protease cleavable linker and shows in vivo therapeutic efficacy. The linker-MMAE conjugate is used in the U.S. FDA approved ADC, Brentuximab vedotin. There are also ADCs adopting linker-MMAE conjugate under clinical trials, such as Enfortumab vedotin and Glembatumumab vedotin.

Finally,we currently have more than 25 antibody-drug conjugates in our pipeline and hope this promisingapproach will help us deliver more medicines to fight other cancers in the future.

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