How to Rapidly Develop Antibody-drug Conjugates for Cancer Treatments?

MolecularCloud Team 01:10:56 04/01/2021

Antibody drug conjugates (ADCs) for cancer treatments refer to a relatively new type of cancer immunotherapy that applies monoclonal antibodies to locate specific malignant cells and meanwhile relies on chemotherapeutic drugs to destroy them. In an ADC, the antibody and the drug are united by a linker, which ensures that the chemical drug won’t be released unexpectedly before reaching to the antibody targeting site, thus avoiding off-target toxicity. With hundreds of on-going clinical trials and more than 8 FDA-approved drugs, ADCs are very promising for the treatment of a variety of cancers.

However, most of conventionally designed ADCs are heterogeneous and not effective for clinical use. Contrastingly, homogenous ADCs are more stable but require a longer procedure of manufacture and could possibly raise considerable immunogenicity. How to quickly make safer and more efficient ADCs? That’s a question of critical concern haunting many scientists.

In a research published in Science Advances, the issue seems to be resolved. A research team from University of Southern California designed a new type of “linker” that can rapidly catalyze the conjugation of drug molecules to the antibodies at a specific site and ensure fast release of the drugs into target cells (Science Advances, 2020). In another word, they found a new way to rapidly synthesize ADCs with enhanced safety and higher efficiency.

In this study, a native human CD38 enzyme was used for the development of site-specific ADCs. CD38 is a transmembrane protein that belongs to the adenosine diphosphate (ADP)-ribosyl cyclase family, thus those newly designed ADCs are termed as ADP-ribosyl cyclase–enabled ADCs (ARC-ADCs). Researchers firstly designed two types of bifunctional antibody-CD38 fusion proteins, named CD38 N-fusion IgG and CD38 C-fusion IgG (as showed in below figure) and then respectively combined them with a novel CD38 covalent inhibitor, which could rapidly bind with CD38 through a stable arabinosyl-ester bond with the catalytic glutamate 226 (E226) residue. Their research data showed that the genetic fusion of CD38 to the antibody has little effects on antibody binding and its enzymatic activity.

Schematic of designed CD38 N-fusion IgG and CD38 C-fusion IgG.

To move forward, they attached the linker to a model payload, tubulin inhibitor monomethyl auristatin F (MMAF) to create an anti-HER2 (human epidermal growth factor receptor 2) ARC-ADC, in vitro cytotoxicity of which was tested in four breast cancer cell lines. The results indicated excellent in vitro potency and specificity for the anti-HER2 ARC-ADC. With the promising data, the researchers further examined in vivo efficacy of the anti-HER2 ARC-ADC for established tumors in mice and found out that it could effectively block the growth of breast cancer tumors and meanwhile leave no loss of body weight or apparent toxicity in the animals.

This study, as concluded by the authors, demonstrates a new approach for generation of site-specific ADCs, which may lead to the development of a novel class of ADCs with potentially enhanced properties for fighting various human diseases.

Reference
Dai, Zhefu, et al. "Synthesis of site-specific antibody-drug conjugates by ADP-ribosyl cyclases." Science Advances 6.23 (2020): eaba6752.

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Q1: Who firstly presented the concept of antibody drug conjugate?