High antitumor activity of Sortase A-generated anti-CD20 antibody fragment drug conjugates.

08:00 EDT 12th April 2019 | BioPortfolio

Summary of "High antitumor activity of Sortase A-generated anti-CD20 antibody fragment drug conjugates."

Antibody fragments, as the products of engineered antibodies, exhibit great potential for cancer therapy and imaging. Antibody fragment drug conjugates (AFDCs), which conjugate the highly specific, low-immunity and small-sized antibody fragments with cytotoxic payloads, can overcome the limitations of traditional IgG format drugs in cancer therapy. In this study, a commercialized anti-CD20 monoclonal antibody, ofatumumab (OFA), was applied to generate two site-specific monomethyl auristain E (MMAE)-conjugated AFDCs (Fab-vcMMAE, Fab-CH3mut-vcMMAE) by Sortase A mediated transpeptidation. Compared with OFA-vcMMAE, the two AFDCs maintained most of the binding affinity and the ability of internalization. In vitro studies revealed that Fab-vcMMAE and OFA-vcMMAE had almost identical IC50 values against CD20-positive cell lines, while Fab-CH3-vcMMAE had a lower anti-tumor activity. In vivo studies showed that Fab-vcMMAE had a significantly higher maximum tolerated dose (MTDs), a 30-fold shorter half-life, and slightly lower antitumor activity within the MTDs than OFA-vcMMAE. The distribution study showed that both of the Fab and Fab-CH3mut had higher penetration rates into the tumors than OFA in a xenograft model. Additionally, no obvious difference in tumor drug accumulation was found between the Fab and OFA groups after the penetration process, but the Fab-CH3mut group exhibited less tumor drug accumulation, possibly contributing to the inferior anti-tumor activity of Fab-CH3mut-vcMMAE in vivo. Overall, we preliminarily demonstrated the characteristics of AFDCs by studying OFA-based AFDCs. Our results revealed that Fab is a promising carrier of MMAE to enhance the anti-tumor activity and increase the safety profile compared with OFA.


Journal Details

This article was published in the following journal.

Name: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
ISSN: 1879-0720


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Medical and Biotech [MESH] Definitions

A murine-derived monoclonal antibody and ANTINEOPLASTIC AGENT that binds specifically to the CD20 ANTIGEN and is used in the treatment of LEUKEMIA; LYMPHOMA and RHEUMATOID ARTHRITIS.

The phenomenon of immense variability characteristic of ANTIBODIES. It enables the IMMUNE SYSTEM to react specifically against the essentially unlimited kinds of ANTIGENS it encounters. Antibody diversity is accounted for by three main theories: (1) the Germ Line Theory, which holds that each antibody-producing cell has genes coding for all possible antibody specificities, but expresses only the one stimulated by antigen; (2) the Somatic Mutation Theory, which holds that antibody-producing cells contain only a few genes, which produce antibody diversity by mutation; and (3) the Gene Rearrangement Theory, which holds that antibody diversity is generated by the rearrangement of IMMUNOGLOBULIN VARIABLE REGION gene segments during the differentiation of the ANTIBODY-PRODUCING CELLS.

Test for tissue antigen using either a direct method, by conjugation of antibody with fluorescent dye (FLUORESCENT ANTIBODY TECHNIQUE, DIRECT) or an indirect method, by formation of antigen-antibody complex which is then labeled with fluorescein-conjugated anti-immunoglobulin antibody (FLUORESCENT ANTIBODY TECHNIQUE, INDIRECT). The tissue is then examined by fluorescence microscopy.

A form of fluorescent antibody technique commonly used to detect serum antibodies and immune complexes in tissues and microorganisms in specimens from patients with infectious diseases. The technique involves formation of an antigen-antibody complex which is labeled with fluorescein-conjugated anti-immunoglobulin antibody. (From Bennington, Saunders Dictionary & Encyclopedia of Laboratory Medicine and Technology, 1984)

An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed.

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