With 5 approved and commercially available antibody-drug conjugates, this class of therapeutics, combining the efficacy of small-molecule therapeutics with the targeting ability of a monoclonal antibody have rapidly become a valuable tool in the treatment of cancer and hematological diseases.

By combining the antibody with highly cytotoxic small-molecule drugs, ADCs can be delivered more effective to cancerous target tissues, enhancing efficacy while reducing the potential systemic toxic side effects of payload drug.

In the development of antibody-drug conjugate, site-specific modification of native antibodies has proven advantageous. One reason is that it enhances the properties of antibody-based bioconjugates without the need to manipulate the genetic code.

However, native antibody modification is typically limited to strategies that introduce a single functional handle.

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In an article published in the August 2019 edition of Bioconjugate Chemistry, Joshua A. Walker, John J. Bohn, Francis Ledesma, et al. addressed the limitation by designing heterobifunctional substrates for microbial transglutaminase (MTG) that contain both azide and methyltetrazine “click” handles.[1]

The scientist evaluated the structure-conjugation relationships for these substrates using the Her2-targeted antibody trastuzumab.

Förster resonance energy transfer (FRET), a widely used single-molecule technique for measuring nanoscale distances from changes in the non-radiative transfer of energy between donor and acceptor fluorophores, was used to demonstrate that these chemical handles are mutually orthogonal. This orthogonality was leveraged for the one-pot synthesis of a bifunctional antibody-drug conjugate.

Containing a maytansine-derived payload and a hydrophobicity-masking polyethylene glycol (PEG) side chain, this ADC demonstrated potent in vitro activity in SKOV3 cells*.

Based on the results, the scientist noted that their studies establish the dual “click” approach as a novel, powerful technique in the toolbox for native antibody modification.

* SKOV3 cell lines, also known as SKOV-3; SK.OV.3; SK-OV-3; Skov3 and SKO3 is an ovarian cancer cell line derived from the ascites of a 64-year-old Caucasian female with an ovarian serous cystadenocarcinoma.

[1] Walker JA, Bohn JJ, Ledesma F, Sorkin MR, Kabaria SR, Thornlow DN, Alabi CA. Substrate Design Enables Heterobifunctional, Dual “Click” Antibody Modification via Microbial Transglutaminase. Bioconjug Chem. 2019 Aug 21. doi: 10.1021/acs.bioconjchem.9b00522. [Pubmed][Article]

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