Antibody-drug conjugates (ADCs) are a genre of targeted therapy that employ the exquisite selectivity of antibodies for cell surface receptors to deliver highly potent cytotoxins to cancer cells. In recent years, much effort and resources have been injected into this research with the aim of generating advanced conjugate therapeutics. Although the field has seen significant development in that time with 4 ADCs gaining Food and Drug Administration approval (brentuximab vedotin, ado-trastuzumab emtansine, gemtuzumab ozogamicin and inotuzumab ozogamicin), and &gt;50 other ADCs in the clinic, issues still remain with current approaches. Construct instability in circulation and heterogeneous mixtures of ADC are two of the most prevalent issues. The use of linkers that form a chemical linkage which is labile in circulation (e.g. maleimides) can result in premature release of the payload and a subsequent increase in off-target effects. Heterogeneity in the synthesized ADC is typically caused by conjugation at lysine or cysteine residues, generating a mixture of ADC products, each with variable and unpredictable pharmacokinetic profiles.<br/><br/>Recent research in the Spring group has involved the development of a novel plasma-stable divinylpyrimidine (DVP) linker platform. The DVP linkers are cysteine-selective and are capable of “rebridging” the heavy and light chains of native IgGs to form a construct that is analogous to the endogenous antibody structure. This method of conjugation gives precise control over the drug-antibody ratio (DAR) and site of attachment, characteristics that are typically only obtainable with engineereed antibodies. Furthermore, the linker is amenable to further modification, either before or after antibody conjugation to attach various modalities, e.g. fluorophores or cytotoxins. These modified antibodies maintained their cellular specificity and receptor affinity, and a DVP-based ADC demonstrated excellent potency and selectivity for its target cells.

Site-selective generation of stable antibody-drug conjugates via cysteine bridging of native antibodies

256th National Meeting (2018)

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