RESUMO
Antibody-drug conjugates (ADCs) are a new class of therapeutics that combine the lethality of potent cytotoxic drugs with the targeting ability of antibodies to selectively deliver drugs to cancer cells. In this study we show for the first time the synthesis of a reactive-oxygen-species (ROS)-responsive ADC (VL-DAB31-SN-38) that is highly selective and cytotoxic to B-cell lymphoma (CLBL-1 cell line, IC50 value of 54.1â nM). The synthesis of this ADC was possible due to the discovery that diazaborines (DABs) are a very effective ROS-responsive unit that are also very stable in buffer and in plasma. DFT calculations performed on this system revealed a favorable energetic profile (ΔGR=-74.3â kcal mol-1 ) similar to the oxidation mechanism of aromatic boronic acids. DABs' very fast formation rate and modularity enabled the construction of different ROS-responsive linkers featuring self-immolative modules, bioorthogonal functions, and bioconjugation handles. These structures were used in the site-selective functionalization of a VL antibody domain and in the construction of the homogeneous ADC.
Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Imunoconjugados/farmacologia , Linfoma de Células B/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Compostos de Boro/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imunoconjugados/química , Imunoconjugados/metabolismo , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Estrutura MolecularRESUMO
Antibody-drug conjugates (ADCs) represent an innovative class of biopharmaceuticals, which aim at achieving a site-specific delivery of cytotoxic agents to the target cell. The use of ADCs represents a promising strategy to overcome the disadvantages of conventional pharmacotherapy of cancer or neurological diseases, based on cytotoxic or immunomodulatory agents. ADCs consist of monoclonal antibodies attached to biologically active drugs by means of cleavable chemical linkers. Advances in technologies for the coupling of antibodies to cytotoxic drugs promise to deliver greater control of drug pharmacokinetic properties and to significantly improve pharmacodelivery applications, minimizing exposure of healthy tissue. The clinical success of brentuximab vedotin and trastuzumab emtansine has led to an extensive expansion of the clinical ADC pipeline. Although the concept of an ADC seems simple, designing a successful ADC is complex and requires careful selection of the receptor antigen, antibody, linker, and payload. In this review, we explore insights in the antibody and antigen requirements needed for optimal payload delivery and support the development of novel and improved ADCs for the treatment of cancer and neurological diseases.
