Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs)

Abstract

Antibody-drug conjugates (ADCs) are emerging as effective tools in cancer therapy, combining the antibody's exquisite specificity for the target antigen-expressing cancer cell together with the cytotoxic potency of the payload. Much success stems from the rational design of “toxic warheads”, chemically linked to antibodies, and from fine-tuning the intricate properties of chemical linkers. Here, we focus on the antibody moiety of ADCs, dissecting the impact of Fab, linkers, isotype and Fc structure on the anti-tumoral and immune-activating functions of ADCs. Novel design approaches informed by antibody structural attributes present opportunities that may contribute to the success of next generation ADCs.

Clearance of solvents and small molecule impurities in antibody drug conjugates via ultrafiltration and diafiltration operation

“…1 This unit operation is a mainstay in concentration of proteins and buffer exchanges and has shown to be effective at removing solutes when the molar masses of the solutes are significantly lower than the protein. 5,6 ADCs are comprised of antigen-targeting monoclonal antibodies (mAbs) and therapeutic drugs that are attached covalently via chemical linkages (i.e., linkers). The results demonstrated effective removal of all seven extractables and leachables.…”

“…2,3 In one study, seven extractables and leachables from single-use technologies, of different chemical families and molecular weights, were spiked in and evaluated for clearance from proteins by UF/DF process. [6][7][8] The chemical Travis Gates and Yaqi F. Lyu contributed equally to this study. 4 Antibody drug conjugates (ADCs) have emerged as a new class of biotherapeutics in areas for oncology, infectious diseases, and immunological indications.…”

“…4 Antibody drug conjugates (ADCs) have emerged as a new class of biotherapeutics in areas for oncology, infectious diseases, and immunological indications. 5,6 ADCs are comprised of antigen-targeting monoclonal antibodies (mAbs) and therapeutic drugs that are attached covalently via chemical linkages (i.e., linkers). Most ADCs rely on chemical methods to link therapeutic drugs to lysines or reduced interchain cysteines on the native antibody, for example, the commercial ADCs, Kadcyla, Mylotarg, Besponsa, and Adcetris.…”

“…Most ADCs rely on chemical methods to link therapeutic drugs to lysines or reduced interchain cysteines on the native antibody, for example, the commercial ADCs, Kadcyla, Mylotarg, Besponsa, and Adcetris. [6][7][8] The chemical Travis Gates and Yaqi F. Lyu contributed equally to this study. processes involved in the ADC production generate a unique collection of solvents and small molecule impurities that is not typically associated with traditional mAb production.…”

N-terminal α-amino group modification of antibodies using a site-selective click chemistry method

“…7 To date, four FDA-approved ADC drugs have shown promise for cancer therapy, and more than 40 are currently undergoing clinical evaluation. 8,9 Typically, ADCs consist of a tumor-specific antibody coupled to cytotoxic drugs through modification and linker technologies. This drug conjugation strategy enables selective targeting and delivery of small cytotoxic molecules to malignant tumor cells.…”