Abstract
Combining the selective targeting of tumor cells through antigen-directed recognition and potent cell-killing by cytotoxic payloads, antibody-drug conjugates (ADCs) have emerged in recent years as an efficient therapeutic approach for the treatment of various cancers. Besides a number of approved drugs already on the market, there is a formidable follow-up of ADC candidates in clinical development. While selection of the appropriate antibody (A) and drug payload (D) is dictated by the pharmacology of the targeted disease, one has a broader choice of the conjugating linker (C). In the present paper, we review the chemistry of ADCs with a particular emphasis on the medicinal chemistry perspective, focusing on the chemical methods that enable the efficient assembly of the ADC from its three components and the controlled release of the drug payload.
Highlights
Cancer is a leading cause of death worldwide and most of the existing therapies use small molecules to eradicate the cancer cells
The amount of the payload in the cytosol is determined by the number of surface antigens per cell, the number of drug payload molecules per antibody-drug conjugates (ADCs), and the time it takes for the return of the antigen on the cell surface [5]
We review some of the key challenges and recent learnings focusing on the diverse aspects of ADC development where chemistry plays an important role
Summary
Cancer is a leading cause of death worldwide and most of the existing therapies use small molecules (chemotherapy) to eradicate the cancer cells. They are widely applied, the use of most chemotherapies is limited by undesired side effects, mostly through action on cells beyond the tumor and its environment, resulting in systemic toxicity and a narrow therapeutic window. The payload might escape the cancer cell either following its death and degradation or traversing its membrane from the cytosol Consequences of this release can be beneficial (e.g., killing neighboring cancer cells, known as the bystander effect), or detrimental leading to systemic toxicity. MMAE: monomethyl auristatin E; DM1: N(20 )-deacetyl-N(20 )-(3-mercapto-1-oxopropyl)- maytansine; HER2: human epidermal growth factor 2; TROP-2: antitrophoblast cell-surface antigen 2; BCMA: B-cell maturation antigen; MMAF: monomethyl auristatin F; PE38: Pseudomonas Aeruginosa exotoxin
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