An Antibody-Drug Conjugate (ADC) represents a sophisticated therapeutic approach composed of a monoclonal antibody conjugated to a drug payload via a linker. This innovative combination harnesses the precision targeting of monoclonal antibodies, ensuring specific delivery to diseased cells, while also utilizing potent drug payloads for efficient cell killing.

Payloads are an important part of the ADC design. The activity and physicochemical properties of the payload have a direct impact on the antitumor efficacy of ADC drugs. The mechanism of action of the payload is an important factor determining the performance of the ADC (e.g., adverse reactions).

The ideal payloads should have the following characteristics: (1) Adequately high cytotoxicity against tumor cells, reaching 0.001 – 1 nM; (2) Proper water solubility; (3) High stability in the blood circulation; (4) Containing a modifiable functional group or a site that can conjugate to the monoclonal antibody; (5) Insensitivity to enzymatic degradation in lysosomes; (6) Low-immunogenicity; (7) Targeting intracellular sites.

The payloads are categorized into three major classes: Tubulin inhibitors, DNA damaging agents, and topoisomerase I inhibitors.

(1) Tubulin Inhibitors: Tubulin inhibitors serve as potent payloads in ADCs, targeting microtubule dynamics within cancer cells to induce cell death. These inhibitors, including auristatins (MMAE, MMAF) and maytansinoids  (DM1, DM4), disrupt the assembly and disassembly of microtubules, ultimately leading to cell cycle arrest and apoptosis.

Figure 1. Chemical structures of MMAE, MMAF and DM1, DM4.

(2) DNA Damaging Agents: ADCs incorporating DNA targeting agents, such as pyrrolobenzodiazepine (PBD) and Calicheamicin, exert their cytotoxic effects by causing DNA damage, thereby impairing cellular replication and leading to tumor cell death.

Figure 2. Chemical structure of pyrrolobenzodiazepine (PBD) and Calicheamicin.

(3) Topoisomerase I Inhibitors: Topoisomerase I inhibitors, represented by SN-38 and deruxtecan (Dxd), are integral components of ADCs, exerting their antitumor effects by interfering with DNA replication and inducing apoptotic cell death.

Figure 3. Chemical structure of SN-38 and deruxtecan.

As of 2024, a total of 15 ADC drugs have been approved worldwide, with 12 of them receiving approval from the Food and Drug Administration (FDA). Of the FDA approved ADCs, 6 utilize microtubule inhibitor payloads. Three approved ADCs use DNA damaging payloads, while 2 carry payloads that inhibit topoisomerase . 

​Table 1. Payloads in Approved ADC Drugs

Biopharma PEG is a professional PEG supplier. We can provide high-purity PEG linkers from milligram to kilogram scale in GMP and Non-GMP grade for your ADC development. The use of PEGs as a linker between the antibody and payload molecules allows for higher ADC loading. PEGs create a protective shield that wraps the ADC payload from its microenvironment, improving solubility and stability. Other benefits include reduced aggregation and thus lower immunogenicity, improved pharmacokinetics, increased circulation time and reduced toxicity.

References:
[1] Wang Z, Li H, Gou L, Li W, Wang Y. Antibody-drug conjugates: Recent advances in payloads. Acta Pharm Sin B. 2023 Oct;13(10):4025-4059. doi: 10.1016/j.apsb.2023.06.015. Epub 2023 Jun 30. PMID: 37799390; PMCID: PMC10547921.
[2] Maecker H, Jonnalagadda V, Bhakta S, Jammalamadaka V, Junutula JR. Exploration of the antibody-drug conjugate clinical landscape. MAbs. 2023 Jan-Dec;15(1):2229101. doi: 10.1080/19420862.2023.2229101. PMID: 37639687; PMCID: PMC10464553.

Related Articles:
​Topoisomerase I inhibitors Based ADCs: SN-38 & DXd
Antibody–Drug Conjugate Payloads: MMAE & MMAF
Maytansinoids as Payloads of ADCs: DM1, DM4