How much do you know about ADC drug development?-Special topic on antibody modification-Tekbiotech-Yeast and Phage Display CRO, Expert in Nano-body and Antibody Drug Development

How much do you know about ADC drug development?

Statistics indicate that cancer was the cause of death for nearly tens of millions of people globally in 2020 ^[1]. The 20th century saw the emergence of cytotoxic compounds capable of rapidly killing cancer cells. However, chemotherapy has a critical drawback: in addition to killing cancer cells, it also damages healthy tissues, leading to severe consequences. To overcome the toxicity of chemotherapy, a novel approach was developed in the early 20th century: antibody-drug conjugates (ADCs). After decades of research, approved ADCs have revolutionized the treatment landscape for multiple cancers.

What does an ADC drug look like?

An ADC drug molecule consists of a cancer cell antigen-specific monoclonal antibody (mAb), a linker, and a potent cytotoxic drug. As shown in Figure 1, the linker attaches one or more cytotoxic drugs to the monoclonal antibody (mAb) to specifically target antigens on the surface of cancer cells.

Figure 1: Molecular structure of an ADC drug ^[2]

ADC Drug Development: An Extremely Complex "Systems Engineering"

Target Selection^[3]: (1) The ideal target antigen should be uniformly expressed on the surface of target cells, with low or absent expression in healthy tissues, or at least limited to a given tissue type. (2) The target antigen should be present on the cell surface for mAb recognition. (3) It should be an internalizing antigen, so that upon mAb binding, the ADC is transported into the cell where the cytotoxic drug can exert its effect. (4) The shedding of the ideal target antigen should be as minimal as possible to prevent free antigen from binding the mAb in the circulation. It has been reported that non-internalizing ADCs can sometimes also show cytotoxicity, a phenomenon known as the "bystander effect," which allows killing of cells adjacent to the target cell.

Antibody Selection: (1) To prevent severe systemic side effects, the antibody immunogenicity should be low; humanized or fully human antibodies are preferred. (2) The antibody must possess adequate antigen specificity and affinity and be capable of internalization. (3) The antibody should have a long circulating half-life.

Toxin Selection: The cytotoxic drug is the component responsible for the ultimate efficacy of the ADC. ADC payloads can target DNA or tubulin. Besides potency, the molecular and physicochemical properties of the cytotoxic drug are also determinants of ADC efficacy. The molecular structure of the toxic drug should facilitate conjugation to the linker. Since ADCs are prepared in aqueous solution and administered intravenously, water solubility and long-term stability in blood are important.

Linker Design: The linker should (1) possess sufficient stability to prevent premature cleavage of the ADC molecule, ensuring accurate target site binding; (2) be capable of rapid cleavage upon internalization to release the payload; and (3) contain functional groups, such as disulfides, hydrazones, or thioethers, to connect the mAb to the payload.

Mechanism of Action of ADCs

ADCs are typically administered intravenously. Upon entering the circulation, ADC drug molecules recognize and bind to cellular targets. Following target binding, they are internalized into cells, forming early endosomes (Figure 2). The acidic environment of early endosomes promotes binding of a portion of ADCs to FcRn (neonatal Fc receptor) via their Fc region, leading to recycling back to the cell surface, where ADC molecules are released into the extracellular environment under neutral pH conditions. Another portion of ADC molecules is delivered to lysosomes. Within the lysosome, under the catalytic action of the acidic environment and various proteases, the ADC is degraded, releasing the payload (for cleavable linkers). For ADCs employing non-cleavable linkers, drug release depends on complete proteolytic digestion of the antibody chain.

Figure 2: Schematic diagram of the ADC mechanism of action^[2]

TekBiotech, with its core expertise in phage display and yeast display antibody development services, is committed to providing high-quality bispecific antibody-drug conjugate (BsADC) development services to scientists worldwide. We also offer comprehensive supporting downstream validation services, including in vitro affinity validation (such as EC50, BLI, and SPR validation), cell killing validation, and in vivo animal imaging validation, providing robust support for our partners' drug development projects.

References

[1] Grairi M, Le Borgne M. Antibody-drug conjugates: prospects for the next generation. Drug Discov Today. 2024;29(12):104241.

[2] Chau CH, Steeg PS, Figg WD. Antibody-drug conjugates for cancer. Lancet. 2019 Aug 31;394(10200):793-804.

[3] Beck A, Goetsch L, Dumontet C, et al. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16(5):315-337.

[4] Patel, Dixita M et al. "A Comprehensive Review of Immunotherapy Clinical Trials for Metastatic Urothelial Carcinoma: Immune Checkpoint Inhibitors Alone or in Combination, Novel Antibodies, Cellular Therapies, and Vaccines." Cancers vol. 16,2 335. 12 Jan. 2024. (Cited in the original file but not explicitly referenced in the main text)

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