Antibody-drug conjugates (ADCs) are a fast-growing drug modality primarily used as a cancer therapeutic. As of early 2023, there are over 213 ADCs in clinical development and 13 ADCs approved by the FDA.1
An ADC is composed of a monoclonal antibody conjugated to a drug payload via a linker. This complex targets the drug to a specific cell type (e.g.: cancer cell) for therapeutic effect. The selectivity of the mAb affects the cancer cell while sparing healthy cells.
Compared to traditional chemotherapy, ADCs have many advantages, including:
There are three primary components of an ADC: the antibody, the payload, and the linker (Figure 1).
Figure 1.An Antibody-drug conjugate consists of an antibody, a linker, and a payload.
For the majority of ADCs with cytotoxic payloads, a cascade of steps lead to killing a cancer cell (Figure 2):
Figure 2.ADC mechanism of action for cancel cell targeting and killing (1) binding, (2) uptake, (3) antibody degradation, (4) payload release, (5) DNA or microtubule disruption, and (6) cell death.
Because ADCs comprise multiple components that have varying effects on the ADC, their design is not trivial. In addition to optimizing mAb, payload, and linker, their conjugation presents additional considerations:
Due to the complexities and containment handling to requirements of ADCs, many developers companies turn to CTDMOs (Contract Testing, Development and Manufacturing organizations) or CDMOs (Contract Development, Manufacturing Organizations) to develop, manufacture, and test ADCs.
CTDMOs, offering end-to-end services to bring ADCs and bioconjugates into the clinic and to commercialization can be the preferred option when looking for an integrated and reliable supply chain from cell line development to testing of bulk drug substance. Adding expertise in regulatory support for seamless scale-up (IND, PPQ, BLA/NDA) and innovative technologies to advance drug discovery and development.
For developers interested in generating ADCs but require expertise or conjugation capabilities, our ADC Express Services™ leverage our extensive bioconjugation experience to provide libraries of development-grade ADCs for best candidate selection.
While traditional ADCs use a monoclonal antibody paired with a pan-cytotoxic small molecule, next-generation bioconjugates have adopted the bioconjugate model for pairing various antibody formats (ex: fragment antigen-binding region (Fab region), single-chain variable fragments (scFv), and nanobodies) with diverse payloads (e.g.: small molecules, radio-nuclides, proteins, and oligonucleotides) (Figure 3). Such novel approaches to bioconjugates opens doors to new mechanisms of action, therapies, and indications.
Figure 3a.mAb as component of an adc or bioconjugate
Figure 3b.Payload, or pan-cytotoxic small molecule as component of an adc or bioconjugate.
Figure 3c.Bispecific antibody and fragment-based bi-/multispecific constructs for payload delivery.
Figure 3d.Small molecule, protein, radio nuclide, oligonucleotide, nanoparticle.
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