Development History of ADC Drugs

Antibody-drug conjugate (ADC) consists of linker, payload, and monoclonal antibody (mAb). It combines the advantages of high specific targeting ability and strong killing effect to achieve accurate and efficient killing of cancer cells, which has become one of the hot spots in the research and development of anticancer drugs. Since the first ADC drug Mylotarg (gemtuzumab ozogamicin) was approved by the FDA in 2000, 14 ADC drugs have been approved globally for hematological malignancies and solid tumors as of December 2021. In addition, There are more than 100 ADC candidates in various stages of clinical trials.


Back in the early 1900s, Paul Ehrlich first proposed the concept of the “magic bullet” and hypothesized that certain compounds could go directly into certain desired targets in cells to cure diseases. In theory, these compounds should be effective at killing cancer cells, but harmless to normal cells.


In 2000, the US Food and Drug Administration (FDA) first approved the ADC drug Mylotarg (gemtuzumab ozogamicin) for adult acute myeloid leukemia (AML), marking the beginning of the era of ADC-targeted cancer therapy. With the continuous expansion of targets and indications, ADCs are leading a new era of targeted cancer therapy and are expected to replace traditional chemotherapy drugs in the future.


  1. Composition of ADC drugs


ADCs consist of antibodies, payloads, and chemical linkers.The ideal ADC drug remains stable in the bloodstream, precisely reaches its therapeutic target, and eventually releases cytotoxic payloads near its target, such as cancer cells. Each factor affects the ultimate efficacy and safety of an ADC. Overall, ADC development needs to consider all of these key components, including the choice of target, antibody, cytotoxic payload, adapter, and coupling method.


  1. The mechanism of action of ADC


ADCs play a “specific” targeting role and a “high-efficiency” effect of killing cancer cells by combining them. Such drugs are like precision-guided “biological missiles” that can precisely destroy cancer cells, increase the therapeutic window, and reduce off-target side effects. The anticancer activity of ADC also involves the role of ADCC, ADCP and CDC. The antibody Fab fragments of some ADCs can bind to antigenic epitopes of virus-infected cells or tumor cells, while the FC fragments bind to the FCR on the surface of killer cells (NK cells, macrophages, etc.), thereby mediating direct killing effects. In addition, the antibody component of ADC can specifically bind to epitope antigens of cancer cells and inhibit downstream signal transduction of antigen receptors.


  1. Research progress of ADC


From the perspective of drug composition and technical characteristics, ADC drugs can be subdivided into three generations.


The first generation of ADC


Early ADCs are mainly composed of conventional chemotherapeutic drugs conjugated to murine derived antibodies through non-cleavable adaptors. These ADCs are not more potent than free cytotoxic drugs and are highly immunogenic. Later, the combination of more potent cytotoxic agents with humanized Mabs greatly improved efficacy and safety, leading to market approval for the first generation of ADCs (including gemtuzumabozogamicin and inotuzumab ozogamicin). In both products, a humanized mAb of the IgG4 isotype was used and conjugated to potent cytotoxic galichecin via an acid-unstable adaptor. However, the system also has major drawbacks.


1) Linker instability: For example, acidic conditions may occur in other parts of the body, and the linker in the first-generation ADC can also be found to be slowly hydrolyzed in the systemic circulation (pH 7.4, 37 °C), resulting in uncontrolled release of toxic payloads and unexpected off-target toxicity.


2) Easy to aggregate: The payloads used in the first generation are hydrophobic and easily cause antibody aggregation, resulting in some defects such as short half-life, fast clearance and immunogenicity.


  • Heterogeneity of drugs: The conjugation of first-generation ADCs is based on random coupling through lysine and cysteine residues, resulting in a highly heterogeneous mixture of DARs. Therefore, the first-generation ADCs exhibit a suboptimal therapeutic window and require further improvement.


The second generation of the ADC


The second generation ADCs, represented by Brentuximabvedotin and Ado-trastuzumab emtansine, were approved after optimizing mAb homology, payload, and linker. The two ADC features:


1) The use of IgG1 isotype mAb is more suitable for bioconjugation with small molecule payloads and high cancer cell targeting capability.


2) More toxic payloads, improved water solubility and coupling efficiency. More payload molecules can be loaded onto each mAb without inducing antibody aggregation.


3) The improvement of linker achieves better plasma stability and uniform DAR distribution.


The improvement of all three factors will improve the clinical efficacy and safety of the second generation ADC. However, many unmet needs remain, such as insufficient therapeutic windows due to off-target toxicity and aggregation or rapid clearance in those ADCs with high DAR. When DAR exceeds 6, ADC exhibits high hydrophobicity and tends to decrease ADC potency due to faster clearance in vivo. In this case, it is also necessary to optimize the DAR by site-specific conjugation, as well as the continuous optimization of mAb, adaptor, and payload.


The third generation of the ADC


The third generation ADCs are represented by polatuzumabvedotin, enfortumab vedotin, fam-trastuzumab deruxtecan and later approved ADCs.


1) ADC with uniform DAR (2 or 4) showed less off-target toxicity and better pharmacokinetic efficiency.


2) Fully humanized antibodies rather than chimeric antibodies to reduce immunogenicity.


In addition, antigen-binding fragments (FABs) are being developed to replace the full mAb in many candidate ADCs because FABs are more stable in the systemic circulation and may be more easily internalized by cancer cells. In addition, more efficient payloads have been developed: such as PBD, microtubules, and immune modulators with novel mechanisms. Although there have been no updates to linker types in the third generation, several new entities have been developed to combine various payloads. In order to avoid interference with the immune system and improve the retention time in the blood circulation, more hydrophilic linker combinations, such as PEG-ylation, are adopted in the third generation ADC. Hydrophilic Linker can also be used to balance the high hydrophobicity of certain cytotoxic payloads such as PBD, where ADCs with hydrophobic payloads are generally prone to aggregation. Overall, third-generation ADCs have lower toxicity and higher anticancer activity as well as higher stability, enabling patients to receive better anticancer therapy.


Several ADC therapies have been successfully developed to benefit tens of thousands of cancer patients. The approval of 14 ADC drugs and the excellent clinical performance of multiple ADCs has also drawn more attention to the field, which is very important for this relatively young but highly complex field. With the continuous efforts of researchers in these fields, it is not difficult to imagine that future ADCs will show more surprises in cancer targeted therapy.


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