40 Billion USD Transactions, ADC Drugs Have Unlimited Potential

10 ADC drugs have been approved by the FDA for the treatment of various cancers including hematological tumors and solid tumors in a decade since 2010. Of the 10 ADC drugs currently on the market, 7 have been approved in the last three or four years. Such intensive approval has made ADC the focus of international pharmaceutical companies carving out space. Within 2020, the transactions completed around ADC drugs reached nearly 40 billion USD. AstraZeneca spent 13 billion USD to deploy multiple core ADC drugs. Gilead acquired Immunomedics for 21 billion USD.

The report released by Nature Reviews Clinical Oncology provides a comprehensive and in-depth review of the current status of ADC drug design, mechanism of action and clinical efficacy, the limitations of ADC drugs, and the exploration of strategies to maximize the anti-cancer potential of ADC drugs.

ADC, a combination of immunotherapy and targeted chemotherapy

As one of the fastest-growing drugs in oncology, ADCs represent a unique family of chemoimmunotherapy drugs that deploy specialized chemical linkers to couple cytotoxic payloads to monoclonal antibodies to. With the high specificity of monoclonal antibodies, small molecule drugs with powerful killing effects can be accurately delivered into tumor cells, which can theoretically enhance the targeted killing of tumors, meanwhile avoiding damaging normal tissue, thereby maximizing the efficacy, and minimizing systemic toxicity.

Advances in chemical synthesis methods, including monoclonal antibody production, linker technology, and new payload discovery can greatly improve the activity and toxicity of previous ADCs.

New evidence shows that, unlike individual antibodies or small molecule drugs, the efficacy of an ADC depends on the complex interactions of specific antibodies, linkers, and payload components with the tumor and its microenvironment, which all have important clinical significance, and make the ADC drug design complex. The choice of antibody, targeting antigen, linker type and coupling strategy, and the activity of small molecule drugs are the four main factors that affect ADC discovery.

Development strategy of ADC drug

Antibody selection:

• The ideal target antigen should have a high level of expression in tumors, with little or no expression in normal tissues, or at least expression limited to a given tissue type, in order to reduce ADC target toxicity and reach an acceptable therapeutic index.
• The target antigen should be present on the cell surface so that the circulating mAbs can enter.
• The target antigen should be an internal antigen, so that after binding, the ADC is transported to the cell, and the cytotoxic agent can play its role.

Linker selection:

• An effective linker must maintain good stability for a few days in circulation and have efficient lysis when delivered to target cells.
• Conditional release of the drug in the cytoplasm of the target cell (cleavable and non-cleavable linker).
• The enhancement and limitation of the bypass effect are achieved by whether the linker-drug metabolite can cross the biomembrane.
• Polar linker improves solubility and reduces MDR.

Synthesis:

The second-generation ADCs are all controlled mixtures of different drug loading substances, with a typical average DAR of 3.5 or 4. Species with a DAR greater than 4 show lower tolerance, higher plasma clearance, and reduced in vivo efficacy.

Cytotoxic molecules:

Auristatin and maytansinogen, which act by inhibiting tubulin assembly, are currently the mostly used payloads for ADCs. Others are based on pyrrolobenzodiazepines (PBD), indolothiadiazepines, Tubulysins, calicheamicin, irinotecan derivatives, docamomycin, camptothecins similar substances, epinephrine, and doxorubicin. In fact, due to fierce competition, the chemical structure of antigen targets and/or payloads and linkers of most ADCs in early clinical trials keep undisclosed.

The mechanism of ADC in vivo

ADC, as one of the most complex strategies for cancer treatment, integrates the effects of antibodies and cytotoxic drugs, and therefore exhibits unique mechanisms of action and pharmacokinetic characteristics. At the same time, ADC plays its therapeutic role with time-series complexity.

ADC can be considered as a prodrug. In many cases, it requires the processing and metabolism of the target cell before it can fully realize its final activity. However, the fate of ADC after administration is dual in general. Due to incomplete coupling and/or unstable conjugation during the production process, an ADC divides into three components before reaching the cancer tissue. Stable ADCs are extrapolated from the capillaries, and the antibody reaches the tumor cells through passive diffusion, which usually results in slow, inefficient, and heterogeneous tissue penetration, with only 1% of the actual dose reaches the tumor cells. These once again emphasize the necessity of effective payload in the ADC design. ADC drugs need to cross the tissue barrier to directly target antigen to obtain the best cytotoxicity. However, the difference of drug distribution in different tissues is also one of the factors that affect ADC efficacy.

Continuous exploration and technological progress enable the innovative development of ADC that will benefit more cancer patients.

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