Three generations of ADC Nearly a decade of development-PIII  

Novel cytotoxic drugs

New cytotoxic drugs have been developed to target cancer cells with low antigen expression or resistance to auristatins or maytansinoids. For this purpose, PBD dimers have been developed, which have a molecular structure containing two alkylated imine functional groups capable of forming covalent bonds with DNA.PBD dimers are about 50-100 times more potent than conventional cytotoxic drugs (MMAE or DM1).

 

Successful 3rd Generation ADC: Enhertu and Trodelvy

Immunomedics, one of the many firms researching ADCs, has created an unexpected ADC by constructing an ADC against a little overexpressed target, employing a mechanism that combines intracellular and extracellular release, and using a less toxic payload than the conventional payload. The anti-TROP-2 monoclonal antibody sacituzumab-govitecan (IMMU-132) is coupled to SN-38 (the active metabolite of irinotecan) via a cleavable maleimide linker with a short polyethylene glycolation unit.

 

The FDA approved it in April 2020, an impressive achievement because this ADC is used in refractory or drug-resistant triple-negative breast cancer (TNBC) for which no effective treatment was previously available.

 

Similarly, to bind irinotecan derivatives to carefully designed linkers, Daiichi Sankyo Japan developed DXd (exatecan or DX-8951), a cytotoxic agent that is 10 times more active against cancer cells in vitro than SN-38. DXd has a better safety profile and optimal solubility to induce bystander-killing effects to kill neighboring cancer cells, which in heterogeneous tumors is an advantage, but with a short half-life to avoid off-target toxicity.

 

ADC Toxicity

The FDA approved gemtuzumab ozogamicin (Mylotarg) in 2000 for the treatment of patients with acute myeloid leukemia (AML). Due to reports of veno-occlusive disease, the FDA issued a warning in 2001. Mylotarg was withdrawn from most markets except Japan in 2010 after a randomized study comparing the efficacy of standard therapy and the combination of Mylotarg.

 

Mylotarg was only later identified as a heterogeneous product in terms of DAR due to the limited analytical methods available in the first clinical study. Although the theoretical DAR was around 2.5, more than 50% of the antibodies in the drug were not coupled and others had a DAR of 4 or 5. At the same time, Mylotarg had difficulty in determining a satisfactory therapeutic index with only one dose regimen and had to be abandoned from development.

 

Following investigations by the Acute Leukemia Association of France (ALFA), it was discovered that breaking the treatment into three doses increased both survival and the absence of major side effects. As a result, Mylotarg was reapproved for marketing in 2017.

 

Brentuximab Vedotin

Brentuximab vedotin (Adcetris) was licensed in 2011 for the treatment of Hodgkin's lymphoma and mesenchymal large cell lymphoma, as well as other CD30-expressing lymphomas. However, Adcetris, when used alone, caused potentially severe peripheral neuropathy, neutropenia, and thrombocytopenia, all of which are typical side effects of antiplatelet drugs. Rare and severe cases of progressive multifocal leukoencephalopathy, on the other hand, were observed.

 

Furthermore, combining Adcetris with bleomycin, a medication routinely used to treat Hodgkin's disease, was shown to cause unacceptable lung toxicity, so this combination was ruled out.

 

Typical or unintended toxicity of ADCs

Based on the classification of ADC payload drugs, such as microtubule disruptors (auristatins and maytansinoids), anti mitotic inhibitors (KSPis), or DNA damaging agents, certain toxicities can be expected (calichaemycin and PBD). These include bone marrow toxicity up to grade 4, as well as sensitive neurological and growth toxicity.

 

Mechanisms of ADC drug resistance

At the level of tumor target cells, ADCs have a multi-stage mode of action that includes antigen binding, internalization, drug release (mostly in the lysosome), drug release into the cytoplasm, and drug action on the target to induce apoptosis. Preclinical research in vitro or in vivo has revealed that each of these phases is linked to resistance.

 

* Defects in antibody binding, internalization, transport, or recirculation, as well as downregulation of the target antigen.

* ADCs with faulty lysosomal degradation or low expression of lysosomal transporters such SLC46A3, resulting in diminished payload release from the cytosol.

* Changes in microtubule proteins or microtubule kinetics regulators.

* Drug retention is reduced intracellularly due to activation of drug resistance transporters like MDR1.