Antibody-drug conjugates (ADCs) have made significant progress in tumor therapy and show a promising future. As per insights from Clarivate experts, the global market for currently marketed ADCs is expected to cross US$16.4 billion by 2026. However, designing an ADC is a challenge requiring a careful combination of the antibody, linker, and the cytotoxic drug.
The approval of Pfizer’s Mylotarg® in 2000 marked the beginning of an era of targeted oncology therapy. But it took almost a decade for the second ADC, Brentuximab vedotin (Adcetris®), to enter the market. What were the problems with the earlier ADCs?
This article highlights the recent advances in ADCs and lessons learned from the developmental challenges faced with the earlier ADCs.
Antibody-Drug Conjugates - A Sneak Peek
Antibody-drug conjugates are biotherapeutics that utilize antibodies to selectively deliver cytotoxic (payloads) drugs to the tumor site.
The antibody in an ADC is attached to the cytotoxic drugs via a linker system. The linkers act as a specific bridge, helping the antibody release the cytotoxic drug selectively and accurately at tumor sites. The linkers also help maintain the ADCs’ stability during their preparation, storage, and systemic circulation.
The antibody in the ADC is designed to target a specific antigen (receptor) that is highly expressed in tumor cells. By selectively delivering the cytotoxic drug to tumors, ADCs limits their systemic exposure, leading to greater efficacy and minimal side effects.
The First Antibody-Drug Conjugate Was Launched In 2000
In 2000, the U.S. Food and Drug Administration (FDA) approved Pfizer’s Mylotarg® (gemtuzumab ozogamicin) for acute myeloid leukemia (AML). In 2010, Pfizer voluntarily withdrew Mylotarg in the U.S. after a confirmatory trial failed to demonstrate clinical benefit and showed increased toxicity compared to chemotherapy. However, in September 2017, the FDA reapproved Mylotarg for adults with newly diagnosed CD33-positive AML and relapsed or refractory CD33-positive AML in patients aged 2 years and older. The FDA specifically highlighted the modified dosing regimen that improved gemtuzumab ozogamicin’s safety and efficacy and led to its reapproval.
It Took Almost a Decade for The Second ADC To Enter the Market - What were the problems with the earlier ADCs?
Seagen’s Brentuximab vedotin (Adcetris®) was the second ADC to be approved. The drug received FDA approval in 2011. A gap of 11 years for the second ADC to enter the market highlights the challenges which manufacturers faced while developing the earlier ADCs.
First-generation Antibody–Drug Conjugates - Gemtuzumab ozogamicin
BR96–doxorubicin and KS1/4–methotrexate were the first ADCs to be developed. These ADCs were basically chemotherapy drugs linked to murine antibodies using a non-cleavable linker. Both drugs were unable to show clinical benefit, and their further development was discontinued.
Next, the researchers experimented with combinations of potent cytotoxic agents and humanized monoclonal antibodies. Gemtuzumab ozogamicin was a humanized anti-CD33 IgG4 antibody, conjugated to calicheamicin using an acid-labile hydrazone linker. Gemtuzumab ozogamicin showed increased efficacy in clinical studies and became the first ADC to enter the market in 2000. However, in subsequent studies, the drug showed poor efficacy and increased toxicities which lead to its withdrawal in 2010. (Gemtuzumab ozogamicin was reapproved in 2017 by the FDA).
Unstable linker, high amount of unconjugated antibody, poor CMC (chemistry, manufacturing, and control) properties, and high toxicity were some of the disadvantages of the first-generation ADCs. Learning from these drawbacks lead to the development of the second-generation ADCs.
Second-generation Antibody–Drug Conjugates - brentuximab vedotin, ado-trastuzumab emtansine, and inotuzumab ozogamicin
The second-generation ADCs showed better safety, efficacy, and CMC characteristics. These ADCs were introduced after optimization of monoclonal antibodies isotypes, cytotoxic payloads, and the linkers. Several potent chemotherapy drugs, such as auristatins and mytansinoids, with improved water solubility and coupling efficiency, were also discovered. The improved linkers helped achieve better plasma stability and homogeneous drug-to-antibody ratio (DAR) distribution.
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