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ADC development is on a positive trajectory from a deeper understanding of therapeutic mechanisms and technological advances.
Following early failures in the market due to toxicity issues, drug developers have rallied around improving the development of antibody drug conjugates (ADCs), and the pharmaceutical pipeline is seeing renewed vigor in progressing these drug candidates through to market. With the help of ongoing research that has brought enhanced understanding to cancer biology and pharmacology, ADCs can yet fulfill their long-held promise of delivering effective cancer treatments and beyond.
The approval rate for ADCs by FDA has significantly improved in the past four years, increasing from only a handful approved in 2017 to 12 approved by 2021 (see Table I). ADCs represent a class of targeted cell immunotherapeutics that are a major stepping-stone to the road for precision drugs, particularly to treat cancers. ADCs comprise a tumor-specific monoclonal antibody (mAb) conjugated to a cytotoxic payload via a linker. The promise of ADCs lays in the fact that the cytotoxic agents used in their make-up are typically more potent than currently used anti-cancer drugs (1). Ongoing research into ADC technology, cancer biology, and a better understanding of pharmacology has enhanced the development of ADCs.
Gemtuzumab ozogamicin (Mylotarg, Pfizer), was one of the earliest ADCs approved by FDA in 2000 but was voluntarily withdrawn from the market because Pfizer was unable to verify a clinical benefit and because of safety concerns (2). The drug was approved again nearly two decades later in 2017.
Since 2017, FDA has had a steady stream of ADC approvals, including moxetumomab pasudotox-tdfk (Lumoxiti, Innate Pharma/AstraZeneca) in 2018; fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo/AstraZeneca), enfortumab vedotin-ejfv (Padcev, Astellas Pharma/Seattle Genetics), and polatuzumab vedotin-piiq (Polivy, Roche) in 2019; sacituzumab govitecan-hziy (Blenrep, GlazoSmithKline) and sacituzumab govitecan-hziy (Trodelvy, Gilead Sciences) in 2020; and tisotumab vedotin-tftv (Tivdak, Seagen) and loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics) in 2021.
Tremendous effort into research coupled with preclinical work has been driving the progress of ADC development. These R&D efforts have given drug developers a better means to strategize and improve the efficacy of ADC drug candidates while reducing toxicity for better therapeutic outcomes. Advances have been largely based on investigational studies that collectively offer deeper understanding of the absorption, distribution, metabolism, and excretion (ADME) and drug metabolism and pharmacokinetics (DMPK) mechanisms of the intact conjugate and the small-molecule (e.g., cytotoxic agent) component (3). Researchers have also started to take into account the interactions between ADCs and the immune system, searching for potential synergistic therapeutics effects that can be used.
Improvements in ADC technology will also be beneficial. The feedback loop from clinical-to-preclinical-to-clinical studies is primarily focused on approaches that reduce off-target toxicities and improve patient outcomes. This is being done through changes not only in ADC composition but also in clinical trial study design. Clinical and preclinical studies will also investigate combination therapies to see if and how ADCs can work with immuno-oncology approaches (3).
Technologies that aim for targeted drug delivery in the absence of an internalizing antigen are the types of technology that can drive a paradigm shift in the way ADCs are developed. One such approach uses cytotoxic payloads that can induce cell death by mediating signals at the cell surface. Another approach involves a two-step delivery method in which the targeting and delivery steps are functionally uncoupled temporarily, allowing for the antibody to deliver the cytotoxic payload at the cell surface and payload release induced by a systemically delivered small molecule (3).
The past decade has also seen considerable progress in antibody engineering, which is allowing for more site-specific conjugation. Engineering advances such as this help to improve the homogeneity and stability of the ADC construct, which is allowing new generations of ADCs to make it to the clinic, with hopes of broadening the therapeutic index that can be achieved. In addition, the development of more tumor-specific antigenic targets and optimized release mechanisms for the cytotoxic payload within a tumor have led to the development of more high-performance ADCs (4).
The early failures of early ADCs primarily revolved around toxicity issues. Certain side effects of some ADCs are similar to the side effects caused by conventional cytotoxic agents that are used in chemotherapy, while other side effects are specific to the specific ADC itself. These side effects can sometimes be severe, and are thought to be induced by the uncontrolled release of the cytotoxic agent in the bloodstream during circulation. This uncontrolled release has been responsible for off-target toxicity (4).
Futhermore, the immunoglobulin G1 (IgG1) isotope of some ADCs can interact with the fragment crystallizable region (Fc)-gamma receptors (FcgR), which can trigger target-independent, FcgR–dependent internalization in FcgR-positive cells. This internalization results in toxic effects on these healthy cells, which are not the targets of the ADC. These unpredictable events have thus made development of the cytotoxic agent component of the ADC a complex endeavor (4).
Today, ADCs are in a good space, despite their earlier clinical failures. Development of these therapeutics has been bolstered by the fruits of labor from ongoing and intensive research, including the availability nowadays of fully human/humanized mAbs, the focus of approaching ADC constructs with site-specific conjugations, a wider range of potent cytotoxic payloads that work through various mechanisms of action, newer and more versatile linker technologies, and the evolution of more sophisticated analytics. Researchers continue to investigate sources of poor efficacy and off-target toxicity, in the meantime. Their efforts are expected to yield ways to improve the therapeutic index of ADCs (3).
The lessons that the biopharma industry has learned from both the failures and successes of ADCs, coupled with the continued advancement of core ADC technologies, are expected to make future ADC development for cancer treatments more successful. ADC development can furthermore branch out beyond oncology indications into other therapeutic arenas. Opportunities exist in infectious diseases, such as through the use of an antibody–antibiotic conjugate, which was shown in studies to be more effective than the antibiotic alone that is used in drug-resistant bacterial infections (3). The strategic design of ADCs can also be useful in treating autoimmune diseases. Clinical trials have already begun to show that some common chemotherapeutic drugs (e.g., methotrexate, cyclophosphamide) are already used in diseases other than cancer (5). ADCs and related conjugates can also be used to help improve treatment for cardiovascular diseases by reducing side effects via a selective payload delivery (3). Future challenges still remain, however, for future ADC development, including improvement of the therapeutic widow, further understanding of the ADC mechanism of action, and decreasing off-target toxicities in vivo.
1. F. Mirasol, BioPharm International 30 (11) 28–33 (2017).
2. Pfizer, “Pfizer Receives FDA Approval for Mylotarg (gemtuzumab ozogamicin),” Press Release, Sep. 1, 2017.
3. P.M. Drake and D. Rabuka, BioDrugs. 31 (6) 521–531 (2017).
4. N. Joubert, et al., Pharmaceuticals 13 (9) 245 (2020).
5. E.G. Kim and K.M. Kim, Biomol Ther (Seoul). 23 (6) 493–509 (2015).
Feliza Mirasol is the science editor for BioPharm International.
Vol. 34, No. 11
When referring to this article, please cite it as F. Mirasol, “Research Advances are Improving ADC Development,” BioPharm International 34 (11) 16–18 (2021).