The Dawn of the Antibody–Drug Conjugates Era: How T-DM1 Reinvented the Future of Chemotherapy for Solid Tumors Free

Developing agents able to successfully treat cancer with minimal side effects has been a long-standing quest in oncology. As theorized by Paul Ehrlich more than a century ago, to be effective, these “magic bullets” would need to tackle a vulnerability of the diseased cells, leading to their selective elimination while sparing healthy tissues (1). The first attempt at an anticancer magic bullet was chemotherapy—cytotoxic compounds that inhibit the replication of rapidly dividing cells, which is a hallmark of cancer (1). Thanks to chemotherapy, we can now improve survival for several types of cancer, and even cure some metastatic tumors. Nonetheless, cancer cells are not the only rapidly dividing cells in the organism, and chemotherapy's lack of specificity is inevitably associated with toxicity, limiting the dosages that can be safely administered. Could a strategy be developed to deliver chemotherapy in a smarter way, leading to an improved therapeutic index?

The answer arrived from the development of a very different type of magic bullet. A short distance from the laboratory in Boston where Sydney Farber had started the first clinical trials of chemotherapy (1), immunologist Stuart Schlossman developed the first therapeutic mAbs (2), with muromonab-CD3 approved in 1984 for the prevention of transplant rejection (2). The first approval of a mAb to treat solid tumors soon followed, with the anti-HER2 antibody trastuzumab gaining approval to treat HER2-positive breast cancer in 1998. In its essence, the mechanism of action of trastuzumab involved the blockade of an aberrantly hyperactivated oncogenic pathway, to which cancer cells are dependent while normal cells are not (3). A quarter of a century from the approval of trastuzumab, we have now reached the impressive number of 100 approved therapeutic mAbs, several of which have reshaped the way we treat cancer and other diseases (2). Compared with chemotherapy, trastuzumab represented a much more tumor-targeted treatment strategy for treating cancer. Nonetheless, it soon became clear that the two strategies were synergistic, leading to future combination strategies of chemotherapy with trastuzumab that significantly improved outcomes for patients with HER2-positive breast cancer (4).

One last piece of the puzzle arrived from advancements in pharmacologic techniques that allowed for linking molecules (5). Several such strategies were mastered in the last decades, allowing researchers to couple chemotherapy payloads to mAbs, creating new powerful entities named antibody–drug conjugates (ADC). It was the gunpowder needed to turn mAbs into true magic bullets, combining the ability to target tumor-specific antigens with the cytotoxic effects of chemotherapy. More importantly, the modular structure of these new compounds, comprised of three different portions (the mAb, the linker, and the payload), generated a flexible platform in which small changes in one of the components could have large therapeutic repercussions. This and other key features related to ADCs emerged clearly from the Cancer Research publication by Lewis Phillips and colleagues in 2008 (3), which represented a milestone piece of evidence to translate the potential of ADCs from the bench to the clinic.

In this publication (3), the authors assessed the preclinical activity, pharmacokinetic profile, and safety of trastuzumab coupled with maytansinoid payloads through different types of linkers. A number of critical observations were made in this pivotal work. First, trastuzumab–maytansine conjugates showed enhanced potency against HER2-positive cells lines and mouse models compared with trastuzumab alone, whereas only minimal activity was seen in cells expressing low levels of HER2. This aspect highlighted the selectivity of trastuzumab emtansine (T-DM1) toward cells overexpressing the antigen of interest. Second, the authors showed that the use of different linkers to conjugate trastuzumab to DM1 resulted in critical differences in the pharmacokinetics of the ADC, with the adoption of a thioether, nonreducible linker as it was associated with the highest stability and sustained serum concentrations compared with more traditional disulphide-based linkers. Importantly, increasing linker stability was also associated with increased antitumor activity of T-DM1, including in the presence of markers of resistance to trastuzumab. Third, increased linker stability was associated with reduced incidence of toxicities, and those observed mostly consisted of mild transaminase elevations and transient thrombocytopenia. In fact, the toxicity profile of T-DM1 harboring a thioether linker was both more favorable than that of free DM1 or of T-DM1 linked with more unstable disulphide linkers. In synthesis, the authors showed that conjugating the highly potent chemotherapy payload DM1 to trastuzumab with a stable linker allowed for an efficient delivery of the cytotoxin, with notable anticancer activity, convenient pharmacokinetic profile, and favorable toxicity profile.

These data foretold many of the revolutions in the treatment of cancer that have followed. Indeed, T-DM1 rapidly confirmed the significant antitumor activity and tolerability that it had shown in preclinical experiments, becoming the first ADC to be approved for the treatment of an advanced solid tumor in 2013, and a few years later making its way toward the early setting. To date, T-DM1 has been found to improve overall survival for metastatic HER2-positive breast cancer, as well as to be a highly effective adjuvant option for residual disease after trastuzumab-based preoperative therapy and for small, node-negative early breast cancers (6). The most common toxicities observed in the clinic with T-DM1 were highly consistent with those preclinically discerned, with relatively common occurrence of transient liver transaminase elevations and thrombocytopenia, but very infrequent occurrence of typical chemotherapy-related toxicities such as alopecia, neutropenia, neuropathy, and gastrointestinal disturbances (6).

The most impactful prediction, however, was the demonstration that slight changes in the structure of a trastuzumab-based ADC could have striking repercussions on its clinical profile. In 2019, the novel trastuzumab-based ADC trastuzumab deruxtecan (T-DXd) was approved for the treatment of HER2-positive breast cancer, after showing unprecedented activity against tumors resistant to both trastuzumab and T-DM1 (7). Despite sharing the same mAb platform and mechanism of action with T-DM1, T-DXd harbored a different payload and linker, having the topoisomerase I inhibitor DXd, linked to trastuzumab through a cleavable tetrapeptide linker, with a more than double drug-to-antibody ratio compared with T-DM1 (8 vs. 3.5). These slight pharmacologic changes allowed to further unleash the trastuzumab-directed delivery of chemotherapy payloads, leading to transformative activity in HER2-positive breast cancer, gastric cancer, colorectal cancer, lung cancer, and beyond (8). More importantly, T-DXd has been shown to be more effective than unconjugated chemotherapy not only in HER2-positive breast tumors, but also for tumors with low HER2 expression, evidence that is currently driving a revolution in the nomenclature and treatment of breast cancer (9). In addition, the experience of T-DM1 ignited the study of several other ADCs targeting different antigens, with multiple novel ADCs recently showing transformative activity for treating solid tumors, including sacituzumab govitecan, enfortumab vedotin, and others (8). It is important to note that the higher potency of novel ADCs comes with a cost of increased toxicity. Most novel conjugates are indeed associated with higher rates of neutropenia, nausea, diarrhea, and alopecia compared with T-DM1, sacrificing some tolerability in order to deliver a more powerful bullet to the tumor (8). This strategy has proven beneficial in the advanced setting, but could lead to even greater impact in the early, curative setting. Clinical trials are ongoing with T-DXd (NCT04622319; NCT05113251), sacituzumab govitecan (NCT04595565), and enfortumab vedotin (NCT04700124) for treating early-stage tumors and may hopefully allow to eradicate cancers before they lead to incurable metastatic recurrences.

Fourteen years after the landmark Cancer Research publication (3) by Lewis Phillips and colleagues, the paradigm of a targeted delivery of cytotoxic payloads has become central in oncology, and it is expected to replace traditional chemotherapy in multiple settings. ADCs have proven to be an exceedingly flexible and successful pharmacologic platform, allowing, with slight modifications, to radically transform their capabilities and to benefit large populations of cancer patients. New paradigms are being written thanks to novel ADCs, with a shift in drug development from targeting of oncogenic drivers to using antigens expressed on the tumor cell surface as targets for chemotherapy delivery, as exemplified by the emergence of the targetability of HER2-low tumors with anti-HER2 ADCs (10). New combinations are being explored in the attempt to identify opportunities for treatment synergy, including with checkpoint inhibition. Finally, a whole new landscape of innovative ADCs lay beyond the boundaries of traditional constructs, with the use of bispecific mAbs, novel conjugating strategies, as well as immunostimulant-targeted therapy or radionuclide payloads that may lead to further improvements in patients’ outcomes (Fig. 1; refs. 5, 8). As often happens in biological matters, the way forward in cancer treatment will not likely rely on the identification of a single magic bullet, but rather in the optimal implementation of a rapidly enlarging arsenal of highly active treatment options. Emerging efficacy and toxicity biomarkers will hopefully help with this task, allowing for an increasingly effective, safe, and tailored way of pursuing a targeted delivery of anticancer drugs for the treatment of cancer.

P. Tarantino reports personal fees from AstraZeneca and personal fees from Daiichi Sankyo during the conduct of the study. S.M. Tolaney reports grants and personal fees from AstraZeneca, Eli Lilly and Company, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedic/Gilead, Bristol-Myers Squibb, Eisai, Nanostring, Sanofi, Seattle Genetics; grants from Exelixis, Cyclacel, Odonate; personal fees from Puma, Daiichi Sankyo, Athenex, OncoPep, Kyowa Kirin Pharmaceuticals, Samsung Bioepsis, Inc., CytomX, Certara, Mersana Therapeutics, Ellipses Pharma, 4D Pharm, OncoSec Medical Incorporated, Chugai Pharmaceuticals, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics; and personal fees from Zetagen outside the submitted work.

This work was supported by an American-Italian Cancer Foundation Post-Doctoral Research Fellowship.