Guided missiles: antibody–drug conjugates

Monoclonal antibodies (mAbs) dominate the list of best-selling drugs owing to their therapeutic effects in inflammatory diseases and cancer. Motivated by this success, companies are continuing to explore approaches to enhance the effectiveness of antibody-based therapies. One of the most widely pursued platforms—bispecific antibodies designed to target two antigens at once—was featured this time last year (BioPharma Dealmakers, September, B21-22; 2016). Here, we analyze the commercial impact of dealmaking for another popular platform: antibody–drug conjugates (ADCs).

ADCs consist of three components: a mAb specific for a particular antigen (typically one that is selectively expressed on the surface of cancer cells), a warhead (typically a highly cytotoxic drug), and a chemical linker between the two. For oncology applications of ADCs, the goal is for the mAb to deliver the cytotoxic drug to the surface of cancer cells specifically, where it is internalized, leading to the release of its payload. In this way, anticancer drugs that are far too toxic to normal cells to be administered alone can be delivered selectively to cancer cells.

In practice, however, achieving this goal has been highly challenging. Research on the ADC concept has been going on since the 1960s, but it is only in recent years that the components of ADC platforms have matured sufficiently for multiple ADCs to gain regulatory approval, with several also close to market (Fig. 1) and a deep pipeline in development (Fig. 2). In 2011, Seattle Genetics, in partnership with Takeda, received approval from the US Food and Drug Administration (FDA) for its CD30‑targeted ADC Adcetris (brentuximab vedotin) for Hodgkin lymphoma and relapsed systemic anaplastic large-cell lymphoma. Two years later, Roche received FDA approval for its HER2‑targeted ADC Kadcyla (trastuzumab emtansine) for HER2‑positive metastatic breast cancer. Both are now marketed in many other countries too. And in June of this year, Pfizer’s CD22‑targeted ADC Besponsa (inotuzumab ozogamicin) was approved in Europe for relapsed or refractory B cell–precursor acute lymphoblastic leukemia.

The current highest-selling ADC, Roche’s Kadcyla, is already close to blockbuster status, with sales in 2016 of ~$840 million. However, analysts at EvaluatePharma predict that by 2022, Seattle Genetics/ Takeda’s Adcetris will have leapfrogged Kadcyla to become the leader, with sales of $1.8 billion (Fig. 1). AbbVie’s rovalpituzumab tesirine (Rova-T), acquired through its $9.8 billion purchase of StemCentrx in April 2016, is forecasted to be in second place.

This recent product acquisition deal indicates the high potential value of particular ADC products in oncology. The underlying technology platforms for ADCs have also been the basis for many deals (Fig. 3). Seattle Genetics and Immunogen—two of the pioneering companies in the ADC field—have signed licensing deals with multiple other companies for their platforms, in addition to pursuing their own drug candidates (Nat. Rev. Drug Discov. 16 , 315–337; 2017). Indeed, many of the ADCs in the later stages of clinical development are based on technology licensed by either Seattle Genetics (consisting of an aurostatin analog such as monomethyl auristatin E (MMAE) as the cytotoxic drug and a linker) or Immunogen (consisting of the maytansinoids DM1 or DM4 and a linker). MMAE is the cytotoxic drug component of Adcetris and another late-stage product, glembatumumab vedotin, while DM1 is a component of Kadcyla and DM4 is a component of mirvetuximab soravtansine, all of which are highlighted in Figure 1.

Other companies that have developed novel linkers, conjugation strategies and/or cytotoxic drug components have also emerged in the past decade, leading to more platform-driven deals. For example, AstraZeneca acquired Spirogen—a company that developed pyrrolobenzodiazepines that are used as the cytotoxic component of ADCs including rovalpituzumab tesirine—in a deal valued at up to $440 million in 2013. And deals such as those involving Abzena, which has signed two deals worth up to $400 million around its ThioBridge linker technology in 2017 alone, indicate the continued interest in ADC technologies.