Antibody Drug Conjugates Against Tumor Stroma:

The Beginning of The End?

by Mirella Zulueta, Business Development Director at Oncomatryx

The potential of a technology trigger

Despite many research breakthroughs over the last few decades, conventional cancer treatment strategies still face many limitations. Antibody-drug conjugates (ADCs) belong to a fairly new class of targeted cell immunotherapeutics. They represent the major hope in the war against cancer and a substantial step towards developing precision drugs. An ADC is a unique combination of a targeted monoclonal antibody, a stable linker and a cytotoxic agent. Appending highly potent cytotoxic compounds to antibodies enables the specific delivery of chemotherapeutics to tumors, avoiding systemic exposure. The stable linkers conjugate cytotoxic molecules to the antibody and are designed to allow ADCs to remain inactive while in circulation. Cytotoxic agents used in ADCs can be up to 1000 fold more potent than any currently used anticancer drug. Once bound to its target on the cell surface, the ADC is internalized into the cell; upon internalization, the ADC is dismantled inside lysosomas into its components, resulting in the release of the cytotoxin inside of the target cell; the free cytotoxin interacts with critical cellular components and thus, causes cell death. The potential of ADCs has been enhanced by a greatly expanded knowledge of ADC technology, cancer biology and pharmacology. It is projected that the global market for ADCs will reach $2.8 billion by 2018.

The first Food and Drug Administration (FDA) approved ADC was the CD33-targeted ADC, Mylotarg (gemtuzumab ozogamicin) for the treatment of acute myeloid leukemia. However, due to lack of target-dependence and narrow therapeutic index, this ADC was withdrawn from the U.S. market. The major breakthrough in ADCs was seen in 2011 with the accelerated approval of Adcetris (brentuximab vedotin) to treat Hodgkin lymphoma and systematic anaplastic large-cell lymphoma. In February 2013, another ADC success was witnessed by the FDA approval of Kadcyla (trastuzumab emtansinem), for the treatment of HER2-positive metastatic breast cancer. Adcetris and Kadcyla were perceived as the ultimate cancer drugs: they had strong single agent activity and provided meaningful benefit to patients with limited toxicity. At this point, it seemed that what was needed next was to replicate these successes with additional antibodies to cover every tumor type.

Disillusionment and Hope

Back in 2010, ADCs were the hottest theme in oncology, with the potential to revolutionize cancer treatment. Five years and more than 20 ADCs later, it seems that ADCs have potentially failed to deliver on their promise. Adcetris and Kadcyla remain the only ADCs with a truly promising clinical profile (i.e., strong efficacy in a large number of patients) and sentiment towards ADCs is at a multi-year low. Although most ADCs which have entered clinical testing demonstrated some activity, response rates are typically low (5-10%) and toxicity issues are common. This has led to an exaggerated undercurrent wave of pessimism for some. However, the industry’s belief in ADCs continues to be high, and there are more than 100 ADCs in the development pipelines of biopharmaceutical companies.

Enlightenment and Potential Catalyst – Targeting the Tumor Stroma

Tumor behavior is governed by the structures and cells of the tumor stroma, the connective, functionally supportive framework of the tumor and its environment. The tumor microenvironment is a dynamic composite of cells within a scaffold of extracellular matrix, where tumor cells thrive. Among the various nonimmune cell types in such environment, cancer stromal cells have been identified as critical players in promoting tumor proliferation, neovascularization, invasion, and metastasis, as well as interacting with immune cells to tilt the equilibrium toward a “tolerant” environment that favors the tumor cells. Emphasis has recently shifted toward the tumor microenvironment for novel therapeutic and prevention strategies. Indeed, depletion of fibroblast activation protein (FAP) expressing tumor stromal cells leads to stunted tumor growth and improved response to tumor vaccination. Thus, the tumor microenvironment is a fertile ground for development of novel ADCs.

Targeting the tumor stroma with ADCs could be the catalyst towards more effective existing cancer treatment and prevention options… Are we seeing the beginning of the end of the battle against cancer?