Antibody drug conjugates comprise three distinct parts: a potent cytotoxic warhead connected via a biodegradable or cleavable linker to a monoclonal antibody directed to a target overexpressed on tumors. The aim of ADCs is to selectively deliver higher doses of cytotoxic to the tumor thereby sparing normal tissues. However, to function optimally it is crucial that the conjugate is stable within the bloodstream until it reaches the tumor target.
In recent months there has been substantial M&A and licensing activity in the ADC landscape, fuelled by the February 2013 approval and early commercial promise of Roche/Genentech's Kadcyla (T-DM1). Kadcyla accrued $168 million sales in the first three quarters of 2013, and is forecast to achieve close to $300 million for the year. Although Kadcyla has exploited the proven characteristics of the trastuzumab monoclonal antibody the development, with ImmunoGen, of the conjugation technology was reportedly challenging.
A second ADC also gained regulatory approval in 2013 : Seattle Genetics in collaboration with Millennium (Takeda) secured a label for their CD30-directed conjugate, Adcetris for Hodgkin's lymphoma and systemic anaplastic large cell lymphoma; additional Phase III trials are ongoing in various CD30-positive T and B-cell lymphomas. Adcetris is linked, using proprietary protease linker technology, to the cytotoxic, monomethyl auristatin E.
However, ADC's haven't generated only good news stories in 2013, development of other ADCs has faltered. Pfizers inotuzumab ozogamicin has been halted in non-Hodgkin's lymphoma (NHL) although its development continues in acute lymphoblastic leukemia (ALL) and in November ImmunoGen announced that the study of the CD56-directed ADC, IMGN901 in small cell lung cancer (SCLC) was to be discontinued as it was unlikely to show an PFS benefit and data revealed an apparent higher rate of infection in the ADC-treated cohort.
Despite the mixed year for ADCs, merger and collaboration activity in the field has been high. In October 2013, the key acquisition of Spirogen by MedImmune (the biologics arm of AstraZeneca) was announced. Spirogen have specialist expertise in developing cytotoxic agents and biodegradable linkers that are amenable to antibody conjugation. At the same time, MedImmune also entered into collaboration with ADC Therapeutics who were partnered with Spirogen on several projects.
More recently (January 2014), Seattle Genetics announced they had extended their collaboration with AbbVie: oncology relevant antibodies developed by AbbVie will be utilized with Seattle Genetics proprietary site-specific conjugation technology. Indeed Seattle Genetics have numerous collaborations in place with major Pharma companies including Agensys (an affiliate of Astellas), Bayer, Genentech, GlaxoSmithKline and Pfizer.
Driven by their success with Kadcyla, Roche revealed in December 2013 that they had entered a deal with Molecular Partners to develop a next generation class of conjugate. It is proposed that the currently experimental DARPins (small proteins) could be used in place of monoclonal antibodies in drug conjugates. Both Roche and Molecular Partners believe DARPins could possess some advantages such as small size and therefore improved tumor penetration, and greater selectivity - over monoclonals.
This week, CytomX signed a deal to access ImmunoGens ADC know-how and technology to combine with CytomX's probody expertise and develop Probody DCs. CytomX state that probodies are a potentially disruptive class of antibody therapeutics that may further broaden the opportunities for ADCs by localizing therapeutic activity to the tumor microenvironment.
This is just a sample of the merger and collaborative activity that is ongoing in the ADC arena. Both clinically and pre-clinically ADC development is an area to watch and, as is typical with oncology drug development, there will be many challenges along the way, 2014 looks to be another busy year for ADCs.