Antibody drug conjugates (ADCs) represent a niche but important area in biotherapeutic drug development. ADCs, which consist
of a monoclonal antibody (mAb) chemically linked to a small-molecule therapeutic, are a promising modality for certain therapeutic
areas such as oncology. ADCs are attracting the interest of both small and large pharmaceutical companies in their drug-development
efforts as well as contract manufacturers specializing in high-potency API manufacturing and related conjugation services.
Patricia Van Arnum
Evaluating the opportunities
In August 2011, FDA approved Adcetris (brentuximab vedotin), codeveloped by Seattle Genetics and Millennium Pharmaceuticals
(now part of Takeda Pharmaceutical), making it only the second ADC approved by FDA. Adcetris was approved for treating Hodgkin's
lymphoma and systemic anaplastic large-cell lymphoma. Adcetris consists of three parts: the chimeric IgG1 antibody cAC10,
specific for human CD30, the microtubule-disrupting agent monomethyl auristatin E (MMAE), and a protease-cleavable linker
that covalently attaches MMAE to cAC10 (1, 2). Before the approval of Adcetris, the only other ADC approved by FDA was Mylotarg
(gemtuzumab ozogamicin), approved more than 10 years ago in 2000. The drug, an anti-CD33 mAb conjugated to the cytotoxin calicheamicin,
was developed by Wyeth (now part of Pfizer) and was granted accelerated approval in 2000 but was voluntarily withdrawn by
Pfizer in 2010 because a required Phase III trial failed to demonstrate a survival advantage for Mylotarg plus chemotherapy
compared with chemotherapy alone (1).
Other ADCs are advancing. Roche's Trastuzumab emtansine (T-DM1) is an ADC in Phase III development. The drug combines trastuzumab,
(Herceptin), which targets human epidermal growth factor receptor 2 (HER2) receptors in breast and stomach cancer, with a
maytansine derivative DM1, a small-molecule cytotoxin that binds to tubulin to prevent microtubule formation, through a nonreducible
bis-maleimido-trixyethylene glycol linker (1, 2). Trastuzumab was developed by Genentech (now part of Roche) and was approved
by FDA in 1998 for use in women with metastatic breast cancer who have tumors that overexpress the HER2 protein. The maytansine
derivative DM1 and linking technology were developed by ImmunoGen (1). Genentech submitted a biologics license application
for trastuzumab emtansine to FDA for use in people with HER2-positive, unresectable locally advanced or metastatic breast
cancer, and Roche submitted a marketing authorization application to EMA for the same indication. Roche presented data showing
encouraging efficacy, safety and quality of life results for T–DM1 at the American Society of Clinical Oncology annual conference
in June 2012. Roche has a total of nine ADCs in its development pipeline. It includes RG7593, a humanized IgG1 anti-CD22 monoclonal
antibody (anti-CD22) conjugated to an antimitotic agent in Phase I development.
Pfizer also is advancing ADCs. Its lead ADC product is inotuzumab ozogamicin, consisting of a mAb targeting CD22, a cell-surface
antigen expressed on approximately 90% of B-cell malignancies, linked to a cytotoxic agent. As of March 2011, Pfizer had 10
ADC programs in preclinical development (3).
In October 2012, the biotechnology company Seattle Genetics expanded its ADC collaboration with Abbott. Under the expanded
deal, Abbott will pay an upfront fee of $25 million for rights to use Seattle Genetics' auristatin-based ADC technology with
antibodies to additional oncology targets. Seattle Genetics's proprietary technology uses synthetic cytotoxic agents, such
as monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF), and stable linker systems that attach these cytotoxic
agents to the antibody. In addition in its deal with Abbott, Seattle Genetics may receive up to $220 million in potential
milestone payments per additional target upon achieving predetermined development and commercial objectives as well as mid-to-high
single-digit royalties on worldwide net sales of any resulting products under the multitarget collaboration. Seattle also
is partnered with Genentech for ADC development and with Takeda for Adcetris.