Recombinant therapeutic antibodies have remained a bright spot in a pharmaceutical industry beset with difficulties in recent years, bringing out a large number of blockbuster drugs. Indeed, during the past couple of years, at least four new antibodies were approved by FDA, namely, Benlysta (belimumab, HGS/Glaxo), Yervoy (ipilimumab, BMS), Adcetris (brentuximab vedotin, Seattle Genetics), and Perjeta (pertuzumab, Genentech/Roche), which have significant revenue potential. While the number of approvals did not set any records in terms of the number of market approvals, it is indeed a remarkable feat for the industry, at least by virtue of the wide array of the functional diversity of the approved antibodies. For example, Benlysta (approved in 2011) is a B-lymphocyte stimulator (BLyS)-specific inhibitor, and is the first FDA-approved immune medication specifically designed for the treatment of lupus. Yervoy (approved in 2011) blocks the modulation of T-cell activity carried out by CTLA-4. Adcetris (approved in 2011) is the first approved antibody-drug conjugate (ADC) from Seattle Genetics, and is also the latest approved ADC in the monoclonal antibody (mAb) therapeutic armamentarium since the market withdrawal by Pfizer of Mylotarg, the first approved mAb-chemotherapy conjugate. With the first regulatory approval of Perjeta in 2012 for use as a combination therapy with trastazumab and docetaxel, the path for future approval of other combination antibody therapeutic products is expected to be significantly eased.
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The commercial advancement of such a diverse array of antibody therapeutics has brought new enthusiasm and fueled an optimistic spirit within the industry concerning the discovery and commercialization of "next-generation" antibodies. This observation was borne out at the IBC Antibody Engineering and Antibody Therapeutics conference held in San Diego in December 2012. In addition to immunomodulatory antibodies and ADCs, bitargeted, bispecific, and multifunctional antibodies were prominently featured in the conference. Furthermore, combination antibody products in the presence or absence of chemotherapeutics were highlighted as one of the significant advancements towards the next generation of antibody therapeutics.
K. John Morrow, Jr., PhD
A few of the salient advances in the field are presented below, along with predictions on the future outcome in this crucial area of drug development.
ANTIBODY DRUG CONJUGATES
Early efforts at developing ADCs for cancer therapeutics were beset by failures (1). One of the most crucial challenges has been the instability of conjugates, whose breakdown may result in the release of a highly toxic, free drug molecule into the patient's circulation. Other serious side effects include binding of the antibody component to nontarget tissues, and concentration of ADCs in the liver and kidneys. The tremendous variability of tumors, allowing them to rapidly generate antigenic variants unresponsive to the ADC, is another vexing source of the loss of efficacy (2). This is, of course, an issue with all anticancer therapies, a consequence of the rampant genetic and epigenetic variability of tumor cells that allows them to rapidly develop resistance to chemotherapeutic intervention.
Rathin C. Das, PhD
There is no single route to the abrogation of these shortcomings, as investigators have determined that every case must be resolved individually. But, over the years, these issues have been addressed one-by-one, and a new generation of highly effective ADCs is being developed with the help of technological advances and a more profound understanding of their mechanism of action in three essential areas: better targets, better linkers, and better toxins (see Figure 1).
Figure 1: Primary mechanism of action of antibody-drug conjugates: targeted delivery of a potent cytotoxic agent to cause cell death.
An ideal target would be the one which is expressed at a high copy number in diseased cells relative to normal, is rapidly internalized, and is not down regulated. For example, human epidermal growth factor receptor (HER2, target of Genentech/Roche's T-DM1, currently under review by FDA for approval) and CD-30, the target antigen of Adcetris, generally satisfy these criteria.
One of the primary reasons for the recent success of ADCs as a therapeutic modality is the technological advancement in linker technology, that is, the chemical group that forms a bridge between the toxin and the antibody. These linkers must combine the property of stability in the circulation with cleavability once the conjugate is internalized within the target cell.
A toxic payload must be sufficiently lethal to effectively kill the target cancer cells. Early studies with ADCs that employed doxorubicin were ineffective, and R&D teams focused on a search for more potent molecules such as DM-1 or the auristatins. Emtansine, or DM-1, developed by Immunogen is a derivative of the chemotherapeutic agent maytansine. Emtansine is 100-fold to 10,000-fold more potent than its parent compound. Auristatins are synthetic antineoplastic compounds developed by Seattle Genetics.
Seattle Genetics obtained FDA approval for its ADC product Adcetris (brentuximab, Brentuximabvedotin). Adcetris is composed of an anti-CD30 antibody linked to an auristatin derivative called vedotin, and is approved to treat Hodgkin lymphoma and a rare lymphoma, systemic anaplastic large cell lymphoma. Additionally, the company is conducting several other late-stage clinical studies in several lymphatic cancer indications.
Immunogen is another leading company in the ADC landscape. Genentech/Roche's Trastuzumab emtansine (T-DM1) is one of the leading representatives of promising ADCs, which uses Immunogen's DM-1 toxin system. Composed of the HER2-targeted antibody trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1, it is in phase III development for HER2-positive cancer. DM-1 possesses in vitro cytotoxicity that is up to 200 times greater than other tubulin inhibitors, such as the taxanes and vinca alkaloids. In the conjugate phase, however, it behaves as a prodrug and is not toxic. When it enters the cell via the endosomes, the thioether bond is broken, releasing the toxin into the cell where it can bring about the demise of the target cancer cell (see Figure 1).
Recently, Roche announced results from the Phase III EMILIA study, which clearly demonstrate that previously treated patients with HER2-positive metastatic breast cancer survived significantly longer when treated with T-DM1 compared with those who received the combination of lapatinib and Xeloda (capecitabine) (3).