(COURTESY: INGRAM PUBLISHING/GETTY IMAGES)
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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.
K. John Morrow, Jr., PhD
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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.
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
Rathin C. Das, PhD
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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.
Figure 1: Primary mechanism of action of antibody-drug conjugates: targeted delivery of a potent cytotoxic agent to cause
cell death.
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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).
Better targets
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.
Better linkers
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.
Better toxins
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.
ADC developers
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).
