Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications
Technology improvements yield fresh line of anticancer clinical candidates.
So far, 2010 has been a good year for antibody-drug conjugates (ADCs) as they advance in the clinic as potential treatments for cancer. On March 3, Genentech submitted an IND for one such compound that was developed using Seattle Genetics’ ADC technology under their collaboration. Seattle Genetics’ stock price rose 4.3% on the news. On the same day Syntarga claimed to have entered into research collaborations with two companies, saying only that they were top-15 biopharma firms. Syntarga further stated that it has five such deals.
ADC developers have had to overcome some significant technical challenges to produce molecules that begin to fulfill the promise of this approach to cancer treatment. Of the total antibodies in clinical trials, the percentage of immunoconjugates decreased from 56% to 49% to 31% in the 1980s, 1990s, and 2000–2005, respectively. These numbers suggest that while the advantages of ADCs are obvious, the technology had not yet fully arrived. In the last five years, however, there has been a surge of technical advances that is beginning to push these candidates through development.
ADCs are targeted chemotherapeutics that consist of three components: the cytotoxic drug, the target-specific mAb, and the linker connecting the drug to the antibody. John Lambert, Ph.D., evp, R&D and CSO, told GEN that to successfully develop an ADC, all three parts need to be optimized. “We explore the whole design space in order to come up with the best therapeutic index. While we would hope in the long run to know, for example, the right linker to use at the outset, there’s an element of empiricism in the design of any ADC for a given target. For example our six ADCs in the clinic today use three different linkers.”
Fine-Tuning ADC Technology
To be effective, ADCs have to carry enough drug to kill cancer cells, not release the drug into the body prior to arriving at the appropriate target, get inside the target cell, and then release the drug compound. Thus one particular challenge has been finding appropriate linker technology to join the antibody to the drug to accomplish these goals. Another issue has been finding sufficiently potent toxins that can exert their killing effects inside cancer cells. The key is finding ADCs that widen the gap between the effective dose and the toxic dose, termed therapeutic window.
ImmunoGen is developing anticancer mAbs attached to what it terms cell-killing agents (CKAs) using its Targeted Antibody Payload (TAP) technology. The company reports that its CKAs are 1,000 to 10,000 times more potent than traditional chemotherapy drugs.
While conjugation of cytotoxic compounds to antibodies that bind to cancer-specific antigens makes these drugs selective in killing cancer cells, many of the compounds used in ADCs can be pumped out of resistant cancer cells through MDR (multiple drug resistance) transporters. Dr. Lambert said that to overcome MDR, the company has designed fundamentally different linkers to counteract MDR pumps.
To some extent these linkers are cancer cell type dependent. He explains that breast cancer cells are not resistant to natural-product drugs such as taxanes or anthracyclines, but colon cancer tends to be resistant to them.
“Linkers designed to keep drugs inside drug-resistant cancer cells are hydrophilic in nature, helping them avoid efflux from the cell via MDR pumps,” Dr. Lambert explains. Research published by the company earlier this month in Cancer Research showed that ImmunoGen’s antibody-maytansinoid conjugated with PEG4Mal linkers bypass MDR1-mediated resistance both in cultured human cell lines and in xenograft tumors in immunodeficient mice. The PEG4Mal-linked conjugates were, according to the authors, much more effective in eradicating MDR1-expressing human xenograft tumors than conjugates prepared with the hydrophobic linker SMCC while being tolerated similarly, thus showing an improved therapeutic index.
ImmunoGen’s lead candidate, T-DM1, is being developed with Roche. It consists of ImmunoGen’s DM1 cell-killing agent attached with its TAP technology to Genentech’s Herceptin. T-DM1 is currently in a Phase II trial as a third-line treatment of Her2+ breast cancer and a Phase III trial as a second-line treatment, both alone and in comparison to GlaxoSmithKline’s Tykerb plus Roche’s Xeloda. The ADC is also in a Phase II trial as a first-line treatment compared to Herceptin plus Taxotere.
In Phase I development are IMGN388, a DM4 cell-killing agent attached to an integrin-targeting antibody developed by Centocor, against several solid tumors, and IMGN901, a anti-CD56 antibody plus DM1, against small-cell lung cancer, ovarian cancer, and other cancers. Both are wholly owned candidates, but Centocor has opt-in rights on IMGN388.
ImmunoGen also has collaborations with Biogen Idec, Biotest, and sanofi-aventis, with all three ADCs in Phase I trials. In late 2009, the company said that it had secured over $230 million in revenues from partners since 2000.
To date Seattle Genetics has reported generating approximately $110 million through ADC technology license agreements. Its partners include Bayer, Daiichi Sankyo, Genentech, GlaxoSmithKline, AstraZeneca, and Millennium: The Takeda Oncology Company, but most are early in development.
Lead candidate, brentuximab vedotin, is partnered with Millennium, and is in Phase III for Hodgkin lymphoma. SGN-75 for renal cell carcinoma and non-Hodgkin lymphoma is a Phase I in-house candidate.
Apart from its licensing deal with Seattle Genetics, Genentech has also taken its own shot at designing conjugates. In a paper published in Nature in July 2008, the company described its TDC (THIOMAB-drug conjugate), designed to allow more controlled ADC construction through genetic engineering and chemistry. Conventional drug-conjugation strategies, the scientists said, produce heterogeneous conjugates with a relatively narrow therapeutic index.
Using information from leads generated through phage display-based methods to predict suitable conjugation sites, the scientists engineered cysteine substitutions at positions on antibody light and heavy chains to provide the requisite reactive thiol groups without disturbing immunoglobulin folding and assembly or altering antigen binding.
When conjugated to monomethyl auristatin E, an antibody against the ovarian cancer antigen MUC16 proved as “efficacious as a conventional conjugate in mouse xenograft models and was tolerated at higher doses in rats and cynomolgus monkeys than the same conjugate prepared by conventional approaches.” The conventional conjugate used in Genentech’s study was the MUC16 antibody conjugated to auristatin with linker technology licensed from Seattle Genetics.
With eight ADCs currently in clinical trials, use of this technology for targeted, efficacious, and safer anticancer treatments may, after massive development efforts, be validated. Given the variations in antibodies, drug potencies, and tumor types, there’s plenty of room for multiple novel linker technologies and techniques that offer better control for making ADCs.
Patricia F. Dimond, Ph.D., is a principal at BioInsight Consulting. Email: firstname.lastname@example.org.