A small biotech company, ImmunoGen, has been developing targeted therapies for cancers, therapies based on attaching anticancer drug payloads to antibodies that home in on cancer cells. This is another “guided missile” strategy that promises to increase the efficacy and reduce the toxicity of treatments for several cancers. The impact on the “war on cancer” is likely to be important.
Guided-missile cancer therapies
These are therapies that are designed to home in on cancer cells and tumors, in contrast to the usual chemotherapy and radiation therapies that affect multiple healthy body tissues as well as cancerous ones. One example was given in the blog entry Trojan-horse stem cells might offer an important new cancer therapy. “The therapeutic concept is simple and based on two observations. The first observation is that for some reason mesenchymal stem cells (MSCs which are normally found in bone marrow) circulating in the body seek out cancer cells. I conjecture that this is because cancers excrete signaling molecules that cause the circulating MSCs to home in on them, a strategy cancers use to achieve rapid growth(ref). The second observation is that it is possible to attach a payload molecule to mesenchymal stem cells which cause them to kill cancer cells but not normal cells, a molecule called TRAIL (TNF-related apoptosis-inducing ligand in case you wanted to know).”
Another example of a guided missile anti-cancer therapy is discussed in the blog entry Terminator stem cells in the early pipeline. “The concept here is engineering stem cells so they differentiate into body cells that target, go after and kill “bad” cells, such as cells infected with HIV or cancer cells.“
A third example is given in the blog entry Progress in stem cell oncolytic virotherapy. In this case “The basic idea is to go after cancer cells with viruses that kill them. To help the viruses escape the immune system, they are packaged in stem cells that are expected to snuggle up to the cancer cells. It is hoped that the approach will go after cancer stem cells as well as mature cancer cells and therefore possibly provide a basic cure for the cancer concerned. The broader area, oncolytic virotherapy is an approach to curing cancers that has been intensely researched for a number of years. What is new is using stem cells or other human cells for safely getting the viruses to and into the target cancer cells.”
Targeted Antibody Payload technology
ImmunoGen is a 200-person biotech company located in Waltham Massachusetts near where I live. ImmunoGen has been developing yet-another guided-missile anti-cancer approach, Targeted Antibody Payload (TAP) technology. This morning there was news that ImmunoGen is cutting a deal with drug giant Novartis. ImmunoGen is riding very high. “Under a collaboration agreement to discover and develop antibody drug conjugates (ADCs) for cancer, Novartis will pay ImmunoGen a US$45 million fee upfront for exclusive rights to combine the TAP technology with antibodies to several as yet unnamed antigen targets. — For each of these targets that results in an anticancer therapeutic, ImmunoGen will be entitled to receive milestone payments potentially totalling US $200.5 million, as well as royalties on any ensuing product sales. — ImmunoGen also stands to get financial compensation for research and any manufacturing it does on behalf of Novartis. The Swiss company is responsible for the development, manufacturing and marketing of any products that emerge from the collaboration. — As ImmunoGen pointed out, the new agreement means it now has partnerships with the pharmaceutical industry’s top three oncology antibody-based therapeutic companies, Roche/Genentech, Sanofi-Aventis and Novartis(ref).”
TAP technology involves attaching cancer-killing substances to antibodies that home in on cancer cells. TAP technology consists of three components, the cancer cell killing agent, the antibodies and what are called linkers that link the two together.
Because the cancer-killing drugs will only affect cancer cells, they can be vastly more powerful than the usual chemotherapy agents. From the Immunogen website “Our cancer-cell killing agents (CKAs) are 1,000- to 10,000-fold more potent than traditional chemotherapy drugs. We developed them specifically for attachment to antibodies for targeted delivery to cancer cells. — The CKAs used in the TAP compounds in clinical testing act by interfering with tubulin and kill cancer cells when they attempt to undergo cell division. We continue to expand our portfolio of CKAs to further extend the utility of our technology, and unveiled our IGN family of DNA-acting agents at a scientific conference last year.”
“Each TAP compound contains an antibody that binds specifically to an antigen found on cancer cells. Each different TAP compound contains a different antibody, enabling different cancers to be targeted. For example, T-DM1, IMGN901, and SAR3419 are in development for HER2+ cancers, CD56+ cancers, and CD19+ cancers, respectively, as their antibodies target these different types of cancers(ref).”
Immunogen has developed what it calls “linkers” to make sure the CKAs do what they are supposed to do and only what they are supposed to do. “Our linkers serve to keep our CKAs attached to the antibody until the TAP compound has entered a cancer cell. They then control the release of the CKA to kill the cancer cell. — Just as different cancers respond better to some drugs than others, we have found that different linkers work better for some cancers than others. Therefore, we have developed a portfolio of linkers to enable us, and our partners, to achieve the best product design for the cancer target. Our modular approach – separate linkers and CKAs – enables rapidly evaluation of different product designs(ref).”
Preliminary clinical results
A press release from the European Society for Medical Oncology describes initial results of a clinical trial using the TAP technology to treat HER2-positive metastatic breast cancer. “Principal investigator Edith Perez, MD, Mayo Clinic in Florida, presented the results of the first ever randomized trial of trastuzumab-DM1 (T-DM1) as a first-line treatment for metastatic breast cancer. — T-DM1 is the first of a new type of cancer medicine known as an antibody-drug conjugate. It binds together two existing cancer drugs with the aim of delivering both drugs specifically to cancer cells: trastuzumab, a monoclonal antibody that targets cells that overproduce the protein HER2; and DM1, a chemotherapy agent that targets microtubules. — “This is the first ever presentation of an anti-HER2 antibody-drug conjugate used as first-line therapy for patients with advanced breast cancer,” said Professor Perez. “We are encouraged by the results. The study demonstrated that T-DM1 has very good anti-tumor activity as well as much lower toxicity when evaluated side by side to the older ‘standard’.” – T-DM1 has shown promising activity in preclinical studies. Other clinical trials have also shown it to be effective in patients whose advanced cancer has not responded to other treatments. “This trial represents the logical step –moving the drug up to patients with newly diagnosed HER2-positive metastases,” Prof Perez said. — In the trial, researchers randomly assigned 137 women to treatment with either trastuzumab plus the chemotherapy drug docetaxel, or T-DM1. All participants had HER2-positive metastatic cancer, with no prior chemotherapy for their metastatic disease. — After a median of approximately 6 months of follow-up, the researchers found an overall response rate of 48% in patients administered T-DM1, compared to 41% in the trastuzumab . Perhaps the most significant finding was a drastic decrease in adverse effects due to the therapy. “Importantly, the rates of clinically relevant adverse events were significantly lower in the T-DM1 arm (37%) compared to the rate in women given traztuzumab plus docetaxel (75%).”
The press release goes on: “This trial is ongoing and the positive outcomes are generating enthusiasm for a larger Phase-III trial which is now underway — The results are important for two reasons, commented Dr Fabrice AndrÃ© from Institut Gustave Roussy in Villejuif, France. “Firstly, they confirm that in coming years chemotherapy could be replaced by a less toxic compound. Indeed, in the present study, the rates of serious adverse events were much lower in patients given T-DM1 compared to the chemotherapy arm. These results suggest that, with the same efficacy, T-DM1 could dramatically reduce the toxicities related to chemotherapy.” — The second important implication of this study is that it proves the concept that linking a monoclonal antibody to a cytotoxic drug leads to an anticancer effect. “This could have several implications beyond drugs that target HER2,” Dr AndrÃ© said.”
The future of TAP
Going back to today’s press release, “Seven such compounds are now in clinical trials through ImmunoGen’s own product programmes and those of its partners, which also include Amgen, Bayer Schering Pharma, Biogen and Biotest. ImmunoGen sees these partnerships as a vital revenue source for its own efforts. — The most advanced TAP compound is T-DM1, currently in Phase III clinical trials under ImmunoGen’s collaboration with Genentech/Roche. — In July, Roche filed a Biologics Licence Application (BLA) with the US Food and Drug Administration for T-DM1, an ADC that combines Genentech’s HER2-targeting antibody, trastuzumab (Herceptin), with ImmunoGen’s DM1 cancer cell-killing agent to treat patients with advanced HER2-positive breast cancer who have previously received multiple HER2-targeted medicines and chemotherapies. Unusually, the submission was based on the results of a 110-women Phase II clinical trial, which showed that T-DM1 shrank tumours in 33% of women who had already received seven drugs on average for advanced HER2-positive breast cancer. In August, however, Roche announced that the FDA had issued a Refuse to File letter denying the trastuzumab-DM1 combination accelerated approval. The company now expects to file T-DM1 worldwide in mid-2012. — In the meantime, last Friday ImmunoGen reported positive interim clinical data with T-DM1 for the first-line treatment of HER2-positive metastatic breast cancer at the 35th European Society for Medical Oncology (ESMO) meeting in Milan, Italy.”
The TAP story will no-doubt have many future chapters. It is a good example of how a relatively tiny but highly innovative biotech company has been able to create a potentially important new technology for combating aggressive cancers, something the drug-company giants have rarely been able to achieve despite spending tens of billions of dollars on conventional approaches to drug discovery.
Incidentally, I still stand by my position that the best way to deal with cancers is not to have them happen in the first place. Further, the best overall way to prevent or combat many cancers is to discover how to delay aging significantly.