Christina Bennett Freelance Writer GEN
ADAs Are Not a Problem—Yet
Our immune systems are powerful, so much so that they can stifle a biologic’s ability to work by unleashing anti-drug antibodies (ADAs). This phenomenon has most recently been seen in gene therapies in clinical development, stirring up concern, but scientists have known for a long time that the immune system wields such power.
The immune system is well known for dramatically reducing a biologic’s efficacy in chronic inflammatory diseases, like rheumatoid arthritis, because these therapies are usually given repeatedly for years—or until the drug stops working, that is.
“Rheumatologists and gastroenterologists are now increasingly becoming aware that ADA formation for their patient is one of the reasons why after 2–3 years of therapy, the patient might not respond as well to the therapy as before,” says Bernd Meibohm, Ph.D., Professor and Associate Dean for Research and Graduate Programs at the University of Tennessee Health Science Center. He explains that these specialists, especially rhuematologists, have started to monitor and measure the concentrations of the therapeutic biologic and potential ADAs through clinical laboratory testing. This information is then used to answer the question, is the lack of clinical response the consequence of too low a dose or ADAs? The answer can then guide treatment.
Less well known, though, is whether the immune system hinders cancer biologics, in particular monoclonal antibodies, from eradicating cancer cells.
“It’s a timely and legitimate question,” says Wayne A. Marasco, M.D, Ph.D., cancer immunologist and virologist at Dana-Farber Cancer Institute. “These antibodies are going to be used more and more, and with everything, the more you use it, the more you find out.”
A 2016 study analyzed 81 clinical trials for cancer biologics, of which 9 included currently marketed drugs. The study authors found that 63% of the clinical trials reported detecting ADAs. Of the clinical trials that reported ADAs, 27% associated it with changes in pharmacodynamics or reduced efficacy and 21% concluded the ADAs had no effect on efficacy. However, 51% did not explore the clinical relevance of the ADAs. According to the study, the clinical relevance was unknown for the following antibodies despite ADAs being found: Avastin (bevacizumab), Cyramza (ramucirumab), Kadcyla (trastuzumab emtansine), Empliciti (elotuzumab), and Blincyto (blinatumomab).
But oncologists say ADAs may not be a huge problem for cancer patients—at least not immediately.
“Because of the immunosuppressed background of cancer patients, many simply do not produce ADAs,” says Gopi Shankar, Ph.D., senior director at Janssen Research & Development, LLC (Johnson & Johnson). He continues, “Clinical studies simply do not generate enough ADA-positive patients in order to statistically correlate ADAs with efficacy and safety outcomes; thus the clinical significance of ADAs remains elusive in these populations.”
Dr. Marasco says the clinical relevance of ADAs “may become more of an issue than we currently realized, but so far we have a pretty good longitudinal record of patient responses to [cancer] antibody drugs.”
“Over the past 20 years, there are but few examples of severely debilitating issues with immunogenicity [in cancer],” says Dr. Shankar. “Past stories of epoetin and cetuximab are often repeated as though they represent all biologic drugs; in fact, the measures taken by manufacturers of those therapies have since addressed the problems that were encountered, and thereafter, these therapeutic proteins continue to be used safely.”
Although experts are not concerned at present about the immune system interfering with cancer biologic efficacy, attitudes could change as prescribing labels expand to include healthier patients and longer treatments regimens.
Immunogenicity, which refers to an antigen’s ability to trigger an immune response, can manifest in several forms. One form in particular is the production of ADAs. ADAs are grouped as either neutralizing antibodies (NAbs) or non-neutralizing antibodies (non-NAbs). NAbs bind to the biologic and form a complex where it cannot interact with its target receptor anymore. In contrast, non-NAbs do not prevent the biologic from interacting with its target, but they can bind to the drug and accelerate its removal from the body, thereby reducing its bioactivity.
Gunn et al. assert that non-NAbs “can lower the drug’s systemic exposure” and produce “a clinically similar outcome to that of NAbs—reduced clinical efficacy.” Gunn et al. writes, “It is a fallacy that only NAbs are clinically relevant.”
A biologic’s ADA incidence rate can be found in the prescribing information, but interpreting what the rate means is not as straightforward. Dr. Meibohm explains: “When one monoclonal antibody, for example, says it has an incidence rate of ADA formation of 20% and the other says it has only 10%, that doesn’t mean one’s better.”
The reason is the incidence rate is highly assay-dependent, and there are certain differences between one biotech company’s assay and another, among other factors.
Dr. Meibohm explains that the incidence rate gives you a “general idea” of whether you have a frequent occurrence or not. “What you really can’t do is you can’t compare between products,” he stresses.
Drug Development Roulette
Proactive measures are taken early in the drug development process to rule out potentially immunogenic biologics; however, sometimes the unexpected happens and a biologic gets knocked down by the immune system.
Dr. Meibohm explains that during preclinical development, biotech companies identify sequences within the biologic therapy that have a high likelihood of triggering the formation of ADAs, and those are eliminated from further development.
Animal studies are also done, but insight is limited.
“All animal data that you get are not predictive of what happens in humans,” says Dr. Meibohm. He explains that, put simply, the reason is a human protein is being administered to an animal species, which makes the protein foreign to the animal’s immune system. “It’s the same thing as if you gave mouse antibody to human; you would also get a strong immune response.” Biotech companies cannot “really know” until they give the drug to humans.
Pfizer felt this firsthand in 2016 when the company discontinued development for its investigational agent bococizumab after taking it through two Phase III clinical trials with a total of 27,438 study participants. The trial results showed that ADAs, particularly NAbs, reduced drug efficacy.
“That turned out to be both bad luck and a substantial problem,” says Paul M. Ridker, M.D., Director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital. He was the lead author on the journal article that detailed the SPIRE-1 and SPIRE-2 clinical trial results. “Clinical development is hard and issues that can arise fairly late in the process are not always clear at the beginning.”
Cancer Biologics: Making Their Move
“Cancer is a unique space with regard to immunogenicity,” explains Dr. Shankar. “Some people say that immunogenicity testing and characterization is not impactful in oncology indications because of the generally low life expectancy of patients. Also, patients are often highly immunocompromised due to prior immune-ablating therapies or immunosuppressants.”
In addition, he explains, “Often, patients drop out early, so samples from drug washout periods are minimal. Overall, the results from such studies are real, but they may not represent what might have been the dataset if all patients had completed the long-term follow-ups, unlike chronic immunologic diseases.”
In terms of immunogenicity, the uniqueness of the cancer space may fade some as cancer biologics, particularly immunotherapies, move into earlier lines of therapy and stages of disease. The reason is these patients will have more robust immune systems and longer life expectancies.
“Initially, for example, immunotherapies have been used in [treatment-] refractory patients,” says Sarah Rutherford, M.D., hematologist/oncologist at Weill Cornell Medicine and NewYork-Presbyterian. She explains that the management of melanoma and lung cancer, in particular, has changed a lot.
Several immune checkpoint inhibitors recently expanded their indications into earlier stages of disease or lines of therapy. For example, Opdivo (nivolumab) expanded its already stacked label to include advanced melanoma patients who had just completed surgery. Imfinzi (durvalumab) was granted Priority Review status last October to expand its label to include patients with mid-stage, unresectable non-small cell lung cancer. Keytruda (pembrolizumab) was approved as a combination therapy for the first-line treatment of metastatic non-small cell lung cancer.
Dr. Shankar says that as any therapy moves into earlier lines of therapy and earlier stages of disease, “the risk/benefit profile is higher.”
In addition, cancer biologics are being combined in treatment regimens, and doing so could increase the incidence of ADAs. Immune checkpoint inhibitors Opdivo and Yervoy (ipilimumab), which are approved as a combination therapy for advanced melanoma, have been shown to have a more than three-fold higher incidence of ADAs and NAbs than when used alone. As a single agent, Opdivo generated detectable ADAs in 11.2% of clinical trial participants and NAbs in 0.7%. When Opdivo was combined with Yervoy, detectable ADAs to Opdivo jumped to 37.8% of clinical trial participants and NAbs in 4.6%.
“In terms of risk/benefit, for non-oncology indications, immunogenicity is considered important because a patient could have an allergic reaction (though rare nowadays) or lose efficacy once ADAs developed,” says Dr. Shankar. “In the case of cancer, one might have to weigh in the idea that if a patient develops ADAs and the drug stops working, the lifetime lost in the duration of inefficacy is more valuable to a cancer patient than say, a rheumatoid arthritis patient.”
About the clinical significance of ADAs, Dr. Rutherford says, “It sounds like something that will likely become more relevant for oncology as well, as we have more of these drugs being approved.”