Yale takes work on synthetic HIV-fighting and prostate cancer-fighting molecules to next level
Team is now designing antibody-recruiting molecule analogs with enhanced potency and improved physicochemical properties
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NEW HAVEN, Conn.—Since announcing in November the development of synthetic molecules capable of enhancing the body's immune response to HIV and HIV-infected cells, as well as to prostate cancer cells, researchers at Yale University continue to advance their efforts by taking on the task of rationally designing antibody-recruiting molecule analogs with enhanced potency and improved physicochemical properties.
The molecules—called "antibody-recruiting molecule targeting HIV" (ARM-H) and "antibody-recruiting molecule targeting prostate cancer" (ARM-P)—work by binding simultaneously to an antibody already present in the bloodstream and to proteins on HIV, HIV-infected cells or cancer cells. By coating these pathogens in antibodies, the molecules flag them as a threat and trigger the body's own immune response. In the case of ARM-H, by binding to proteins on the outside of the virus, they also prevent healthy human cells from being infected.
"In addition, we are investigating ways in which we can use ARM-H based molecules as a delivery vehicle to target HIV/HIV-infected cells with cytotoxic agents," says Dr. David Spiegel, assistant professor of chemistry at Yale University and the corresponding author of two papers released late last year detailing the results of their work. "This would utilize a small molecule both to block HIV entry and to disrupt virus replication, and it would be complementary to the antibody recruiting approach."
Lastly, in a new collaboration with National Institute of Allergy and Infectious Diseases of the National Institutes of Health and Cheryl Stoddart's lab at the University of California, San Francisco, Spiegel's team is studying the efficacy of ARM-H based molecules in humanized Thy/Liv mouse models for HIV infection.
"In this effort, we will not only learn about the pharmacological properties of our molecules, but also measure their ability to induce a long-term immune response," he notes.
In the ARM-P area, Spiegel notes researchers are also working in mouse xenograft models, with the goal of establishing whole organism efficacy.
"These studies are currently ongoing, and results should be arriving shortly," he says. "We have also explored some interesting trends we observed in our initial studies related to compound linker lengths. These follow-up studies have revealed some interesting strategies for making even more potent and effective ARM-P derivatives. The results of these studies will be published shortly."
Finally, Spiegel notes researchers have invested considerable time in gaining a fundamental understanding of the nuances behind ternary complex therapeutics in order to maximize the efficiency of this general "antibody-recruiting" therapeutic approach.
"To this end, mathematical studies to predict ternary complex formation have been highly successful, and have provided crucial insights into the interactions between small molecule, target protein and antibody," he says. "For example, we are realizing that the concentration of anti-DNP antibodies in the bloodstream is going to be very important in order for this approach to be effective. Thanks to these studies, which will hopefully appear in the literature in the not-too-distant future, we have become very good at predicting ideal concentrations of our ARMs for in vitro experiments and are optimistic that these analyses will extend to animal models."
Because both HIV and cancer have methods for evading the body's immune system, treatments and vaccinations for the two diseases have proven difficult. Current treatment options for HIV and prostate cancer—including antiviral drugs, radiation and chemotherapy—involve severe side effects and are often ineffective against advanced cases. While there are some antibody drugs available, they are difficult to produce in large quantities and are costly. They also must be injected and are accompanied by severe side effects of their own.
By contrast, the ARM-H and ARM-P molecules, which the team started testing in mice, are structurally simple, inexpensive to produce, and could in theory be taken in pill form, Spiegel says. And because they are unlikely to target essential biological processes in the body, the side effects could be smaller, he noted.
"This is an entirely new approach to treating these two diseases, which are extraordinarily important in terms of their impact on human health," Spiegel says.
Spiegel, who has a background in synthetic organic chemistry, says the research offers a new model for improving therapeutics that target these diseases and added that he hopes their findings can be applied to a wider range of diseases.
"This is an evolving paradigm in disease treatment and if we are able to implement this strategy in treating pathogenic illnesses, it could have a profound effect on public health," he says.
Moving forward, Spiegel notes that the Holy Grail for his team, of course, would be to show that this technique can be useful clinically in the treatment of human diseases.
"Currently, there are only a handful of examples of small-molecule antibody-recruiting approaches in the literature," he notes. "We hope to demonstrate that this strategy possesses advantageous over conventional therapeutic approaches. We believe that there will be an explosion of interest in developing new antibody-recruiting molecules similar to the explosion of interest in monoclonal antibody development that has taken hold over the last few decades."
HIV is a global pandemic that affects 33 million people worldwide, while prostate cancer is the second leading cause of cancer-related death among American men, with one out of every six American men expected to develop the disease. Spiegel notes the research methods being used also could lead to novel therapeutic approaches for other forms of cancer or other diseases.
Efforts to apply this technology to other disease areas are currently underway in our laboratories," he says. "An important goal of our research program would be to develop potent, bifunctional molecules that are capable of redirecting the immune response to the widest possible variety of human pathogens. One can imagine advancing this technology as a general therapeutic strategy toward diseases ranging from viral and bacterial infections to cancers to autoimmune diseases."
Spiegel says it was part of his team's goal to demonstrate the versatility of this approach by publishing the first two papers in areas as disparate as HIV and prostate cancer.
"Such an approach would take advantage of the body's potent, endogenous defense system through utilization of small molecules that could, theoretically, be taken in pill-form," he notes.
However, Spiegel also notes that there are still many fundamental questions that need to be answered, and his team is currently working to answer them. Researchers also are looking forward to measuring their continued success.
"Our lab will continue to advance this exciting technology through multiple novel pathways in effort to better understand its fundamental mechanisms as well as to increase its overall therapeutic applicability," Spiegel says. "We are a basic science research group, so the success of this project will be measured as much in basic research discoveries as in clinically applicable advances. Of course a critical metric for us will be the extent to which this approach can be successfully applied clinically to diseases and we can begin helping people."
The molecules—called "antibody-recruiting molecule targeting HIV" (ARM-H) and "antibody-recruiting molecule targeting prostate cancer" (ARM-P)—work by binding simultaneously to an antibody already present in the bloodstream and to proteins on HIV, HIV-infected cells or cancer cells. By coating these pathogens in antibodies, the molecules flag them as a threat and trigger the body's own immune response. In the case of ARM-H, by binding to proteins on the outside of the virus, they also prevent healthy human cells from being infected.
"In addition, we are investigating ways in which we can use ARM-H based molecules as a delivery vehicle to target HIV/HIV-infected cells with cytotoxic agents," says Dr. David Spiegel, assistant professor of chemistry at Yale University and the corresponding author of two papers released late last year detailing the results of their work. "This would utilize a small molecule both to block HIV entry and to disrupt virus replication, and it would be complementary to the antibody recruiting approach."
Lastly, in a new collaboration with National Institute of Allergy and Infectious Diseases of the National Institutes of Health and Cheryl Stoddart's lab at the University of California, San Francisco, Spiegel's team is studying the efficacy of ARM-H based molecules in humanized Thy/Liv mouse models for HIV infection.
"In this effort, we will not only learn about the pharmacological properties of our molecules, but also measure their ability to induce a long-term immune response," he notes.
In the ARM-P area, Spiegel notes researchers are also working in mouse xenograft models, with the goal of establishing whole organism efficacy.
"These studies are currently ongoing, and results should be arriving shortly," he says. "We have also explored some interesting trends we observed in our initial studies related to compound linker lengths. These follow-up studies have revealed some interesting strategies for making even more potent and effective ARM-P derivatives. The results of these studies will be published shortly."
Finally, Spiegel notes researchers have invested considerable time in gaining a fundamental understanding of the nuances behind ternary complex therapeutics in order to maximize the efficiency of this general "antibody-recruiting" therapeutic approach.
"To this end, mathematical studies to predict ternary complex formation have been highly successful, and have provided crucial insights into the interactions between small molecule, target protein and antibody," he says. "For example, we are realizing that the concentration of anti-DNP antibodies in the bloodstream is going to be very important in order for this approach to be effective. Thanks to these studies, which will hopefully appear in the literature in the not-too-distant future, we have become very good at predicting ideal concentrations of our ARMs for in vitro experiments and are optimistic that these analyses will extend to animal models."
Because both HIV and cancer have methods for evading the body's immune system, treatments and vaccinations for the two diseases have proven difficult. Current treatment options for HIV and prostate cancer—including antiviral drugs, radiation and chemotherapy—involve severe side effects and are often ineffective against advanced cases. While there are some antibody drugs available, they are difficult to produce in large quantities and are costly. They also must be injected and are accompanied by severe side effects of their own.
By contrast, the ARM-H and ARM-P molecules, which the team started testing in mice, are structurally simple, inexpensive to produce, and could in theory be taken in pill form, Spiegel says. And because they are unlikely to target essential biological processes in the body, the side effects could be smaller, he noted.
"This is an entirely new approach to treating these two diseases, which are extraordinarily important in terms of their impact on human health," Spiegel says.
Spiegel, who has a background in synthetic organic chemistry, says the research offers a new model for improving therapeutics that target these diseases and added that he hopes their findings can be applied to a wider range of diseases.
"This is an evolving paradigm in disease treatment and if we are able to implement this strategy in treating pathogenic illnesses, it could have a profound effect on public health," he says.
Moving forward, Spiegel notes that the Holy Grail for his team, of course, would be to show that this technique can be useful clinically in the treatment of human diseases.
"Currently, there are only a handful of examples of small-molecule antibody-recruiting approaches in the literature," he notes. "We hope to demonstrate that this strategy possesses advantageous over conventional therapeutic approaches. We believe that there will be an explosion of interest in developing new antibody-recruiting molecules similar to the explosion of interest in monoclonal antibody development that has taken hold over the last few decades."
HIV is a global pandemic that affects 33 million people worldwide, while prostate cancer is the second leading cause of cancer-related death among American men, with one out of every six American men expected to develop the disease. Spiegel notes the research methods being used also could lead to novel therapeutic approaches for other forms of cancer or other diseases.
Efforts to apply this technology to other disease areas are currently underway in our laboratories," he says. "An important goal of our research program would be to develop potent, bifunctional molecules that are capable of redirecting the immune response to the widest possible variety of human pathogens. One can imagine advancing this technology as a general therapeutic strategy toward diseases ranging from viral and bacterial infections to cancers to autoimmune diseases."
Spiegel says it was part of his team's goal to demonstrate the versatility of this approach by publishing the first two papers in areas as disparate as HIV and prostate cancer.
"Such an approach would take advantage of the body's potent, endogenous defense system through utilization of small molecules that could, theoretically, be taken in pill-form," he notes.
However, Spiegel also notes that there are still many fundamental questions that need to be answered, and his team is currently working to answer them. Researchers also are looking forward to measuring their continued success.
"Our lab will continue to advance this exciting technology through multiple novel pathways in effort to better understand its fundamental mechanisms as well as to increase its overall therapeutic applicability," Spiegel says. "We are a basic science research group, so the success of this project will be measured as much in basic research discoveries as in clinically applicable advances. Of course a critical metric for us will be the extent to which this approach can be successfully applied clinically to diseases and we can begin helping people."
