Using Stem Cells to Study the Immunology of Alzheimer's Disease
Crossing the Blood-brain Barrier for Neurotherapeutics
The blood-brain barrier (BBB) poses a major challenge for developing large molecule therapeutics for central nervous system (CNS) diseases. By taking advantage of an endogenous transport system at the BBB, we show that antibodies that bind transferrin receptor (TfR) can accumulate in brain when dosed systemically in wild-type mice. Optimizing the binding affinity of anti-TfR improves both its peripheral pharmacokinetics and brain exposure over time. A bispecific antibody that binds both TfR and the amyloid precursor protein cleavage enzyme BACE1 can significantly reduce mouse brain Abeta levels after a single systemic dose. Furthermore, we demonstrate that this BBB-crossing platform can be safely and robustly translated to primates, where a systemic dose of anti-TfR/BACE1 accumulates in brain to reduce Abeta in cynomolgus monkeys. These results lay the foundation for utilizing antibodies against TfR for BBB transport for any number of neurological disease targets. More generally, our results demonstrate that antibodies targeting endogenous BBB transport systems can be used to deliver therapeutically relevant levels of large molecule therapeutics to the brain.
Development of a monoclonal antibody cocktail for Ebola virus therapy: convergence of plants, mice, and primates
MB-003 is a cocktail of 3 monoclonal antibodies (mAbs), originally developed for the treatment of Ebola Virus Disease (EVD). These mAbs bind to non-overlapping epitopes on Ebola virus glycoprotein, and one of the mAbs is also reactive with Sudan, Reston, and Taï Forest virus. The mAbs have been chimerized with a human constant region and expressed using a Rapid Antibody Manufacturing Platform (RAMP) in Nicotiana benthamiana. Individually the mAbs protect mice from lethal challenge prophylactically and two days post-exposure (p.e.) at doses < 5 mg/kg. When cocktailed, MB-003 protects Rhesus macaques from lethal IM challenge (1000 pfu), with 100% protection demonstrated when treatment was initiated 1 hour p.e., 67%-100% protection when initiated 1 or 2 days p.e., and 43% protection when administered after detection of virus by both RT-PCR and a sustained fever (triggers met 100-120 hours p.e.). The majority of treated survivors display minimal morbidity and no side effects were observed from the treatment regimen in any animals. To improve on efficacy, various combinations of antibodies developed by Public Health Agency of Canada (ZMAb) were used to optimize protection in rodents and primates. The resulting combination of antibodies ZMappTM demonstrated improved efficacy over Zmab or MB-003. It is the result of an unusual partnership involving Mapp Biopharmaceutical, Inc. (San Diego, CA) and Kentucky BioProcessing (Owensboro, KY) working with the U.S. government, and Defyrus, Inc. (Ontario, Canada) working with the Canadian government. Data to date indicate ZMappTM can provide therapeutic efficacy in non-human primates at least 5 days after infection.
The Search for an HIV Vaccine: Lessons from the Development of the “Prime-Boost” Vaccine Concept
Since the discovery of human immunodeficiency virus (HIV) as the etiologic agent of acquired immunodeficiency syndrome (AIDS) more than 30 years ago, the search has been on for a vaccine against this virus. However, despite significant and intense effort, a safe and efficacious vaccine against HIV/AIDS remains elusive. Many factors contribute to this failure, including the highly mutable and adaptive nature of HIV, which makes it a moving target for vaccine developers.
To date, more than 100 candidate vaccines and vaccine concepts have been tested in the clinic. Only one that used a combination of a poxvirus and a subunit envelope protein (gp120) of HIV in a “prime-boost” regimen has resulted in a modest level of protection. This finding, together with a substantial body of work from preclinical models, provided the first indication that vaccine protection against HIV/AIDS is possible. Although the efficacy of this vaccine approach needs to be confirmed and improved upon, and the underlying mechanisms understood, the “prime-boost” concept has been the basis of many current vaccines being developed and evaluated in the clinic.
In this talk, I will review the lessons learned from the development of the “prime-boost” vaccine concept, the significant challenges remaining, and the prospect for future advances.
T Cell Rx: Considerations for the Design of Novel Chimeric Antigen Receptors
Trials utilizing CARs: Driving immunotherapy in hematologic malignancies
Chimeric antigen receptor technology has revolutionized T-cell cellular therapy, making it an effective approach for patients with advanced lymphoid malignancies. Patients with acute lymphoblastic leukemia have shown dramatic responses to CD19-directed CAR T cell therapy. In this talk, I will review the current CAR T cell constructs, and observed responses and toxicities in clinical trials.
Immunotherapy development: Challenging the status quo
Immunotherapy has demonstrated exciting activity in the treatment of cancer, and is becoming a viable systemic treatment option along with chemotherapy and targeted therapy. The distinct pharmacology of these agents, which involves the education and maturation of specific anti-tumor immunity, rather than direct tumor cell killing, is raising a number of new challenges in development of these agents. This presentation will review the unique promise of immunotherapy, and how their unique behavior is challenging the status quo in oncology development.