Purging Latent HIV Reservoirs through a Combination HIV Therapeutic

Period of Performance: 08/01/2016 - 07/31/2017

$463K

Phase 1 SBIR

Recipient Firm

Aphios Corporation
Woburn, MA 01801
Principal Investigator

Abstract

PROJECT SUMMARYWe hypothesize that Protein Kinase C (PKC) agonists such as the non-tumorigenic Bryoids combined withHDAC inhibitors (HDACi) represent a valuable pharmacological approach to purge latent HIV-1 from cellularreservoirs. We also hypothesize that a combination of a Bryoid and an HDACi co-encapsulated in a long-circulation pegylated immunonanosomes coated with anti-PD-L1 nanobodies will provide efficient HIV latencyactivation and immunological depletion of latent reservoirs. This combination nanosomal approach has theadded benefit of concomitantly and significantly reducing systemic toxicities of both PKC and HDACi.Our Phase I Specific Aims are: (1) construct and characterize nanosomes containing the Bryoid, Bryostatin-1in the lipid membrane and nanosomes of HDAC inhibitors SAHA, Romidepsin and Panobinostat in theaqueous core; (2) evaluate the cytotoxicity of Bryostatin-1, HDACi and of their corresponding nanosomes incell culture models, and in vivo cytotoxicity and biodistribution in BALB/c mouse model to select mostefficacious combination; and (3) evaluate the synergistic and anti-HIV-1 latency antagonistic effects of twonanosomes of different combination of Bryostatin-1 and the alternate HDAC inhibitors in cell culture and inhumanized mice models of HIV latency.We plan to conduct this Proof-of-Concept study over a 24-month period with a multidisciplinary team of 1.10full-time equivalents (FTE) of an engineer, virologist, and manufacturing technician. Additionally, our lean butexperienced research team will be advised and supported by Dr. Robert F. Siliciano, Professor of Medicine,Johns Hopkins University School of Medicine and Investigator, Howard Hughes Medical Institute who will alsoprovide support with respect to the ex vivo evaluation of the combination PKC-HDACi nanosomes; Dr. EduardoMunoz, University of Cordoba, Spain, an immunologist, an HIV latency researcher and Scientific Advisor toAphios Corporation; Dr. Santiago Moreno, Head, Infectious Diseases, Ramón y Cajal Hospital and Professorof Infectious Diseases, University of Alcalá, Madrid, Spain, an HIV clinician and Principal Investigator of anongoing Phase I/IIa clinical trial of Bryostatin-1 for HIV latency in HIV patients on cART; and Dr. Joseph L.Bryant, D.V.M at the Institute of Human Virology, University of Maryland Medical School, an HIV animal modelexpert, who will lead the in vivo toxicity and efficacy animal studies planned. We will establish a ScientificAdvisory Review Panel with Drs. Siliciano, Bryant, Munoz and Santiago for the research.Should we be successful in achieving our Phase I milestones, we will prepare and propose a comprehensivePhase II research and development program which will: (1) systematically construct immunonanosomes bycoating the most promising nanosomes identified in Phase I anti-PD-L1 nanobodies, and physically, chemicallyand biologically characterize the immunonanosomes; (2) evaluate most potent HIV latency drug combination inan induction/activation therapy protocol in the SHIV/macaque or alternative model of viral persistence andlatency; and (3) determine the potential effects of treatment on selected immunological functions duringinduction therapy.The end-goal of our research program is to develop a combination therapeutic to clear and free HIV patientsfrom latent viruses, curing a chronic disease and reducing the burden of personal toxicities and ending theeconomic burden of this disease in both developing and developed countries. In order to reach theseobjectives, we plan to conduct rigorous clinical studies in a Phase III clinical research program with acommercial partner/investor in which we will: (1) perform cGMP manufacturing of HIV latency combinationtherapeutic at the pilot-scale level; (2) establish a Drug Master File; (3) design IND-enabling preclinical studiesand Phase I/II clinical trials; (4) prepare pre-IND package; and (5) establish and conduct pre-IND meeting withFDA and file an IND with the FDA. We will then conduct Phase I and II clinical trials, and license thetherapeutic to a multinational pharmaceutical company such as Roche, J&J, Pfizer, Merck or GSK.In summary, we will utilize Aphios? proprietary critical fluid nanosomes (CFN) process for the formation ofsmall, uniform liposomes for the co-encapsulation of Bryoids and HDAC inhibitors [US Patent, Castor, 2014],and take advantage of promising data we have generated from preliminary studies [Perez et al., 2010], todevelop responsive protocols for Phase I and II clinical studies in HIV-1 patients being treated with cART andhaving a suppressed viral load [Gutiérrez et al., 2016]. The outcomes of the proposed studies will informproduct development for HIV latency, and fast-track the field to complete elimination of HIV infection andsterilizing cure.