Description:
RT&L FOCUS AREA(S): General Warfighting Requirements (GWR)
TECHNOLOGY AREA(S): Bio Medical
OBJECTIVE: Development of a platform for DNA-encoded monoclonal antibody delivery in large animal models of HIV infection and a prototype delivery device for use in humans.
DESCRIPTION: U.S. military personnel are exposed to and impacted by the diverse global HIV epidemic. Despite advances in non-vaccine prevention, the US military experiences a steady epidemic of approximately 350 new HIV infection every year. Effective prevention and therapeutic modalities are of utmost importance in combatting HIV/AIDS in the DoD. The US Military HIV research program (MHRP) is engaged in collaborative research with multiple academic, corporate, and governmental partnerships to develop and test immunologic approaches to prevention and therapy.
Monoclonal antibodies have great potential for use in prevention and treatment for many infectious diseases including HIV. However, current approaches to monoclonal antibody delivery are limited by price and durability of effect. MHRP seeks to develop innovative ways by which broadly neutralizing monoclonal antibodies (mAbs) can be delivered to overcome these challenges. Delivery of gene encoded mAbs by electroporation (EP) is a potential approach. EP has been used in basic research for the past 25 years to aid in the transfer of DNA into cells in vitro. EP in vivo enhances transfer of DNA vaccines and therapeutic plasmids to the skin, muscle, tumors, and other tissues resulting in high levels of expression. EP delivery of vaccines has been demonstrated to induce immune responses in numerous pre-clinical animal models and in human clinical trials for many different infectious diseases and cancer. Delivery of gene-encoded antibodies differs from these active vaccination approaches in that it seeks to minimize immune response to mAb delivery. The method of delivery by using EP technologies and a device capable of delivering selected mAbs will be the desired end product for this effort.
PHASE I: The awardee will demonstrate the scientific, technical, commercial merit and feasibility of a platform technology that relies on delivery of DNA-encoded mAbs. Research could be built upon similar existing technology for other products such as DNA vaccines and therapeutic plasmids. Phase I will focus on technology conceptualization of DNA-encoded mAbs including performance parameters. The performer will develop rapid methods of delivery of DNA-encoded mAbs. These methods may include the administration of DNA via an intramuscular injection followed by very short electrical pulses (electroporation or EP) that enable the efficient uptake of the DNA by the muscle cells, leading to much higher levels of expression of the delivered genes than with an injection alone. MAb-encoding DNA should be delivered in a way that minimizes tissue perturbation, avoiding any immune responses and enabling stable, long-term gene expression. Upon completion of Phase I the awardee will have developed, demonstrated and validated the delivery method for DNA-encoded mAbs.
PHASE II: After successful completion of the Phase I, the awardee will focus on finalizing and refining delivery method and use the results from Phase I studies to optimize the capability of gene encoded mAb technology in small and large animal models. Phase II efforts will focus on developing methods for manufacture of the delivery device for clinical use. The awardee will develop and optimize large animal model for the evaluation of DNA/EP as their musculature permits the evaluation of a human-sized prototype EP device, their larger size and proportionally increased blood volume better mimics what would be observed in humans in terms of dilutional effects of muscle cell-produced mAb. Further the studies should be conducted to demonstrate proof-of-concept that therapeutically relevant serum mAb levels can be achieved in animal models with large blood volumes using human-sized prototype of EP devices. The awardee will then design a prototype device that will be easy to use in delivering mAbs in clinical settings and/or field testing and ready for transition to manufacturing. The prototype specifications will be defined based on feedback from large animal data to meet the requirements of the delivery system in humans. An initial FDA regulatory plan should be submitted at this stage if appropriate to the product development effort.
Upon completion of Phase II of this project, the awardee will be able:
(1) to develop, optimize and manufacture the desired EP device prototype for mAb gene transfer based on Phase I modeling and design. Conduct life cycle and environmental testing with the prototype.
(2) to develop processes and demonstrate feasibility of a large scale manufacturing of the EP device that can be ready for a future proof-of-concept clinical trial in human volunteers.
PHASE III DUAL USE APPLICATIONS: The expected Phase II end-state is qualified, easy to use device to deliver clinically relevant mAbs of interest. The awardee is expected to obtain funding from non-SBIR/STTR government sources and/or the private sector to develop or transition the prototype into a viable FDA-regulated product or service for sale in the military or private sector markets. The performer will provide data package plan required for application to the FDA after successful large field testing of the assay prototype.
For HIV applications, the technology and/or product generated from the Phase III SBIR may be integrated in MHRP’s objective of developing broad spectrum and potent mAbs for prevention and treatment of HIV/AIDS. A potential method of transition for this product will be through the Army futures command following the decision gate process which includes a technology transfer agreement with U.S. Army Medical Materiel Development Activity (USAMMDA). In addition, civilian commercialization of this product is likely to include GLP production and GMP manufacture and distribution.
The end-state for this product is a commercially viable technology that will be incorporated into the Army’s strategy of developing countermeasures against HIV/AIDS.
REFERENCES:
- Neumann E, et al. Gene transfer into mouse lyoma cells by electroporation in high electric fields. EMBO J. 1982;1:841–845
- Cemazar M., and , Sersa G. Electrotransfer of therapeutic molecules into tissues. Curr Opin Mol Ther. 2007;9:554–562.
- Patel A, et al. In vivo delivery of synthetic human DNA-encoded monoclonal antibodies protect against Ebolavirus infection in a mouse model. Cell Reports, Volume 25, Issue 7, 13 November 2018, Pages 1982-1993.e4
