SBIR-STTR Award

There is need for an artificial oxygen O carrier to substitute for banked blood in settings where stored blood is unavailable pre hospital care transport austere environments undeveloped countries or undesirable transfusion risk exceeds benefit To address this need we developed ErythroMer EM a first in class nano cyte blood substitute EM is a deformable cross linked polymeric nanoparticle that incorporates high per particle payloads of hemoglobin Hb Our artificial cell design has yielded a prototype that emulates RBC physiology in all key respects and represents a potentially disruptive introduction into Transfusion Medicine To date efforts to develop Hb based oxygen carriers HBOCs have failed because of design flaws which do not preserve physiologic interactions of Hb with O they capture O in lungs but do not release O effectively to tissue and nitric oxide NO they trap NO causing vasoconstriction The EM design surmounts these weaknesses by encapsulating Hb controlling O capture release with a novel DPG shuttle DPG is the major heterotropic effector for Hb and diminishes O affinity attenuating NO uptake through shell properties and retarding metHb formation by co packaging a reduction system Moreover EM is designed for sterile lyophilization and so is amenable to facile reconstitution after extended dry storage under ambient conditions EM offers a pragmatic approach to a complex need and is designed for cost effective production at scale Our prototype has passed rigorous initial ex vivo and in vivo proof of concept testing We founded KaloCyte so that we may translate ErythroMer innovations into a pragmatic therapeutic and as well as realize the commercial potential of a disruptive introduction into transfusion medicine Our project goals are to scale up reliable EM production perform pharmacokinetic studies initiate toxicity screening and affirm efficacy in a robust animal model of hemorrhagic shock resuscitation ErythroMer intellectual property is robust and secured by KaloCyte which has been supported by robust entrepreneur incubator programs that have afforded business and regulatory expertise initial space and administrative support STTR funding will enable KaloCyte to transition EM production from research to pilot scale Phase I and initiate groundwork required for IND authorization Phase II Of note our initial studies and the approach herein meet published FDA expectations for blood substitutes Given the significant potential for Department of Defense DoD collaboration and support we have chosen to pursue hemorrhagic shock as the first indication for FDA approval Our strategy to accelerate EM to human study involves collaborating with the DoD on a highly prioritized project to develop a Multifunctional Resuscitation Fluid MRF We have established firm collaborations with the US Army and the MRF program which currently lacks an O carrier Following a successful trial for hemorrhagic shock we would expand EM into other settings pre hospital use blood banking in the developing world and exploit the design to extend efficacies beyond that of stored blood PROJECT NARRATIVE There is need for an artificial oxygen carrier to care for anemic and bleeding patients in settings in settings where donated human blood is unavailable or undesirable To address this need we developed ErythroMer EM a first in class nano cyte blood substitute and founded KaloCyte to we may translate these innovations into a pragmatic therapeutic This proposal will support that effort

There is need for an artificial oxygen (O2) carrier to substitute for banked blood in settings where: (1) stored blood is unavailable (pre-hospital care/transport, austere environments, undeveloped countries) or (2) undesirable (transfusion risk exceeds benefit). To address this need, we developed ‘ErythroMer’ (EM), a first-in- class nano-cyte blood substitute. EM is a deformable, cross-linked polymeric nanoparticle that incorporates high per particle payloads of hemoglobin (Hb). Our ‘artificial cell’ design has yielded a prototype that emulates RBC physiology in all key respects and represents a potentially disruptive introduction into Transfusion Medicine. To date, efforts to develop Hb-based oxygen carriers (HBOCs) have failed, because of design flaws which do not preserve physiologic interactions of Hb with: (1) O2 (they capture O2 in lungs, but do not release O2 effectively to tissue) and (2) nitric oxide (NO) (they trap NO, causing vasoconstriction). The EM design surmounts these weaknesses by: 1) encapsulating Hb, 2) controlling O2 capture/release with a novel 2,3-DPG shuttle (2,3-DPG is the major heterotropic effector for Hb and diminishes O2 affinity), 3) attenuating NO uptake through shell properties, and 4) retarding metHb formation by co-packaging a reduction system. Moreover, EM is designed for sterile lyophilization and so, is amenable to facile reconstitution after extended dry storage under ambient conditions. EM offers a pragmatic approach to a complex need and is designed for cost-effective production at scale. Our prototype has passed rigorous initial ex vivo and in vivo “proof of concept” testing. We founded KaloCyte so that we may translate ErythroMer innovations into a pragmatic therapeutic and as well as realize the commercial potential of a disruptive introduction into transfusion medicine. Our project goals are to scale up reliable EM production, perform pharmacokinetic studies, initiate toxicity screening and affirm efficacy in a robust animal model of hemorrhagic shock resuscitation. ErythroMer intellectual property is robust and secured by KaloCyte, which has been supported by robust entrepreneur / incubator programs that have afforded business and regulatory expertise, initial space and administrative support. STTR funding will enable KaloCyte to transition EM production from research- to pilot-scale (Phase I) and initiate groundwork required for IND authorization (Phase II). Of note, our initial studies and the approach herein meet published FDA expectations for blood substitutes. Given the significant potential for Department of Defense (DoD) collaboration and support, we have chosen to pursue hemorrhagic shock as the first indication for FDA approval. Our strategy to accelerate EM to human study involves collaborating with the DoD on a highly prioritized project to develop a “Multifunctional Resuscitation Fluid (MRF)”. We have established firm collaborations with the US Army and the MRF program, which currently lacks an O2 carrier. Following a successful trial for hemorrhagic shock, we would expand EM into other settings (pre-hospital use, blood banking in the developing world, and exploit the design to extend efficacies beyond that of stored blood).

Public Health Relevance Statement:
PROJECT NARRATIVE There is need for an artificial oxygen carrier to care for anemic and bleeding patients in settings in settings where donated human blood is unavailable or undesirable. To address this need, we developed ‘ErythroMer’ (EM), a first-in-class nano-cyte blood substitute and founded KaloCyte to we may translate these innovations into a pragmatic therapeutic. This proposal will support that effort.

Project Terms:
Address; Affinity; Animal Model; Attenuated; Authorization documentation; base; Biodistribution; biomaterial compatibility; Blood; Blood Banks; Blood Substitutes; Businesses; Caring; Cell physiology; Cells; Coagulation Process; Collaborations; Complex; cost effective; Country; crosslink; Department of Defense; design; Dose; Drug Kinetics; Encapsulated; Environment; Erythrocytes; expectation; Formulation; Freeze Drying; Funding; Goals; Hemoglobin; Hemorrhage; Hemorrhagic Shock; Hospitals; Human; human study; in vivo; Incubators; innovation; Intellectual Property; Life; Liquid substance; Lung; manufacturing process; Medicine; Metabolic Clearance Rate; Modeling; nano; nanoparticle; nanoscale; Nitric Oxide; novel; Organ; Oryctolagus cuniculus; Oxygen; particle; Patients; Phase; Physiological; Polymers; Pre-hospitalization care; Process; process optimization; Production; programs; Property; prototype; Publishing; reconstitution; Research; Resuscitation; Risk; Route; Safety; scale up; screening; Secure; Small Business Technology Transfer Research; Source; Sterility; System; Testing; Therapeutic; Tissues; Toxic effect; Transfusion; Translating; Universities; uptake; vasoconstriction; Washington