SBIR-STTR Award

According to the American Diabetes Association, Type 2 diabetes mellitus (T2D) affects at least 30 million Americans and is a major unmet public health concern with an annual cost in the United States of over $300billion dollars. Additionally, nearly 25% of the U.S. population is already considered prediabetic, or at high risk of developing T2D. These individuals are characterized by poor glycemic control as a result of insulin resistancecombined with reduced insulin secretion in response to glucose stimulation. At the prediabetic or early diabeticstages, insulin insufficiency is frequently managed by medications that stimulate pancreatic secretion, which isaccompanied by increased levels of human islet amyloid polypeptide, hIAPP (amylin). Native hIAPP in itsmonomeric form is a hormone that inhibits glucagon secretion, delays gastric emptying, and acts as a satietyagent. However, when hIAPP misfolds, which is common at elevated production, it results in structures calledprotofibrils. These protofibrils are soluble, highly toxic, and capable of inducing cell death. The stimulated co-secretion of hIAPP with insulin leads to a pathologic cycle of increased hIAPP, including misfolded hIAPP, thatleads to β cell toxicity in prediabetics and diabetics. The ensuing deficits in β cell function drive an increasedneed for insulin secretion, which is accompanied by further hIAPP secretion. In this sense, T2D is an amyloid-induced disease as evidenced by the presence of hIAPP plaque deposits in the pancreata of more than 90% ofT2D patients. Developing new therapeutic strategies that target toxic hIAPP protofibrils, inhibit their depositionas toxic amylin fibrils, and ultimately preserve β cell health is a priority for addressing this major unmet need inT2D.Current standard-of-care in T2D is able to provide some control of blood glucose levels, but it fails to addressthe  cell decline and its contribution to T2D progression. In this application we propose to advance a noveltherapeutic platform and our lead product from that platform, CM-TS1. CM-TS1 is a monoclonal antibody thatspecifically targets protofibrils, soluble conformations of hIAPP for rapid clearance prior to plaque deposition and cell destruction. We have already demonstrated that CM-TS1 is capable of binding to these soluble protofibrilsin peripheral blood and in the pancreata of a T2D murine model. We will continue therapeutic development byfirst validating our initial finding by demonstrating that CM-TS1 can clear hIAPP in an industry standard preclinicalmodel leading to a reduction of T2D pathology. Following this in vivo proof-of-concept, we will then advance CM-TS1 through humanization and into early preclinical development including manufacturability, stable cell lineconstruction, and non-GLP pharmacokinetic and toxicity studies ultimately culminating in a pre-IND Type Bmeeting with the FDA. The milestone of ultimate success will be launching this promising product into futureIND-enabling studies in order to successfully reach the patients that need it the most.

Public Health Relevance Statement:
ProjNeacrtrative HerweeporpostoedevelCoM-pT1S,anovaentilboddiyreactstoelduabndltxeoimcisfoclnofdoerdmations ofhumanaimsylpeotildype(phtliAdcPeaPl)plreodtoTfhiebspreriolitsbo.rhfialvbseeednemonstroated causetehdestroufchteitinosnuliingn-ppanrcorde�uaccteilaclnesdxpeddiitseeparsoegreisTnysepi2on daibetemsell(Ti2Dt),uaschroanndipcrogrecsosnidvitethiafoftenc0ttso251%ofthUe.Sp.opulation anrdesuinlatpsatieponptulatthicaonotntinuteobseundersweirtcvhuerdroenn-rtmkatehteraTphiees. overargcohaoilftnhgFiassTtraacpklicisattoviaoalnetiCdMT-S1'asbitlopirteysvee�rcefulnlticoannd ultimdaeltaeydliyseparsoegreusssiiannogindnussttrayndianvirvdporfo-foo-ocncetappproacndh, subsequaedvnatnlCcyMe-TiSn1ptroecldeievnliocpamlfeotnrhteraetmeonfTt2D.

Project Terms:
<β-cell><β-cells><βCell>

According to the American Diabetes Association, Type 2 diabetes mellitus (T2D) affects at least 30 millionAmericans and is a major unmet public health concern with an annual cost in the United States of over $300billion dollars. Additionally, nearly 25% of the U.S. population is already considered prediabetic, or at high risk ofdeveloping T2D. These individuals are characterized by poor glycemic control as a result of insulin resistancecombined with reduced insulin secretion in response to glucose stimulation. At the prediabetic or early diabeticstages, insulin insufficiency is frequently managed by medications that stimulate pancreatic secretion, which isaccompanied by increased levels of human islet amyloid polypeptide, hIAPP (amylin). Native hIAPP in itsmonomeric form is a hormone that inhibits glucagon secretion, delays gastric emptying, and acts as a satietyagent. However, when hIAPP misfolds, which is common at elevated production, it results in structures calledprotofibrils. These protofibrils are soluble, highly toxic, and capable of inducing cell death. The stimulated co-secretion of hIAPP with insulin leads to a pathologic cycle of increased hIAPP, including misfolded hIAPP, thatleads to β cell toxicity in prediabetics and diabetics. The ensuing deficits in β cell function drive an increasedneed for insulin secretion, which is accompanied by further hIAPP secretion. In this sense, T2D is an amyloid-induced disease as evidenced by the presence of hIAPP plaque deposits in the pancreata of more than 90% ofT2D patients. Developing new therapeutic strategies that target toxic hIAPP protofibrils, inhibit their depositionas toxic amylin fibrils, and ultimately preserve β cell health is a priority for addressing this major unmet need inT2D.Current standard-of-care in T2D is able to provide some control of blood glucose levels, but it fails to addressthe  cell decline and its contribution to T2D progression. In this application we propose to advance a noveltherapeutic platform and our lead product from that platform, CM-TS1. CM-TS1 is a monoclonal antibody thatspecifically targets protofibrils, soluble conformations of hIAPP for rapid clearance prior to plaque deposition and cell destruction. We have already demonstrated that CM-TS1 is capable of binding to these soluble protofibrilsin peripheral blood and in the pancreata of a T2D murine model. We will continue therapeutic development byfirst validating our initial finding by demonstrating that CM-TS1 can clear hIAPP in an industry standard preclinicalmodel leading to a reduction of T2D pathology. Following this in vivo proof-of-concept, we will then advance CM-TS1 through humanization and into early preclinical development including manufacturability, stable cell lineconstruction, and non-GLP pharmacokinetic and toxicity studies ultimately culminating in a pre-IND Type Bmeeting with the FDA. The milestone of ultimate success will be launching this promising product into futureIND-enabling studies in order to successfully reach the patients that need it the most.

Public Health Relevance Statement:
ProjNeacrtrative HerweeporpostoedevelCoM-pT1S,anovaentilboddiyreactstoelduabndltxeoimcisfoclnofdoerdmations ofhumanaimsylpeotildype(phtliAdcPeaPl)plreodtoTfhiebspreriolitsbo.rhfialvbseeednemonstroated causetehdestroufchteitinosnuliingn-ppanrcorde�uaccteilaclnesdxpeddiitseeparsoegreisTnysepi2on daibetemsell(Ti2Dt),uaschroanndipcrogrecsosnidvitethiafoftenc0ttso251%ofthUe.Sp.opulation anrdesuinlatpsatieponptulatthicaonotntinuteobseundersweirtcvhuerdroenn-rtmkatehteraTphiees. overargcohaoilftnhgFiassTtraacpklicisattoviaoalnetiCdMT-S1'asbitlopirteysvee�rcefulnlticoannd ultimdaeltaeydliyseparsoegreusssiiannogindnussttrayndianvirvdporfo-foo-ocncetappproacndh, subsequaedvnatnlCcyMe-TiSn1ptroecldeievnliocpamlfeotnrhteraetmeonfTt2D.

Project Terms: