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Engineering Glucose Responsiveness Into Insulin

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Engineering Glucose Responsiveness Into Insulin Diabetes Volume 67, February 2018 299 Engineering Glucose Responsiveness Into Insulin Niels C. Kaarsholm, Songnian Lin, Lin Yan, Theresa Kelly, Margaret van Heek, James Mu, Margaret Wu, Ge Dai, Yan Cui, Yonghua Zhu, Ester Carballo-Jane, Vijay Reddy, Peter Zafian, Pei Huo, Shuai Shi, Valentyn Antochshuk, Aimie Ogawa, Franklin Liu, Sandra C. Souza, Wolfgang Seghezzi, Joseph L. Duffy, Mark Erion, Ravi P. Nargund, and David E. Kelley Diabetes 2018;67:299–308 | https://doi.org/10.2337/db17-0577 Insulin has a narrow therapeutic index, reflected in a small modulate its action in the face of descending (or ascending) margin between a dose that achieves good glycemic control plasma glucose and thus do not change the intrinsically and one that causes hypoglycemia. Once injected, the narrow therapeutic index of exogenously administered insulin. PHARMACOLOGY AND THERAPEUTICS clearance of exogenous insulin is invariant regardless of To address the latter, the notion of a glucose-responsive blood glucose, aggravating the potential to cause hypo- insulin (GRI) was proposed four decades ago (8). Attempts glycemia. We sought to create a “smart” insulin, one that at creating a GRI have sought to incorporate insulin within can alter insulin clearance and hence insulin action in re- a subcutaneous depot matrix containing glucose-sensitive sponse to blood glucose, mitigating risk for hypoglyce- chemical “triggers” that release insulin (9–12), but there is mia. The approach added saccharide units to insulin to a substantial challenge in sufficiently modulating insulin create insulin analogs with affinity for both the insulin re- release across the narrow physiological range of plasma glu- ceptor (IR) and mannose receptor C-type 1 (MR), which cose. An alternative strategy for a GRI, to exploit endogenous functions to clear endogenous mannosylated proteins, a lectin–based clearance, was reported by Zion and Lancaster principle used to endow insulin analogs with glucose responsivity. Iteration of these efforts culminated in the (13), and is the focus of this report. discovery of MK-2640, and its in vitro and in vivo preclinical Lectins recognize and bind carbohydrate domains of properties are detailed in this report. In glucose clamp glycoproteins. Circulating and cell-based lectins function in experiments conducted in healthy dogs, as plasma glu- immune surveillance and as clearance of glycoproteins cose was lowered stepwise from 280 mg/dL to 80 mg/dL, (14,15). Mannose receptor C-type 1 (MR) is the prototypical progressively more MK-2640 was cleared via MR, reduc- member of the mannose receptor family of transmembrane ing by ∼30% its availability for binding to the IR. In dose lectins. Its main function is to recognize endogenous senes- escalations studies in diabetic minipigs, a higher thera- cent proteins tagged for destruction and pathogens iden- peutic index for MK-2640 (threefold) was observed versus tified by their surface glycan and to deliver these for regular insulin (1.3-fold). lysosomal degradation without eliciting an immune response or cytokine release (16–19). MR is an abundant lectin in hepatic sinusoidal endothelial cells and on certain macro- Nearly a century has passed since the discovery of insulin, yet phages and dendritic cells, with a well-conserved homology the remarkable success of insulin therapy has been tempered across species (14). Glucose has a low affinity for MR but by the risk of iatrogenic hypoglycemia, which stands as a nevertheless can compete with binding of other ligands. major barrier to the achievement of tight glycemic control A concept of a GRI that could be engineered into an (1–4). To mitigate risk for hypoglycemia, insulin analogs insulin analog by targeting MR-based clearance is illustrated have been developed with improvements in pharmaco- in Fig. 1. This concept involves creating a chimeric insulin kinetics (PKs) (5–7). However, efforts to improve insulin analog that undergoes a substantial fraction of its clearance PKs do not enable exogenous insulin to autonomously through MR when plasma glucose is within the euglycemic Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ © 2017 by the American Diabetes Association. Readers may use this article as fi Corresponding author: Ravi P. Nargund, [email protected], or David E. long as the work is properly cited, the use is educational and not for pro t, and the Kelley, [email protected]. work is not altered. More information is available at http://www.diabetesjournals .org/content/license. Received 29 May 2017 and accepted 30 October 2017. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db17-0577/-/DC1. 300 Glucose-Responsive Insulin Diabetes Volume 67, February 2018 Figure 1—A concept for GRI is illustrated that is based on adding saccharide modifications to the insulin molecule. The resulting analog has affinity for the IR as well as for an MR, which clears insulin via endocytosis and lysosomal degradation. Glucose competes for binding to the MR. At high ambient glucose, less of the analog is cleared by MR and a larger proportion becomes available for IR pharmacology; conversely, at low glucose, a proportionally larger fraction of the analog is cleared via MR, lowering availability for IR interaction. ICC, insulin-carbohydrate conjugate. or hypoglycemic range, thus lessening availability for interac- of mice was cannulated for perfusion with MK-2640, tion with the insulin receptor (IR), with the opposite direc- and varying concentrations of glucose were added to tion effect at a progressively higher ambient glucose. We the infusion buffer. Liver caudate lobe samples were will describe our initial steps in creating a GRI using lectin- taken and fixed(10%bufferedformalin),andimmuno- based clearance (J. Mu et al., unpublished observations), whereas histochemistry was performed with guinea pig anti- the current report focuses on a single GRI, MK-2640. We insulin antibody (Invitrogen #180067). Digital images describe the preclinical development of MK-2640, includ- were captured, and the percentage of immunoreactive cells ing dog and minipig in vivo studies designed to assess glu- was determined via instrument software (Membrane v9, cose responsivity. Aperio Technologies). RESEARCH DESIGN AND METHODS In Vivo Evaluations of MK-2640 In Vitro Binding Assays Allanimalprocedureswerereviewedandapprovedbythe MK-2640 binding to IR was determined in a scintillation Merck Research Laboratories (Merck & Co., Kenilworth, NJ) proximity assay with membranes prepared from CHO cells Institutional Animal Care and Use Committee. The Guide overexpressing human, minipig, or dog IR(B), and insulin for the Care and Use of Laboratory Animals was followed in as the competitive ligand (J. Mu et al., unpublished the conduct of the animal studies. Veterinary care was given observations). MK-2640 direct binding to human or dog to any animals requiring medical attention. MR was assessed via surface plasmon resonance using His- Male Yucatan minipigs from the Sinclair Research Center, tagged purified receptors immobilized onto a Biacore CM5 healthy (nondiabetic [ND]) or rendered type 1 diabetic (D) chip. To appraise glucose inhibition of MR binding, the by alloxan injections, underwent placement of two jugular surface plasmon resonance assay was modified to include venous vascular access ports for administration of MK-2640 varying concentrations of glucose or a-methylmannose or recombinant human insulin (RHI; Humulin R, Lilly) (a-MM) in the presence of a fixed concentration of MK- intravenously (i.v.) and for blood sampling. The study used 2640, approximating its Kd value, to determine the glucose minipigs rendered diabetic by alloxan that attained plasma inhibitory IC50 for MK-2640 binding to human or dog MR. glucose levels of ;300 mg/dL. RHI or MK-2640 was coad- Competition binding assays for MR, DC-SIGN, and MBL ministered with PBS or a-MM (9.4 mg/kg/min), the latter a were conducted using mannosylated-BSA, labeled with high-affinityligandforMRthatcanactasachemical europium for fluorescent detection, and varying concentra- blockade of MR (20). Insulin levels were measured by ELISA tions of MK-2640 to determine affinity for the human (RHI) or by liquid chromatography–mass spectrometry lectin receptors. An ex vivo assay of glucose inhibition of for MK-2640. To elucidate glucose-responsiveness of MK-2640 binding in the liver was conducted by perfusing RHI or MK-2640, respective clearances were assessed the compound into the portal vein of mice with varying in D minipigs and compared with corresponding values concentrations of glucose and then imaging liver sections obtained in ND minipigs that had been coinfused with with an anti-insulin antibody. Briefly, the portal vein PBS or a-MM. To appraise therapeutic index, MK-2640 or diabetes.diabetesjournals.org Kaarsholm and Associates 301 RHI was administered subcutaneously (s.c.) to D minipigs reflecting glucose responsive PKs. MK-2640 was tested for with dose escalation (successive 30% dose increments), activation of cytokine release in the plasma of dogs receiv- and plasma glucose monitoring for 8 h (AU480 Clinical ing MK-2640 or RHI infusions. Cytokine levels (interleukin Chemistry Analyzer, Beckman Coulter) until a dose that [IL]-6, IL-10, IL-8, IL-2, and tumor necrosis factor-a)were caused hypoglycemia was identified. Plasma epineph- evaluated by ELISA (Meso Scale Diagnostics, Rockville, MD), rine was assessed by liquid chromatography–mass spec- and dog blood exposed ex vivo to lipopolysaccharide trometry to monitor the hypoglycemic counterregulatory (10 pg/mL) was a positive control. response. Statistical Analysis MK-2640 was examined in healthy 4- to 6-year-old male Data analyses were performed in GraphPad Prism (GraphPad beagle dogs with euglycemic and hyperglycemic clamps to Software, San Diego, CA). Calculations of P values were examine its PK and pharmacodynamic (PD) effects across a based on ANOVA and the unpaired Student t test, which- range of steady-state plasma glucose concentrations. Dogs ever was applicable. Statistical significance was defined as were fasted overnight before a clamp and had previously P , 0.05.
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