The Development and Characterization of an scFv-Fc Fusion–Based Gene Therapy to Reduce the Psychostimulant Effects of Methamphetamine Abuse

Hay, Charles E.; Ewing, Laura; Hambuchen, Michael D.; Zintner, Shannon M.; Small, Juliana C.; Bolden, Chris; Fantegrossi, William E.; Margaritis, Paris; Owens, S. Michael; Peterson, Eric C.

doi:10.1124/jpet.119.261180

Cited by 7 publications

(4 citation statements)

References 24 publications

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“…Firstly, 2R13 is a scFv-Fc format that is useful for characterizing potential scFvs chosen from phage display libraries along with Fc-mediated effector functions. Although some scFv-Fcs can be employed for therapy and diagnostics, the full-length IgG is still deemed the most appropriate format for clinical applications [ 34 – 36 ]. Therefore, in order to advance the clinical application of 2R13, its conversion to the full-length IgG format and optimization, including improving affinity, is required.…”

Section: Discussionmentioning

confidence: 99%

Thrombopoietin receptor agonist antibody for treating chemotherapy-induced thrombocytopenia

et al. 2023

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Background Thrombocytopenia is a common complication in cancer patients undergoing chemotherapy. Chemotherapy-induced thrombocytopenia (CIT) leads to dose reduction and treatment delays, lowering chemotherapy efficacy and survival rate. Thus, rapid recovery and continuous maintenance of platelet count during chemotherapy cycles are crucial in patients with CIT. Thrombopoietin (TPO) and its receptor, myeloid proliferative leukemia (MPL) protein, play a major role in platelet production. Although several MPL agonists have been developed to regulate thrombopoiesis, none have been approved for the management of CIT due to concerns regarding efficacy or safety. Therefore, the development of effective MPL agonists for treating CIT needs to be further expanded. Methods Anti-MPL antibodies were selected from the human combinatorial antibody phage libraries using phage display. We identified 2R13 as the most active clone among the binding antibodies via cell proliferation assay using BaF3/MPL cells. The effect of 2R13 on megakaryocyte differentiation was evaluated in peripheral blood CD34+ cells by analyzing megakaryocyte-specific differentiation markers (CD41a+ and CD42b+) and DNA ploidy using flow cytometry. The 2R13-induced platelet production was examined in 8- to 10-week-old wild-type BALB/c female mice and a thrombocytopenia mouse model established by intraperitoneal injection of 5-fluorouracil (150 mg/kg). The platelet counts were monitored twice a week over 14 days post-initiation of treatment with a single injection of 2R13, or recombinant human TPO (rhTPO) for seven consecutive days. Results We found that 2R13 specifically interacted with MPL and activated its signaling pathways. 2R13 stimulated megakaryocyte differentiation, evidenced by increasing the proportion of high-ploidy (≥ 8N) megakaryocytes in peripheral blood-CD34+ cells. The platelet count was increased by a single injection of 2R13 for up to 14 days. Injection of 5-fluorouracil considerably reduced the platelet count by day 4, which was recovered by 2R13. The platelets produced by 2R13 sustained a higher count than that achieved using seven consecutive injections of rhTPO. Conclusions Our findings suggest that 2R13 is a promising therapeutic agent for CIT treatment.

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Section: Discussionmentioning

confidence: 99%

Thrombopoietin receptor agonist antibody for treating chemotherapy-induced thrombocytopenia

et al. 2023

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“…For example, a single-chain variable fragment Fc-fusion (100,000 g/mol vs 150,000 g/mol for a standard mAb) specific to methamphetamine has been developed that displays efficacy against the psychostimulant effects of methamphetamine. 77 Furthermore, because instances of exposure to multiple opioids are frequent, 78 , 79 treatment with mAbs that bind to structurally distinct opioids may be desirable. Both lead mAbs showed affinity for acetylfentanyl, HY11-7E1 showed affinity for carfentanil, and a previous mAb has shown in vivo efficacy against carfentanil in mice; 21 however, methods for evaluating the ability of a cross-reactive mAb to counteract polydrug exposure need to be developed.…”

Section: Discussionmentioning

confidence: 99%

Advancing humanized monoclonal antibody for counteracting fentanyl toxicity towards clinical development

Hicks

Baehr

Silva-Ortiz

et al. 2022

Human Vaccines & Immunotherapeutics

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Innovative therapies to complement current treatments are needed to curb the growing incidence of fatal overdoses related to synthetic opioids. Murine and chimeric monoclonal antibodies (mAb) specific for fentanyl and its analogs have demonstrated pre-clinical efficacy in preventing and reversing drug-induced toxicity in rodent models. However, mAb-based therapeutics require extensive engineering as well as in vitro and in vivo characterization to advance to first-in-human clinical trials. Here, novel murine anti-fentanyl mAbs were selected for development based on affinity for fentanyl, and efficacy in counteracting the pharmacological effects of fentanyl in mice. Humanization and evaluation of mutations designed to eliminate predicted post-translational modifications resulted in two humanized mAbs that were effective at preventing fentanyl-induced pharmacological effects in rats. These humanized mAbs showed favorable biophysical properties with respect to aggregation and hydrophobicity by chromatography-based assays, and thermostability by dynamic scanning fluorimetry. These results collectively support that the humanized anti-fentanyl mAbs developed herein warrant further clinical development for treatment of fentanyl toxicity.

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“…Our previous cross-sectional study revealedimportant associations between the key neurotransmitters GABA, serotonin andcholine, and the severities of anxiety and depression symptoms in MUDs ( 4 , 5 ). Despite studies showing that METH is neurotoxic, pharmacologic interventions focusedon modulating monoaminergic pathways have largely failed and no medications to datehave been approved by the U.S. Food and Drug Administration (FDA) for treating METHdependence ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Psychiatric Comorbidities and Liver Injury Are Associated With Unbalanced Plasma Bile Acid Profile During Methamphetamine Withdrawal

Wang

et al. 2022

Front. Endocrinol.

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BackgroundThe pathogenesis of methamphetamine usedisorders (MUDs) remains largely unknown; however, bile acids may play arole as potential mediators of liver injury and psychiatric comorbidities.The aim of this study was to characterize bile acid (BA) profiles in plasmaof patients with MUDs undergoing withdrawal.MethodsLiver functions and psychiatric symptoms wereevaluated in a retrospective cohort (30 MUDs versus 30 control subjects) andan exploratory cohort (30 MUDs including 10 subjects each at the 7-day,3-month, and 12-month withdrawal stages versus 10 control subjects). BAcompositions in plasma samples from MUD patients in the exploratory cohortwere determined by gas-liquid chromatography.ResultsBoth psychiatric comorbidities andmethamphetamine-induced liver injury were observed in patients in both MUDcohorts. The plasma concentrations of the total BA, cholic acid (CA), andchenodeoxycholic acid (CDCA) were lower in MUD patients relative tocontrols. The maximum decline was observed at the 3-month stage, withgradual recovery at the 12-month stage. Notably, the ratios of deoxycholicacid (DCA)/CA and lithocholic acid (LCA)/CDCA were statistically significantat the 3-month stage comparing with controls. Significant correlations werefound between the LCA/CDCA and taurolithocholic acid (TLCA)/CDCA ratios andthe levels of alanine transaminase and aspartate aminotransferase, andbetween the LCA/CDCA ratio and the HAM-A score.ConclusionBA profile during METH withdrawal weremarkedly altered, with these unbalanced BAs being associated with liverinjury. The associations between BA profiles and psychiatric symptomssuggest an association between specific BAs and disease progression,possibly through the liver-brain axis.

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The Development and Characterization of an scFv-Fc Fusion–Based Gene Therapy to Reduce the Psychostimulant Effects of Methamphetamine Abuse

Abstract: The development and characterization of an scFv-Fc fusion based gene therapy to reduce the psychostimulant effects of methamphetamine abuse

Cited by 7 publications

References 24 publications

Thrombopoietin receptor agonist antibody for treating chemotherapy-induced thrombocytopenia

Thrombopoietin receptor agonist antibody for treating chemotherapy-induced thrombocytopenia

Advancing humanized monoclonal antibody for counteracting fentanyl toxicity towards clinical development

Psychiatric Comorbidities and Liver Injury Are Associated With Unbalanced Plasma Bile Acid Profile During Methamphetamine Withdrawal

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