Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model

The National Institutes of Health (NIH) has long supported using nonhuman primate (NHP) models for research on kidney, pancreatic islet, heart, and lung transplantation. The primary purpose of this research has been to develop new treatments for down-modulating or preventing deleterious immune responses after transplantation in human patients. Here, we discuss NIH-funded NHP studies of immune cell depletion, costimulation blockade, regulatory cell therapy, desensitization, and mixed hematopoietic chimerism that either preceded clinical trials or prevented the human application of therapies that were toxic or ineffective.

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Functional and Selective Targeting of Adenovirus to High-Affinity Fcγ Receptor I-Positive Cells by Using a Bispecific Hybrid Adapter

Journal of Virology ◽

10.1128/jvi.75.1.480-489.2001 ◽

2001 ◽

Vol 75 (1) ◽

pp. 480-489 ◽

Cited By ~ 55

Author(s):

Christina Ebbinghaus ◽

Ahmed Al-Jaibaji ◽

Elisabeth Operschall ◽

Angelika Schöffel ◽

Isabelle Peter ◽

...

Keyword(s):

Fold Increase ◽

Adapter Protein ◽

Fcγ Receptor ◽

Monocytic Cell ◽

Coxsackie Adenovirus Receptor ◽

Amino Terminal ◽

High Affinity ◽

Selective Targeting ◽

Human Monocytic Cell ◽

Adenovirus Receptor

ABSTRACT Adenovirus (Ad) efficiently delivers its DNA genome into a variety of cells and tissues, provided that these cells express appropriate receptors, including the coxsackie-adenovirus receptor (CAR), which binds to the terminal knob domain of the viral capsid protein fiber. To render CAR-negative cells susceptible to Ad infection, we have produced a bispecific hybrid adapter protein consisting of the amino-terminal extracellular domain of the human CAR protein (CARex) and the Fc region of the human immunoglobulin G1 protein, comprising the hinge and the CH2 and CH3 regions. CARex-Fc was purified from COS7 cell supernatants and mixed with Ad particles, thus blocking Ad infection of CAR-positive but Fc receptor-negative cells. The functionality of the CARex domain was further confirmed by successful immunization of mice with CARex-Fc followed by selection of a monoclonal anti-human CAR antibody (E1-1), which blocked Ad infection of CAR-positive cells. When mixed with Ad expressing eGFP, CARex-Fc mediated an up to 250-fold increase of transgene expression in CAR-negative human monocytic cell lines expressing the high-affinity Fcγ receptor I (CD64) but not in cells expressing the low-affinity Fcγ receptor II (CD32) or III (CD16). These results open new perspectives for Ad-mediated cancer cell vaccination, including the treatment of acute myeloid leukemia.

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Combination induction therapy with monoclonal antibodies specific for CD80, CD86, and CD154 in nonhuman primate renal transplantation

Transplantation Journal ◽

10.1097/00007890-200211270-00002 ◽

2002 ◽

Vol 74 (10) ◽

pp. 1365-1369 ◽

Cited By ~ 47

Author(s):

Sean P. Montgomery ◽

He Xu ◽

Douglas K. Tadaki ◽

Abbie Celniker ◽

Linda C. Burkly ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Renal Transplantation ◽

Induction Therapy ◽

Nonhuman Primate

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A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: Synthesis and preclinical characterization of [18F]SDM-16

10.1101/2021.06.25.449978 ◽

2021 ◽

Author(s):

Chao Zheng ◽

Daniel Holden ◽

Ming-Qiang Zheng ◽

Richard Pracitto ◽

Kyle C. Wilcox ◽

...

Keyword(s):

Synaptic Vesicle ◽

Nonhuman Primate ◽

Specific Binding ◽

Volume Of Distribution ◽

Binding Potential ◽

Time Activity ◽

Peripheral Tissues ◽

High Affinity ◽

Arterial Blood ◽

Pet Tracer

Purpose: To investigate the synaptic vesicle glycoprotein 2A (SV2A) expression in the whole central nervous system and peripheral tissues, a metabolically stable SV2A radiotracer is desirable to minimize a potential confounding effect of radiometabolites. The aim of this study was to develop and evaluate a metabolically stable SV2A radiotracer, [18F]SDM-16, in nonhuman primate brains. Methods: The racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one ) was synthesized and assayed for in vitro SV2A binding affinity. We synthesized the enantiopure [18F]SDM-16 using the corresponding arylstannane precursor. Nonhuman primate brain PET was performed on a FOCUS 220 system. Arterial blood was drawn for metabolite analysis and construction of plasma input function. Regional time-activity curves (TACs) were evaluated with the one-tissue compartment (1TC) model to obtain the volume of distribution (VT). Binding potential (BPND) was calculated using either the nondisplaceable volume of distribution (VND) or the centrum semiovale (CS) as the reference region. Results: Racemic SDM-16 was synthesized in 3 steps with 44% overall yield and has high affinity (Ki = 3.7 nM) to human SV2A. [18F]SDM-16 was prepared in greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in brain and was metabolically more stable than other SV2A PET tracers. The plasma free fraction (fP) of [18F]SDM-16 was 69%, which was higher than those of [11C]UCB-J (46%), [18F]SynVesT-1 (43%), [18F]SynVesT-2 (41%), and [18F]UCB-H (43%). The TACs were well described with the 1TC. The averaged test-retest variability (TRV) was -9%, and averaged absolute TRV (aTRV) was 10% for all analyzed brain regions. Conclusion: We have successfully synthesized a metabolically stable and high affinity SV2A PET tracer, [18F]SDM-16, which showed high specific and reversible binding in the NHP brain. [18F]SDM-16 may have potential application in the visualization and quantification of SV2A beyond the brain.

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A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: Synthesis and preclinical characterization of [18F]SDM-16

10.21203/rs.3.rs-672703/v1 ◽

2021 ◽

Author(s):

Chao Zheng ◽

Daniel Holden ◽

Ming-Qiang Zheng ◽

Richard Pracitto ◽

Kyle C. Wilcox ◽

...

Keyword(s):

Synaptic Vesicle ◽

Nonhuman Primate ◽

Specific Binding ◽

Volume Of Distribution ◽

Binding Potential ◽

Time Activity ◽

Peripheral Tissues ◽

High Affinity ◽

Arterial Blood ◽

Pet Tracer

Abstract PurposeTo investigate the synaptic vesicle glycoprotein 2A (SV2A) expression in the whole central nervous system and peripheral tissues, a metabolically stable SV2A radiotracer is desirable to minimize a potential confounding effect of radiometabolites. The aim of this study was to develop and evaluate a metabolically stable SV2A radiotracer, [18 F]SDM-16, in nonhuman primate brains. MethodsThe racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1yl)methyl)pyrrolidin-2-one) was synthesized and assayed for in vitro SV2A binding affinity. We synthesized the enantiopure [18F]SDM-16 using the corresponding arylstannane precursor. Nonhuman primate brain PET was performed on a FOCUS 220 system. Arterial blood was drawn for metabolite analysis and construction of plasma input function. Regional time-activity curves (TACs) were evaluated with the one-tissue compartment (1TC) model to obtain the volume of distribution (VT). Binding potential (BPND) was calculated using either the nondisplaceable volume of distribution (VND) or the centrum semiovale (CS) as the reference region. ResultsRacemic SDM-16 was synthesized in 3 steps with 44% overall yield and has high affinity (K i = 3.7 nM) to human SV2A. [18F]SDM-16 was prepared in greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in brain and was metabolically more stable than other SV2A PET tracers. The plasma free fraction (fP) of [ 18 F]SDM-16 was 69%, which was higher than those of [11C]UCB-J (46%), [18F]SynVesT-1 (43%), [18F]SynVesT-2 (41%), and [18F]UCB-H (43%). The TACs were well described with the 1TC. The averaged test-retest variability (TRV) was -9±8%, and averaged absolute TRV (aTRV) was 10±7% for all analyzed brain regions. ConclusionWe have successfully synthesized a metabolically stable and high affinity SV2A PET tracer, [18F]SDM-16, which showed high specific and reversible binding in the NHP brain. [18F]SDM-16 may have potential application in the visualization and quantification of SV2A beyond the brain.

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Corticosteroids and methotrexate as adjuvants to costimulation blockade in non‐human primate renal transplantation

Clinical Transplantation ◽

10.1111/ctr.13568 ◽

2019 ◽

Vol 33 (6) ◽

Author(s):

Douglas J. Anderson ◽

Denise J. Lo ◽

Francis Leopardi ◽

Mingqing Song ◽

Elizabeth A. Strobert ◽

...

Keyword(s):

Renal Transplantation ◽

Costimulation Blockade ◽

Human Primate

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