Eric Burak

General Fusion (Canada)

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Ryan Simms

Rhodes College

John F. Valliant

McMaster University

James J. Vornov

Johns Hopkins University

John Forbes

Calvary Mater Newcastle Hospital

Charles T. Gombar

Endo Pharmaceuticals (United States)

Meiduo Hu

Centre for Probe Development and Commercialization

Natalie Grinshtein

McMaster University

H. Schwilden

Friedrich-Alexander-Universität Erlangen-Nürnberg

Harald Ihmsen

Universitätsklinikum Erlangen

Lucy M. Anderson

Rocky Mountain Biological Laboratory

Cooperative Institutions

Guilford College

Johns Hopkins University

University of Toronto

National Cancer Institute

National Institutes of Health

McMaster University

Centre for Probe Development and Commercialization

Friedrich-Alexander-Universität Erlangen-Nürnberg

Johns Hopkins Medicine

Frederick National Laboratory for Cancer Research

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Pharmacodynamics of AQUAVANTM Injection, a Water-Soluble Prodrug of Propofol as a Bolus Injection : A Phase I Dose Escalation Comparison with DIPRIVAN©

Anesthesiology (2002)

Ann L. G. Vanluchene Luc Van Bortel James J. Vornov Eric Burak Michel Struys

Pharmacodynamics

Bolus (digestion)

10.1097/00000542-200209002-00455

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Citations (1)

Pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 in rates

European Journal of Anaesthesiology (2005)

M. Schywalsky Harald Ihmsen Alexander Tzabazis J. Fechner Eric Burak

SummaryBackground and objective: We studied the pharmacokinetics and pharmacodynamics of GPI 15715 (Aquavan® injection), a new water-soluble prodrug metabolized to propofol by hydrolysis.Methods: Nine adult male Sprague–Dawley rats (398 ± 31 g) received a bolus dose of 40 mg GPI 15715. The plasma concentrations of GPI 15715 and propofol were determined from arterial blood samples, and the pharmacokinetics of both compounds were investigated using compartment models whereby the elimination from the central compartment of GPI 15715 was used as drug input for the central compartment of propofol. Pharmacodynamics were assessed using the median frequency of the EEG power spectrum.Results: A maximum propofol concentration of 7.1 ± 1.7 μg mL−1 was reached 3.7 ± 0.2 min after bolus administration. Pharmacokinetics were best described by two-compartment models. GPI 15715 showed a short half-life (2.9 ± 0.2 and 23.9 ± 9.9 min), an elimination rate constant of 0.18 ± 0.01 min−1 and a central volume of distribution of 0.25 ± 0.02 L kg−1. For propofol, the half-life was 1.9 ± 0.1 and 45 ± 7 min, the elimination rate constant was 0.15 ± 0.02 min−1 and the central volume of distribution was 2.3 ± 0.6 L kg−1. The maximum effect on the electroencephalogram (EEG) – EEG suppression for >4 s – occurred 6.5 ± 1.2 min after bolus administration and baseline values of the EEG median frequency were regained 30 min later. The EEG effect could be described by a sigmoid Emax model including an effect compartment (E0 = 16.9 ± 7.9 Hz, EC50 = 2.6 ± 0.8 μg mL−1, ke0 = 0.35 ± 0.04 min−1).Conclusions: Compared with known propofol formulations, propofol from GPI 15715 showed a longer half-life, an increased volume of distribution, a delayed onset, a sustained duration of action and a greater potency with respect to concentration.

Pharmacodynamics

Bolus (digestion)

Elimination rate constant

Arterial blood

10.1017/s0265021503000322

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Citations (43)

Estimation of the fraction of the dose of N-nitrosodimethylamine metabolized to methylamine in rats

Cancer Letters (1991)

Eric Burak George W. Harrington R Koseniauskas Charles T. Gombar

N-Nitrosodimethylamine

10.1016/0304-3835(91)90017-c

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Citations (6)

Pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 in rats: Retracted

European Journal of Anaesthesiology (2003)

M. Schywalsky Harald Ihmsen Alexander Tzabazis J. Fechner Eric Burak

Background and objective: We studied the pharmacokinetics and pharmacodynamics of GPI 15715 (Aquavan® injection), a new water-soluble prodrug metabolized to propofol by hydrolysis. Methods: Nine adult male Sprague-Dawley rats (398 ± 31 g) received a bolus dose of 40 mg GPI 15715. The plasma concentrations of GPI 15715 and propofol were determined from arterial blood samples, and the pharmacokinetics of both compounds were investigated using compartment models whereby the elimination from the central compartment of GPI 15715 was used as drug input for the central compartment of propofol. Pharmacodynamics were assessed using the median frequency of the EEG power spectrum. Results: A maximum propofol concentration of 7.1 ± 1.7 μg mL−1 was reached 3.7 ± 0.2 min after bolus administration. Pharmacokinetics were best described by two-compartment models. GPI 15715 showed a short half-life (2.9 ± 0.2 and 23.9 ± 9.9 min), an elimination rate constant of 0.18 ± 0.01 min−1 and a central volume of distribution of 0.25 ± 0.02 L kg−1. For propofol, the half-life was 1.9 ± 0.1 and 45 ± 7 min, the elimination rate constant was 0.15 ± 0.02 min−1 and the central volume of distribution was 2.3 ± 0.6 L kg−1. The maximum effect on the electroencephalogram (EEG) - EEG suppression for >4 s - occurred 6.5 ± 1.2 min after bolus administration and baseline values of the EEG median frequency were regained 30 min later. The EEG effect could be described by a sigmoid Emax model including an effect compartment (E0 = 16.9 ± 7.9 Hz, EC50 = 2.6 ± 0.8 μg mL−1, ke0 = 0.35 ± 0.04 min−1). Conclusions: Compared with known propofol formulations, propofol from GPI 15715 showed a longer half-life, an increased volume of distribution, a delayed onset, a sustained duration of action and a greater potency with respect to concentration.

Pharmacodynamics

Bolus (digestion)

Elimination rate constant

Arterial blood

10.1097/00003643-200303000-00002

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Citations (35)

Pre-clinical dosimetry for 124I-CPD-1028 immunoconjugate targeting IGF-1R.

Journal of Nuclear Medicine (2015)

John Forbes Ryan Simms Tianfu Wu Sean Collens Ryan Kelly

Immunoconjugate

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Citations (0)

Combination of IGF-1R targeted alpha therapy with checkpoint inhibitors results in synergistic efficacy in a syngeneic colorectal tumor model

Journal of Nuclear Medicine (2021)

Sonal Patel Natalie Grinshtein Ryan Simms Meiduo Hu John F. Valliant

1271 Objectives: In the last decade, immunotherapy has revolutionized cancer care and became a mainstream therapy along with surgery, chemotherapy and radiation. Unfortunately, only a limited number of cancers exhibit intrinsic sensitivity to immunotherapies and the overall response rate is only 20-25%. Therefore, there is a strong impetus to identify treatments which can sensitize patients to immunotherapies. Fusion utilizes targeted alpha therapy (TAT) which enables delivery of alpha particle emitting isotopes (actinium 225) to the targeted tumor cells. The rationale for the combination of TAT and immunotherapy stems from known immune stimulating properties of radiation, leading to release of tumor-associated antigens, maturation of antigen-presenting cells (APCs) and in turn activation and proliferation of CD8+ T cells. Therefore, we have hypothesized that combination of TAT with immunotherapy will lead to a robust therapeutic effect resulting in a synergistic response as compared to monotherapy alone. Methods: The syngeneic CT26 colon cancer model was used to evaluate therapeutic efficacy of combination treatment with actinium 225-radiolabelled IGF-1R antibody (mAb), FPI-1792, and checkpoint inhibitors. FPI-1792 was used as a surrogate therapeutic that cross-reacts with mouse IGF1R. Mice with subcutaneous tumors (tumor volume ~175 mm3) were treated with either vehicle, an anti-CTLA-4 mAb (5 mg/kg) or anti-PD-1 mAb alone (5 mg/kg), FPI-1792 alone (375 kBq/kg) or the respective combinations. CD8+ T cells infiltration was evaluated via flow cytometry. Results: While only transient tumor growth suppression was detected in animals treated with either checkpoint inhibitors or FPI-1792 alone, complete tumor regression was observed in 13 out of 15 mice treated with combination therapies, indicating development of potent synergy in the combination groups. To investigate whether animals with regressing tumors will be able to reject a secondary tumor, all surviving animals were re-challenged with CT26 cells on the contralateral flank. Rejection of the secondary tumors was detected in 87% of mice previously treated with either FPI-1792 alone or a combination therapy, while tumors grew in all control animals. To gain a better understanding of the mechanism responsible for tumor regression, tumors were collected 14 days post re-challenge and analyzed via flow cytometry. An increased frequency of CD8+ T cells was observed in mice treated with combination therapy as compared to untreated animals (5-20% vs 1-2%, respectively). Importantly, high frequency of AH1 antigen-specific T cells was detected using a tetramer staining - 30-70% in the treated animals as compared to 2-3% in the control mice. Conclusions: The combination of targeted alpha therapy with checkpoint inhibitors led to tumor regression in a CT26 syngeneic model. Moreover, mice re-challenged with the same tumor on the contralateral flank were protected due to development of a strong immune response. Finally, increased frequency of antigen specific CD8+ T cells in re-challenged tumors suggests that combined treatment can break T cell tolerance and elicit a strong CD8+ T cell mediated immune response, culminating in tumor rejection.

Combination therapy

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AQUAVANO (R) injection, a water-soluble prodrug of propofol, as a bolus injection

Anesthesiology (2005)

Ekaterina Gibiansky Michel Struys Leonid Gibiansky A. Vanluchene James J. Vornov

Bolus (digestion)

Intravenous bolus

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Citations (32)

Interspecies scaling of the pharmacokinetics of N-nitrosodimethylamine.

PubMed (1990)

Charles T. Gombar George W. Harrington Harry M. Pylypiw Lucy M. Anderson A. E. Palmer

The pharmacokinetics of N-nitrosodimethylamine was studied in patas monkeys following i.v. doses of 0.5, 1.0, and 5.0 mg/kg and a p.o. dose of 1.0 mg/kg, and in Swiss mice at i.v. doses of 1.0 and 2.0 mg/kg. In the patas monkey the pharmacokinetics was linear over the i.v. dose range studied. The mean clearance (Cl), steady-state volume of distribution (Vss), mean residence time, and elimination half-life (t 1/2) were 103.3 +/- 26.7 (SD) ml/min, 3061 +/- 821 ml, 30.8 +/- 10.8 min, and 21.1 +/- 8.5 min, respectively. Assuming that the pharmacokinetics was linear at the p.o. dose used, the p.o. bioavailability of N-nitrosodimethylamine in the monkey was 49%. The pharmacokinetics was also linear in mice, and the average Cl, Vss, mean residence time, and t 1/2 were 3.81 ml/min, 21.0 ml, 5.5 min, and 11.9 min, respectively. These data and data for rats, hamsters, rabbits, dogs, and pigs taken from the literature were used to scale Cl and Vss to body weight using the allometric equation. The resulting equation for Cl was Cl = 49.7B0.998 and the equation for Vss was Vss = 748B1.05 where B is body weight in kg. The fit of the data to the equation was excellent in both cases. Using these equations and assuming a body weight of 70 kg for humans, the Cl and Vss for N-nitrosodimethylamine in humans are estimated to be 3450 ml/min and 64,800 ml, respectively.

N-Nitrosodimethylamine

Half-life

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Citations (16)

Abstract LB155: Combination of IGF-1R targeted alpha therapy with checkpoint inhibitors results in synergistic efficacy in a syngeneic colorectal tumor model

Cancer Research (2021)

Sonal Patel Natalie Grinshtein Ryan Simms Meiduo Hu John F. Valliant

Abstract Objective: In the last decade, immunotherapy has revolutionized cancer care and became a mainstream therapy along with surgery, chemotherapy and radiation. Unfortunately, only a limited number of cancers exhibit intrinsic sensitivity to immunotherapies and the overall response rate is only 20-25%. Therefore, there is a strong impetus to identify treatments which can sensitize patients to immunotherapies. Fusion utilizes targeted alpha therapy (TAT) which enables delivery of alpha particle emitting isotopes (actinium 225) to the targeted tumor cells. The rationale for the combination of TAT and immunotherapy stems from known immune stimulating properties of radiation, leading to release of tumor-associated antigens, maturation of antigen-presenting cells (APCs) and in turn activation and proliferation of CD8+ T cells. Therefore, we have hypothesized that combination of TAT with immunotherapy will lead to a robust therapeutic effect resulting in a synergistic response as compared to monotherapy alone. Methods: The syngeneic CT26 colon cancer model was used to evaluate therapeutic efficacy of combination treatment with actinium 225-radiolabelled IGF-1R antibody (mAb), FPI-1792, and checkpoint inhibitors. FPI-1792 was used as a surrogate therapeutic that cross-reacts with mouse IGF1R. Mice with subcutaneous tumors (tumor volume ~175 mm3) were treated with either vehicle, an anti-CTLA-4 mAb (5 mg/kg) or anti-PD-1 mAb alone (5 mg/kg), FPI-1792 alone (375 kBq/kg) or the respective combinations. CD8+ T cells infiltration was evaluated via flow cytometry. Results: While only transient tumor growth suppression was detected in animals treated with either checkpoint inhibitors or FPI-1792 alone, complete tumor regression was observed in 13 out of 15 mice treated with combination therapies, indicating development of potent synergy in the combination groups. To investigate whether animals with regressing tumors will be able to reject a secondary tumor, all surviving animals were re-challenged with CT26 cells on the contralateral flank. Rejection of the secondary tumors was detected in 87% of mice previously treated with either FPI-1792 alone or a combination therapy, while tumors grew in all control animals. To gain a better understanding of the mechanism responsible for tumor regression, tumors were collected 14 days post re-challenge and analyzed via flow cytometry. An increased frequency of CD8+ T cells was observed in mice treated with combination therapy as compared to untreated animals (5-20% vs 1-2%, respectively). Importantly, high frequency of AH1 antigen-specific T cells was detected using a tetramer staining - 30-70% in the treated animals as compared to 2-3% in the control mice. Conclusions: The combination of targeted alpha therapy with checkpoint inhibitors led to tumor regression in a CT26 syngeneic model. Moreover, mice re-challenged with the same tumor on the contralateral flank were protected due to development of a strong immune response. Finally, increased frequency of antigen specific CD8+ T cells in re-challenged tumors suggests that combined treatment can break T cell tolerance and elicit a strong CD8+ T cell mediated immune response, culminating in tumor rejection. Citation Format: Sonal Patel, Natalie Grinshtein, Ryan Simms, Meiduo Hu, John Valliant, Eric Burak. Combination of IGF-1R targeted alpha therapy with checkpoint inhibitors results in synergistic efficacy in a syngeneic colorectal tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB155.

Combination therapy

10.1158/1538-7445.am2021-lb155

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Abstract A146: FPI-2068: A novel anti-EGFR/cMET, alpha-particle emitting, radioimmunoconjugate for cancer therapy

Molecular Cancer Therapeutics (2023)

Sadaf Aghevlian Sean Collens Julie Metcalf Natalie Grinshtein John Forbes

Abstract Introduction: FPI-2068, a targeted alpha therapeutic (TAT), consists of a humanized EGFR and cMET targeting bispecific antibody (FPI-2053) radiolabeled with actinium-225 [225Ac]. FPI-2068 leverages the EGFR/cMET co-expression in cancer (high vs. low in normal tissues) and internalizing nature of the receptors to deliver radionuclides into tumor cells. The primary tumoricidal mechanism of FPI-2068 is double-strand DNA breaks (DSB) induced by alpha radiation, which lead to cell death. Methods: FPI-2068 consists of FPI-2053 conjugated with a DOTA-chelate and radiolabeled with [225Ac]. FPI-2071 is the lutetium-177 analogue. The binding and internalization of FPI-2071 was studied in vitro using cancer cell lines (HT29 colorectal and H292, H441, H1975, HCC827 lung cancers). In vivo studies were performed in corresponding xenograft models. For biodistribution studies FPI-2071 was injected intravenously into mice and tumor/organ radioactivity was quantified ex vivo at selected timepoints. For therapeutic studies, a single dose of FPI-2068 was administered to groups of mice over a range from 92.5 to 740 kBq/kg. Explanted HT29 and H441 tumors from FPI-2068 treated mice were analyzed by immunoblotting to detect activation of DDR and cell death pathways. Results: FPI-2071 demonstrated in vitro binding to all cell lines tested, followed by internalization and retention of the radioisotope into target cells. The biodistribution profile of FPI-2071 showed low normal organ uptake in all xenograft models tested, while tumor uptake varied. The peak tumor uptake in each model was: H292 (~73 %ID/g), H441 (~38 %ID/g), HT29 (~30 %ID/g), HCC827 (~25 %ID/g) and H1975 (20 %ID/g). Delivery of FPI-2068 to target xenografts resulted in anti-tumor efficacy; treatment was well-tolerated by animals. Sustained tumor regression (>28 days) was generally observed at doses of 370 kBq/kg and 740 kBq/kg across models. Lower doses were tumor growth suppressive. FPI-2068 treatment resulted in a dose-dependent increase in pATM and pRad50 expression indicating activation of DDR pathways in HT29 and H441 xenografts. Formation of DSB (pH2AX) and the induction of apoptosis (cleaved caspase 3) was also observed, consistent with the proposed primary mechanism of action. Conclusions: FPI-2068 demonstrated its anti-tumor efficacy in colorectal and lung tumor xenograft mouse models. Single-dose administration of FPI-2068 led to prolonged tumor regression. FPI-2068 caused activation of the DDR pathway as well as apoptosis, suggesting an inability of the cellular machinery to repair the DNA damage induced by the alpha radiation. These data support initiation of clinical trials in patients with solid tumors. Citation Format: Sadaf Aghevlian, Sean Collens, Julie Metcalf, Natalie Grinshtein, John Forbes, Frank Comer, Darshan Dalal, Puja Sapra, Eric Burak. FPI-2068: A novel anti-EGFR/cMET, alpha-particle emitting, radioimmunoconjugate for cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A146.

Biodistribution

Internalization

Radionuclide therapy

10.1158/1535-7163.targ-23-a146

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Citations (2)