Pharmacokinetics and Pharmacodynamic Effects of Nemvaleukin Alfa, a Selective Agonist of the Intermediate-Affinity IL-2 Receptor, in Cynomolgus Monkeys

Abstract CD22 is a B cell-specific glycoprotein expressed on the cell surface of all mature B cells. A candidate therapeutic anti-CD22 antibody, 10F4v3, was conjugated to the anti-mitotic agent maytansine (10F4v3-DM1). DM1 disrupts cellular mitosis through inhibition of tubulin polymerization when internalized into cells. The anti-CD22 DM1 conjugate was shown to have significant potency in preclinical efficacy models of NHL. In order to further characterize this antibody-drug conjugate in preclinical studies, we first evaluated the binding characteristics of the 10F4v3 to peripheral blood B cells from various geographical sources of cynomolgus monkeys. 10F4v3 bound to peripheral blood B cells from all cynomolgus monkeys of Indonesian and Mauritian origins, but displayed only limited binding to cynomolgus monkeys of Chinese and Cambodian origins. Therefore, further pre-clinical evaluation of 10F4v3-DM1 was conducted in Indonesian cynomolgus monkeys to examine the safety, pharmacokinetic, and pharmacodynamic effects in monkeys dosed at 10, 20, and 30 mg/kg (2000, 4000, and 6000 mg/m2 DM1). Pharmacodynamic assessments of peripheral blood and lymphoid tissues included examination of B cells, B cell subsets, CD4+ T cells, CD8+ T cells, and CD3−CD20− (NK) cells. B cell subsets included CD20+, CD20+CD21+, CD20+CD21−, CD20+CD21+CD27+, CD20+CD21+CD27−, and CD20+CD21high lymphocytes which are phenotypically similar to human B cells, mature B cells, germinal center B cells, memory B cells, naïve B cells, and marginal zone B cells, respectively. B cells and B cell subsets were substantially depleted in peripheral blood at all doses, with no apparent dose-dependent effects. In lymphoid tissue, B cells were also depleted, with substantial depletion of CD20+CD21− and CD20+CD21high B cell subsets in spleen and bone marrow. Based on the nonclinical data, 10F4v3-DM1 exhibits an encouraging pharmacodynamic profile that supports clinical development for the potential treatment of non-Hodgkin’s lymphoma.

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Pharmacodynamic effects of administration of maytansine conjugated anti-CD22 monoclonal antibodies to cynomolgus monkeys

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.3051 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 3051-3051

Author(s):

F. K. Fuh ◽

R. Fuji ◽

K. A. Poon ◽

W. Manning ◽

K. K. Berry ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Peripheral Blood ◽

Clinical Activity ◽

Large Variability ◽

Cynomolgus Monkeys ◽

Pharmacodynamic Effects ◽

Pharmacodynamic Profile ◽

Hodgkin's Lymphomas ◽

Antibody Drug

3051 Antibody-based B-cell specific therapeutic approaches have revolutionized the treatment of non-Hodgkin's lymphomas (NHL) as well as other hematological malignancies. However, a large variability in clinical response has been observed, and the need to develop effective new treatments remains urgent. A promising approach is the use of antibody-drug conjugates (ADCs), cytotoxic drugs covalently linked to antibodies through specialized chemical linkers for the treatment of NHL. CMC-544, an antibody to a B-cell specific glycoprotein CD22 conjugated to the cytotoxin calicheamicin, has shown clinical activity in patients. In addition, antibodies directed to B-cell targets such as rituximab and epratuzumab are in clinical trials for the treatment of NHL and autoimmune disorders. We have generated10F4v3, an anti-CD22 antibody conjugated to the antimitotic agent maytansine (10F4v3-DM1). DM1 disrupts cellular mitosis through inhibition of tubulin polymerization when internalized into cells. The anti-CD22 DM1 conjugate was shown to have significant potency in preclinical efficacy models of NHL. In order to further characterize this antibody-drug conjugate in preclinical studies, we first evaluated the binding characteristics of the 10F4v3 to peripheral blood B-cells from various geographical sources of cynomolgus monkeys. 10F4v3 bound to peripheral blood B-cells from all cynomolgus monkeys of Indonesian and Mauritian origins, but displayed only limited binding to cynomolgus monkeys of Chinese and Cambodian origins. Therefore, further preclinical evaluation of 10F4v3-DM1 was conducted in Indonesian cynomolgus monkeys to examine the safety, pharmacokinetic, and pharmacodynamic effects in monkeys. B-cells and B-cell subsets were depleted in peripheral blood and lymphoid tissue (spleen, bone marrow) at all doses, with no apparent dose-dependent effects or substantial safety limitations. Based on the nonclinical data, 10F4v3-DM1 exhibits an encouraging pharmacodynamic profile for the potential treatment of non-Hodgkin's lymphoma. [Table: see text]

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FRI0002 Pharmacodynamic Effects of the CD22-Targeted Monoclonal Antibody Epratuzumab on B Cells in Cynomolgus Monkeys and in Patients with Systemic Lupus Erythematosus

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-eular.2255 ◽

2015 ◽

Vol 74 (Suppl 2) ◽

pp. 420.2-420

Author(s):

A. Shock ◽

B. Kilgallen ◽

W. Koetse ◽

C. Stach ◽

S. Bongardt ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Monoclonal Antibody ◽

B Cells ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Cynomolgus Monkeys ◽

Pharmacodynamic Effects

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Different Fumaric Acid Esters Elicit Distinct Pharmacologic Responses

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000950 ◽

2021 ◽

Vol 8 (2) ◽

pp. e950 ◽

Cited By ~ 1

Author(s):

Brian T. Wipke ◽

Robert Hoepner ◽

Katrin Strassburger-Krogias ◽

Ankur M. Thomas ◽

Davide Gianni ◽

...

Keyword(s):

Fumaric Acid ◽

Transcriptional Profiling ◽

Differentially Expressed Gene ◽

Absolute Lymphocyte Count ◽

Primary Metabolite ◽

Cynomolgus Monkeys ◽

Fumaric Acid Esters ◽

Pharmacodynamic Effects ◽

Apoptosis Pathways ◽

Acid Esters

ObjectiveTo test the hypothesis that dimethyl fumarate (DMF, Tecfidera) elicits different biological changes from DMF combined with monoethyl fumarate (MEF) (Fumaderm, a psoriasis therapy), we investigated DMF and MEF in rodents and cynomolgus monkeys. Possible translatability of findings was explored with lymphocyte counts from a retrospective cohort of patients with MS.MethodsIn rodents, we evaluated pharmacokinetic and pharmacodynamic effects induced by DMF and MEF monotherapies or in combination (DMF/MEF). Clinical implications were investigated in a retrospective, observational analysis of patients with MS treated with DMF/MEF (n = 36).ResultsIn rodents and cynomolgus monkeys, monomethyl fumarate (MMF, the primary metabolite of DMF) exhibited higher brain penetration, whereas MEF was preferentially partitioned into the kidney. In mice, transcriptional profiling for DMF and MEF alone identified both common and distinct pharmacodynamic responses, with almost no overlap between DMF- and MEF-induced differentially expressed gene profiles in immune tissues. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated oxidative stress response pathway was exclusively regulated by DMF, whereas apoptosis pathways were activated by MEF. DMF/MEF treatment demonstrated that DMF and MEF functionally interact to modify DMF- and MEF-specific responses in unpredictable ways. In patients with MS, DMF/MEF treatment led to early and pronounced suppression of lymphocytes, predominantly CD8+ T cells. In a multivariate regression analysis, the absolute lymphocyte count (ALC) was associated with age at therapy start, baseline ALC, and DMF/MEF dosage but not with previous immunosuppressive medication and sex. Furthermore, the ALC increased in a small cohort of patients with MS (n = 6/7) after switching from DMF/MEF to DMF monotherapy.ConclusionsFumaric acid esters exhibit different biodistribution and may elicit different biological responses; furthermore, pharmacodynamic effects of combinations differ unpredictably from monotherapy. The strong potential to induce lymphopenia in patients with MS may be a result of activation of apoptosis pathways by MEF compared with DMF.

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Hexachlorobenzene toxicity in the monkey ovary: III. Ultrastructure induced by high (10 mg/kg) dose exposure

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100084958 ◽

1991 ◽

Vol 49 ◽

pp. 130-131

Author(s):

A. Singh ◽

A. Dykeman ◽

J. Jarrelf ◽

D. C. Villeneuve

Keyword(s):

Present Report ◽

Reproductive Toxicity ◽

Control Group ◽

Primate Model ◽

Human Follicular Fluid ◽

Thin Sections ◽

Cynomolgus Monkeys ◽

Cacodylate Buffer ◽

Induction Cycle ◽

Comprehensive Study

Hexachlorobenzene (HCB), a persistent and mobile organochlorine pesticide, occurs in environment. HCB has been shown to be present in human follicular fluid. An objective of the present report, which is part of a comprehensive study on reproductive toxicity of HCB, was to determine the cytologic effects of the compound on ovarian follicles in a primate model.Materials and Methods. Eight Cynomolgus monkeys were housed under controlled conditions at Animal facility of Health and Welfare, Ottawa. Animals were orally administered gelatin capsules containing HCB mixed with glucose in daily dosages of 0.0 or 10 mg/kg b.w. for 90 days; the former was the control group. On the menstrual period following completion of dosing, the monkeys underwent an induction cycle of superovulation. At necropsy, one-half of an ovary from each animal was diced into ca. 2- to 3-mm cubed specimens that were fixed by immersion in 2.5% glutaraldehyde in 0.1 M cacodylate buffer (pH 7.3). Subsequent procedures followed to obtain thin sections that were examined in a Hitachi H-7000 electron microscope have been described earlier.

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