Effects of administration of a single dose of a humanized monoclonal antibody to CD11a on the immunobiology and clinical activity of psoriasis

doi:10.1016/S0190-9622(00)90214-7

Journal of the American Academy of Dermatology

Volume 42, Issue 3, March 2000, Pages 428-435

https://doi.org/10.1016/S0190-9622(00)90214-7 Get rights and content

Abstract

Background: CD11a/CD18 comprise subunits of leukocyte function associated antigen (LFA-1), a T-cell surface molecule important in T-cell activation, T-cell emigration into skin, and cytotoxic T-cell function. Objective: We explored the immunobiologic and clinical effects of treating moderate to severe psoriasis vulgaris with a single dose of humanized monoclonal antibody against CD11a (hu1124). Methods: This was an open label study with a single dose of hu1124 at doses of 0.03 to 10 mg/kg. Clinical (Psoriasis Area and Severity Index [PASI]) and immunohistologic parameters (epidermal thickness, epidermal and dermal T-cell numbers, and keratinocyte intercellular adhesion molecule 1 [ICAM-1] expression) were followed. Results: Treatment with hu1124, at doses higher than 1.0 mg/kg (group III), completely blocks CD11a staining for at least 14 days in both blood and psoriatic plaques. At 0.3 to 1.0 mg/kg, T-cell CD11a staining was completely blocked; however, blockade lasted less than 2 weeks (group II). Only partial saturation of either blood or plaque cellular CD11a was observed at doses of hu1124 between 0.01 and 0.1 mg/kg (group I). This pharmacodynamic response was accompanied by decreased numbers of epidermal and dermal CD3⁺ T cells, decreased keratinocyte and blood vessel expression of ICAM-1, and epidermal thinning. Statistically significant drops in PASI compared with baseline were observed in group II patients at weeks 3 and 4 and in group III patients at weeks 2 through 10. No significant drop in PASI score was observed in group 1. Adverse events were mild at doses of 0.3 mg/kg or less and included mild chills, abdominal discomfort, headache, and fever. At a single dose of 0.6 mg/kg or higher, headache was the most common dose-limiting toxicity observed. Conclusion: Targeting CD11a may improve psoriasis by inhibiting T-cell activation, T-cell emigration into the skin, and cytotoxic T-cell function. (J Am Acad Dermatol 2000;42:428-35.)

Section snippets

Study procedures

In an open label, dose-escalating, multicenter, institutional review board–approved study, 31 patients with moderate to severe plaque psoriasis were treated with a single infusion of humanized monoclonal antibody (hu1124) directed against CD11a in doses ranging from 0.03 to 10.0 mg/kg. Before entry in this study, patients received no photochemotherapy or systemic medications for 4 weeks, and no UVB irradiation or topical drugs (except emollients) for 2 weeks. Clinical activity was assessed by

RESULTS

A total of 31 subjects were enrolled after a 4-week washout period for photochemotherapy and systemic therapies and a 2-week washout period for UVB irradiation and topical treatments (except emollients). Each of the 31 subjects completed all safety and clinical activity assessments and was evaluated for safety and for effects on psoriasis clinical activity. One subject (1.0 mg/kg dose group) discontinued infusion of the study drug prematurely because of vomiting, nausea, fever, chills, and

DISCUSSION

A single dose of hu1124 blocked CD11a surface expression measured on peripheral blood and skin lymphocytes at dosages of 0.3 mg/kg or higher. Sustained (>2 weeks) and complete blockade of CD11a in both peripheral blood and psoriatic plaques is achieved at dosages of 2.0 mg/kg or higher. Clearance of hu1124 is concentration dependent. Higher dosages of hu1124 are required to block surface CD11a expression on cells in psoriatic plaques than on circulating T cells, suggesting the potential need

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^☆: Supported in part by XOMA (US) LCC, Johnson and Johnson Focused Giving Program (to A. B. G.). J. G. K. is supported in part by grant No. AI/AR39214 from the National Institutes of Health.

^☆☆: Reprint requests: Alice Gottlieb, MD, PhD, WH Conzen Chair in Clinical Pharmacology, UMDNJ-Robert Wood Johnson Medical School, 1 Robert Wood Johnson Place, New Brunswick, NJ 08903.

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Effects of administration of a single dose of a humanized monoclonal antibody to CD11a on the immunobiology and clinical activity of psoriasis☆,☆☆

Abstract

Section snippets

Study procedures

RESULTS

DISCUSSION

Immunol Today

Expression of HLA-DR molecules by keratinocytes and presence of Langerhans cells in the dermal infiltrate of active psoriatic plaques

J Exp Med

The role of activated T lymphocytes in the pathogenesis of psoriasis

Successful ultraviolet B treatment of psoriasis is accompanied by a reversal of keratinocyte pathology and by selective depletion of intraepidermal T cells

J Exp Med

Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis

Nat Med

Adhesions receptors of the immune system

Nature

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris

J Clin Invest

Regulatory properties of LFA-1 alpha and beta chains in human T-lymphocyte activation

Nature

Severe psoriasis: oral therapy with a new retinoid

Dermatologica

Response of psoriasis to a lymphocyte-selective toxin (DAB₃₈₉IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis