CD20-Directed Small Modular Immunopharmaceutical, TRU-015, Depletes Normal and Malignant B Cells

April 8, 2009

Published online first on April 7, 2009

[Clinical Cancer Research, 10.1158/1078-0432.CCR-08-1694]

CD20-Directed Small Modular Immunopharmaceutical, TRU-015, Depletes Normal and

Malignant B Cells

Martha S. Hayden-Ledbetter , Chuck G. Cerveny , Espling , A. Brady

, S. Grosmaire , Philip Tan , Bader , Sonya Slater , Christy A.

Nilsson , Dauphine S. Barone , Simon , Cheryl Bradley , A.

, Alan F. Wahl *, and A. Ledbetter

Authors' Affiliation: Trubion Pharmaceuticals, Inc., Seattle, Washington

* To whom correspondence should be addressed. E-mail: awahl@...

Abstract

Purpose: CD20-directed therapy with rituximab is effective in many patients with

malignant lymphoma or follicular lymphoma. However, relapse frequently occurs

within 1 year, and patients become increasingly refractory to retreatment. Our

purpose was to produce a compact, single-chain CD20-targeting immunotherapeutic

that could offer therapeutic advantages in the treatment of B-cell lymphoma.

Experimental Design: Rituximab is a chimeric antibody containing two heavy

chains and two light chains. Here, we describe the properties of TRU-015, a

small modular immunopharmaceutical specific for CD20, encoded by a single-chain

construct containing a single-chain Fv specific for CD20 linked to human IgG1

hinge, CH2, and CH3 domains but devoid of CH1 and CL domains.

Results: TRU-015 mediates potent direct signaling and antibody-dependent

cellular cytotoxicity but has reduced size and complement-mediated cytotoxicity

activity compared with rituximab. TRU-015 is a compact dimer of 104 kDa that

comigrates with albumin in size exclusion chromatography and retains a long

half-life in vivo. TRU-015 induced growth arrest in multiple B lymphoma cell

lines in vitro and showed effective antitumor activity against large,

established subcutaneous Ramos or Daudi xenograft tumors in nude mice. TRU-015

also showed rapid, dose-dependent, and durable depletion of peripheral blood B

cells following single-dose administration to nonhuman primates.

Conclusion: These results indicate that TRU-015 may improve CD20-directed

therapy by effectively depleting embedded malignant B cells and nonmalignant

pathogenic B cells and do so with reduced complement activation.

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