CD20-directed small modular immunopharmaceutical, TRU-015, depletes normal and malignant B cells.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Hayden-Ledbetter
Martha S
MS
Trubion Pharmaceuticals, Inc., Seattle, Washington 98121, USA.
Cerveny
Chuck G
CG
Espling
Erik
E
Brady
William A
WA
Grosmaire
Laura S
LS
Tan
Philip
P
Bader
Robert
R
Slater
Sonya
S
Nilsson
Christy A
CA
Barone
Dauphine S
DS
Simon
Alexander
A
Bradley
Cheryl
C
Thompson
Peter A
PA
Wahl
Alan F
AF
Ledbetter
Jeffrey A
JA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008212:Lymphocyte Depletion; D016393:Lymphoma, B-Cell / Q000628:therapy*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D000069283:Rituximab; D014183:Transplantation, Heterologous / Q000276:immunology
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C540931:TRU-015 protein; D000069283:Rituximab