Antibody-targeted chemotherapy of B-cell lymphoma using calicheamicin conjugated to murine or humanized antibody against CD22.

Abstract

Antibody-targeted chemotherapy with immunoconjugates of calicheamicin is a clinically validated strategy in cancer therapy. This study describes the selection of a murine anti-CD22 mAb, m5/44, as a targeting agent, its conjugation to a derivative of calicheamicin (CalichDM) via either acid-labile or acid-stable linkers, the antitumor activity of CalichDM conjugated to m5/44, and its subsequent humanization by CDR grafting. Murine IgG1 mAb m5/44 was selected based on its subnanomolar affinity for CD22 and ability to be internalized into B cells. CalichDM conjugated to m5/44 caused potent growth inhibition of CD22+ human B-cell lymphomas (BCLs) in vitro. The conjugate of m5/44 with an acid-labile linker was more potent than an acid-stable conjugate, a nonbinding conjugate with a similar acid-labile linker, or unconjugated CalichDMH in inhibiting BCL growth. CalichDM conjugated to m5/44 caused regression of established BCL xenografts in nude mice. In contrast, both unconjugated m5/44 and a nonbinding conjugate were ineffective against these xenografts. Based on the potent antitumor activity of m5/44-CalichDM conjugates, m5/44 was humanized by CDR grafting to create g5/44, an IgG4 anti-CD22 antibody. Both m5/44 and g5/44 bound CD22 with subnanomolar affinity. Competitive blocking with previously characterized murine anti-CD22 mAbs suggested that g5/44 recognizes epitope A located within the first N-terminal Ig-like domain of human CD22. Antitumor efficacy of CalichDM conjugated to g5/44 against BCL xenografts was more potent than its murine counterpart. Based on these results, a calicheamicin conjugate of g5/44, CMC-544, was selected for further development as a targeted chemotherapeutic agent for the treatment of B-cell malignancies.

• Authors: John F DiJoseph, Andrew Popplewell, Simon Tickle, Heather Ladyman, Alastair Lawson, Arthur Kunz, Kiran Khandke, Douglas C Armellino, Erwin R Boghaert, Philip Hamann, Karen Zinkewich-Peotti, Sue Stephens, Neil Weir, Nitin K Damle
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 54 Issue 1 Pg. 11-24 (Jan 2005) ISSN: 0340-7004 [Print] Germany
• PMID: 15693135 (Publication Type: Journal Article)

Chemical References

• Aminoglycosides
• Antibodies, Monoclonal
• Antigens, CD
• Antigens, Differentiation, B-Lymphocyte
• Antineoplastic Agents
• CD22 protein, human
• Cd22 protein, mouse
• Cell Adhesion Molecules
• Epitopes
• Immunoconjugates
• Lectins
• Sialic Acid Binding Ig-like Lectin 2
• calicheamicinone

Topics

• Amino Acid Sequence
• Aminoglycosides (chemistry, immunology, therapeutic use)
• Animals
• Antibodies, Monoclonal (genetics, immunology, therapeutic use)
• Antigens, CD (immunology)
• Antigens, Differentiation, B-Lymphocyte (immunology)
• Antineoplastic Agents (immunology, therapeutic use)
• Binding, Competitive
• Cell Adhesion Molecules (immunology)
• Cell Line, Tumor
• Epitopes (immunology)
• Female
• Humans
• Immunoconjugates (immunology, therapeutic use)
• Lectins (immunology)
• Lymphoma, B-Cell (immunology, therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Sequence Data
• Sialic Acid Binding Ig-like Lectin 2
• Xenograft Model Antitumor Assays (methods)