title: 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.affiliation: Oncology Discovery, Wyeth Research, 200/4604, 401 North Middletown Road, Pearl River, NY 10965, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: DiJoseph
authors.forename: Andrew
authors.initials: A
authors.lastname: Popplewell
authors.forename: Simon
authors.initials: S
authors.lastname: Tickle
authors.forename: Heather
authors.initials: H
authors.lastname: Ladyman
authors.forename: Alastair
authors.initials: A
authors.lastname: Lawson
authors.forename: Arthur
authors.initials: A
authors.lastname: Kunz
authors.forename: Kiran
authors.initials: K
authors.lastname: Khandke
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Armellino
authors.forename: Erwin R
authors.initials: ER
authors.lastname: Boghaert
authors.forename: Philip
authors.initials: P
authors.lastname: Hamann
authors.forename: Karen
authors.initials: K
authors.lastname: Zinkewich-Peotti
authors.forename: Sue
authors.initials: S
authors.lastname: Stephens
authors.forename: Neil
authors.initials: N
authors.lastname: Weir
authors.forename: Nitin K
authors.initials: NK
authors.lastname: Damle
mesh_terms: D000595:Amino Acid Sequence; D000617:Aminoglycosides / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use*; D001667:Binding, Competitive; D015815:Cell Adhesion Molecules / Q000276:immunology*; D045744:Cell Line, Tumor; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000627:therapeutic use*; D037102:Lectins / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D051918:Sialic Acid Binding Ig-like Lectin 2; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D000970:Antineoplastic Agents; C497867:CD22 protein, human; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D000939:Epitopes; D018796:Immunoconjugates; D037102:Lectins; D051918:Sialic Acid Binding Ig-like Lectin 2; C422086:calicheamicinone