title: Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies.
abstract: Antibody-targeted chemotherapy with gemtuzumab ozogamicin (CMA-676, a CD33-targeted immunoconjugate of N-acetyl-gamma-calicheamicin dimethyl hydrazide [CalichDMH], a potent DNA-binding cytotoxic antitumor antibiotic) is a clinically validated therapeutic option for patients with acute myeloid leukemia (AML). Here, we describe the preclinical profile of another immunoconjugate of CalichDMH, CMC-544, targeted to CD22 expressed by B-lymphoid malignancies. CMC-544 comprises a humanized IgG4 anti-CD22 monoclonal antibody (mAb), G5/44, covalently linked to CalichDMH via an acid-labile 4-(4'-acetylphenoxy) butanoic acid (AcBut) linker. Both CMC-544 and unconjugated G5/44 bound human CD22 with subnanomolar affinity. CMC-544, but not unconjugated G5/44, exerted potent cytotoxicity against CD22+ B-cell lymphoma (BCL) cell lines (inhibitory concentration of 50%: 6-600 pM CalichDMH). CMC-544 caused a potent inhibition of growth of small but established BCL xenografts leading to cures (therapeutic index > 10). CMC-544 prevented the establishment of BCL xenografts and also caused regression of large BCLs (> 1.5 g tumor mass). In contrast, unconjugated CalichDMH, unconjugated G5/44, and an isotype-matched control conjugate, CMA-676, were ineffective against these BCL xenografts. Thus, CD22-targeted delivery of CalichDMH is a potent and effective preclinical therapeutic strategy for BCLs. The strong antitumor profile of CMC-544 supports its clinical evaluation as a treatment option for B-lymphoid malignancies.
authors: Department of Oncology Discovery, Wyeth Research, Pearl River, NY 10965, USA.
authors: John F
authors: JF
authors: DiJoseph
authors: Douglas C
authors: DC
authors: Armellino
authors: Erwin R
authors: ER
authors: Boghaert
authors: Kiran
authors: K
authors: Khandke
authors: Maureen M
authors: MM
authors: Dougher
authors: Latha
authors: L
authors: Sridharan
authors: Arthur
authors: A
authors: Kunz
authors: Philip R
authors: PR
authors: Hamann
authors: Boris
authors: B
authors: Gorovits
authors: Chandrasekhar
authors: C
authors: Udata
authors: Justin K
authors: JK
authors: Moran
authors: Andrew G
authors: AG
authors: Popplewell
authors: Sue
authors: S
authors: Stephens
authors: Philip
authors: P
authors: Frost
authors: Nitin K
authors: NK
authors: Damle
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000096:biosynthesis* / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D015815:Cell Adhesion Molecules; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods; D020128:Inhibitory Concentration 50; D000080045:Inotuzumab Ozogamicin; D037102:Lectins / Q000096:biosynthesis* / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000628:therapy*; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D011485:Protein Binding; D051918:Sialic Acid Binding Ig-like Lectin 2; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D000970:Antineoplastic Agents; C497867:CD22 protein, human; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D018796:Immunoconjugates; D007074:Immunoglobulin G; D037102:Lectins; D051918:Sialic Acid Binding Ig-like Lectin 2; D000080045:Inotuzumab Ozogamicin