title: Enhancement of the selectivity and antitumor efficacy of a CC-1065 analogue through immunoconjugate formation.
abstract: Bis-indolyl-(seco)-1,2,9a-tetrahydrocyclopropa[c]benz[e]indol-4-on e compounds are synthetic analogues of CC-1065 that are highly cytotoxic toward a broad spectrum of tumor cell lines. One of these compounds, called DC1, was conjugated to antibodies via novel cleavable disulfide linkers. Conjugates of DC1 with murine mAbs anti-B4 and N901 directed against tumor-associated antigens CD19 and CD56, respectively, proved to be extremely potent and antigen selective in killing target cells in culture. DC1 conjugates with humanized versions of anti-B4 and N901 antibodies were also constructed and demonstrated to be as cytotoxic and selective as the respective murine antibody conjugates. The anti-B4-DC1 conjugate showed antitumor efficacy in an aggressive metastatic human B-cell lymphoma survival model in SCID mice and completely cured animals hearing large tumors. Anti-B4-DC1 was considerably more effective in this tumor model than doxorubicin, cyclophosphamide, etoposide, or vincristine at their maximum tolerated doses.
authors.affiliation: ImmunoGen. Inc., Cambridge, Massachusetts 02139-4239, USA.
authors.forename: R V
authors.initials: RV
authors.lastname: Chari
authors.forename: K A
authors.initials: KA
authors.lastname: Jackel
authors.forename: L A
authors.initials: LA
authors.lastname: Bourret
authors.forename: S M
authors.initials: SM
authors.lastname: Derr
authors.forename: B M
authors.initials: BM
authors.lastname: Tadayoni
authors.forename: K M
authors.initials: KM
authors.lastname: Mattocks
authors.forename: S A
authors.initials: SA
authors.lastname: Shah
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.forename: W A
authors.initials: WA
authors.lastname: Blättler
authors.forename: V S
authors.initials: VS
authors.lastname: Goldmacher
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D019002:CD56 Antigen; D000080890:Duocarmycins; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D007211:Indoles; D007933:Leucomycins / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000628:therapy; D051379:Mice; D016513:Mice, SCID; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; D000945:Antigens, Differentiation, T-Lymphocyte; D019002:CD56 Antigen; D000080890:Duocarmycins; D000922:Immunotoxins; D007211:Indoles; D007933:Leucomycins; C018782:CC 1065