Enhancement of the selectivity and antitumor efficacy of a CC-1065 analogue through immunoconjugate formation.
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.
Chari
R V
RV
ImmunoGen. Inc., Cambridge, Massachusetts 02139-4239, USA.
Jackel
K A
KA
Bourret
L A
LA
Derr
S M
SM
Tadayoni
B M
BM
Mattocks
K M
KM
Shah
S A
SA
Liu
C
C
Blättler
W A
WA
Goldmacher
V S
VS
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
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