Monoclonal antibody therapy of B cell lymphoma: signaling activity on tumor cells appears more important than recruitment of effectors.
Despite the recent success of mAb in the treatment of certain malignancies, there is still considerable uncertainty about the mechanism of action of anti-cancer Abs. Here, a panel of rat anti-mouse B cell mAb, including Ab directed at surface IgM Id, CD19, CD22, CD40, CD74, and MHC class II, has been investigated in the treatment of two syngeneic mouse B cell lymphomas, BCL1 and A31. Only three mAb were therapeutically active in vivo, anti-Id, anti-CD19, and anti-CD40. mAb to the other Ags showed little or no therapeutic activity in either model despite giving good levels of surface binding and activity in Ag-dependent cellular cytotoxicity and complement assays, and in some cases inhibiting cell growth in vitro. We conclude that the activity of mAb in vitro does not predict therapeutic performance in vivo. Furthermore, in vivo tracking experiments using fluorescently tagged cells showed that anti-Id and anti-CD40 mAb probably operate via different mechanisms: the anti-Id mAb cause growth arrest that is almost immediate and does not eliminate cells over a period of 5 or 6 days, and the anti-CD40 mAb have a delayed effect that allows tumor to grow normally for 3 days, but then abruptly eradicates lymphoma cells. This work supports the belief that mAb specificity is critical to therapeutic success in lymphoma and that, in addition to any effector-recruiting activity they may possess, in vivo mAb operate via mechanisms that involve cross-linking and signaling of key cellular receptors.
Tutt
A L
AL
Lymphoma Research Unit, Tenovus Laboratory, General Hospital, Southampton, United Kingdom.
French
R R
RR
Illidge
T M
TM
Honeychurch
J
J
McBride
H M
HM
Penfold
C A
CA
Fearon
D T
DT
Parkhouse
R M
RM
Klaus
G G
GG
Glennie
M J
MJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity; D001666:Binding Sites, Antibody; D002455:Cell Division / Q000276:immunology; D003165:Complement System Proteins / Q000502:physiology; D003601:Cytotoxicity Tests, Immunologic; D004195:Disease Models, Animal; D005452:Fluoresceins / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D007116:Immunization, Passive; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D015398:Signal Transduction / Q000276:immunology*; D013388:Succinimides / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D000911:Antibodies, Monoclonal; D005452:Fluoresceins; D005456:Fluorescent Dyes; D013388:Succinimides; D003165:Complement System Proteins