Bispecific antibodies target operationally tumor-specific antigens in two leukemia relapse models.
Despite improved procedures in chemotherapy and bone marrow transplantation (BMT), post-BMT leukemia relapse rates have remained rather constant in the last decade. Immunotherapy with monoclonal or bispecific antibodies (bsAb) is a promising approach to improve this situation, but is hampered by the absence of tumor-specific antigens on the majority of tumors. To evade this problem, we developed a new tumor-specific approach in which bispecific antibodies exploit chimerism after allogeneic BMT by redirecting donor T cells against recipient-specific antigens on tumor cells. Two different leukemia relapse models were established using a T-cell lymphoma (ST-1) and a B-cell lymphoma (BCL1) to evaluate the efficiency of such a therapy. In these experiments, irradiated BALB/c (Thy-1.2+, I-Ad) mice were transplanted with C57BL/6 Thy-1.1 (I-Ab) BM cells under the protection of graft-versus-host disease-preventing monoclonal antibodies. Forty-five days after BMT, the chimeric mice were injected with either 2 x 10(4) recipient-type, Thy-1.2+, CD3- ST-1 cells or major histocompatability complex (MHC) class II+ (I-Ad)-BCL1 cells. Four days later, the mice were treated with 8 microg bsAb G2 (anti-CD3 x anti-Thy-1.2) or 10 microg (+10 microg, day 6) bsAb BiC (anti-CD3 x anti-I-Ad), respectively. These combinations guaranteed exclusive binding of the bsAbs target arms to tumor cells, leaving the surrounding, donor-type hematopoietic cells unbound. Compared with the parental antibodies, the bsAbs markedly reduced tumor mortality. Between 34% and 83% of mice survived in the bsAb groups compared with 0% of the control groups treated with parental antibodies, clearly documenting the benefit of the redirection principle. Furthermore, cytokine release (interleukin-6) after anti-CD3 antibody or bsAb treatment was decreased by administering a low-dose antibody preinjection. We have shown (1) that 6 weeks after BMT, when donor T-cell reconstitution is still in progress, T-cell-redirecting bsAb are clearly superior to parental antibodies in terms of tumor cell elimination; and (2) that the polymorphism of a common antigen such as Thy-1 or a clinically more relevant target antigen such as MHC class II can be used as an operational tumor-specific antigen after allogeneic BMT.
Lindhofer
H
H
Forschungszentrum für Umwelt und Gesundheit (GSF)-Institut für Immunologie, Munich, Germany.
Menzel
H
H
Günther
W
W
Hültner
L
L
Thierfelder
S
S
D000818:Animals; D018033:Antibodies, Bispecific / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology; D000918:Antibody Specificity; D000937:Antigen-Antibody Reactions; D000938:Antigen-Presenting Cells / Q000637:transplantation; D000951:Antigens, Neoplasm / Q000276:immunology*; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003967:Diarrhea / Q000209:etiology; D004195:Disease Models, Animal; D005260:Female; D016393:Lymphoma, B-Cell / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013945:Thymoma / Q000628:therapy; D013953:Thymus Neoplasms / Q000628:therapy; D015431:Weight Loss / Q000276:immunology
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm