Effector-mediated eradication of precursor B acute lymphoblastic leukemia with a novel Fc-engineered monoclonal antibody targeting the BAFF-R.
B-cell activating factor receptor (BAFF-R) is expressed on precursor B acute lymphoblastic leukemia (pre-B ALL) cells, but not on their pre-B normal counterparts. Thus, selective killing of ALL cells is possible by targeting this receptor. Here, we have further examined therapeutic targeting of pre-B ALL based on the presence of the BAFF-R. Mouse pre-B ALL cells lacking BAFF-R function had comparable viability and proliferation to wild-type cells, but were more sensitive to drug treatment in vitro. Viability of human pre-B ALL cells was further reduced when antibodies to the BAFF-R were combined with other drugs, even in the presence of stromal protection. This indicates that inhibition of BAFF-R function reduces fitness of stressed pre-B ALL cells. We tested a novel humanized anti-BAFF-R monoclonal antibody optimalized for FcRγIII-mediated, antibody-dependent cell killing by effector cells. Antibody binding to human ALL cells was inhibitable, in a dose-dependent manner, by recombinant human BAFF. There was no evidence for internalization of the antibodies. The antibodies significantly stimulated natural killer cell-mediated killing of different human patient-derived ALL cells. Moreover, incubation of such ALL cells with these antibodies stimulated phagocytosis by macrophages. When this was tested in an immunodeficient transplant model, mice that were treated with the antibody had a significantly decreased leukemia burden in bone marrow and spleen. In view of the restricted expression of the BAFF-R on normal cells and the multiple anti-pre-B ALL activities stimulated by this antibody, a further examination of its use for treatment of pre-B ALL is warranted.
Authors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, SwitzerlandAuthors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, Switzerland.
Reshmi
R
Parameswaran
Authors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, SwitzerlandAuthors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, Switzerland.
Min
M
Lim
Authors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, SwitzerlandAuthors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, Switzerland.
Fei
F
Fei
Authors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, Switzerland.
Hisham
H
Abdel-Azim
Authors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, SwitzerlandAuthors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, Switzerland.
Anna
A
Arutyunyan
Authors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, SwitzerlandAuthors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, Switzerland.
Isabelle
I
Schiffer
Authors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, Switzerland.
Margaret E
ME
McLaughlin
Authors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, Switzerland.
Hermann
H
Gram
Authors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, Switzerland.
Heather
H
Huet
Authors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, SwitzerlandAuthors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, SwitzerlandAuthors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, Switzerland.
John
J
Groffen
Authors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, SwitzerlandAuthors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, SwitzerlandAuthors' Affiliations: Section of Molecular Carcinogenesis; Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute, Children's Hospital Los Angeles; Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Oncology Translational Medicine and Oncology Research, Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts; and Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, Switzerland heisterk@hsc.usc.edu.
Nora
N
Heisterkamp
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D053265:B-Cell Activation Factor Receptor / Q000037:antagonists & inhibitors / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000276:immunology; D007167:Immunotherapy; D051379:Mice; D058990:Molecular Targeted Therapy; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
D061067:Antibodies, Monoclonal, Humanized; D053265:B-Cell Activation Factor Receptor; D007141:Immunoglobulin Fc Fragments; C435926:TNFRSF13C protein, human