Fully human, HLA-DR-specific monoclonal antibodies efficiently induce programmed death of malignant lymphoid cells.
The Human Combinatorial Antibody Library (HuCAL) was screened for antibodies specific to human leukocyte antigen-DR (HLA-DR) that induce programmed death of lymphoma/leukemia cells expressing the target antigen. The active Fab fragments were affinity-matured, and engineered to IgG(4) antibodies of sub-nanomolar affinity. The antibodies exhibited potent in vitro tumoricidal activity on several lymphoma and leukemia cell lines and on chronic lymphocytic leukemia patient samples. They were also active in vivo in xenograft models of non-Hodgkin lymphoma. Cell death occurred rapidly, without the need for exogenous immunological effector mechanisms, and was selective to activated/tumor-transformed cells. Although the expression of HLA-DR on normal hematopoietic cells is a potential safety concern, the antibodies caused no long-lasting hematological toxicity in primates, in vivo. Such monoclonal antibodies offer the potential for a novel therapeutic approach to lymphoid malignancies.
Nagy
Zoltan A
ZA
GPC Biotech AG, Martinsried/Munich, Germany. zoltan.nagy@gpc-biotech.com
Hubner
Bernd
B
Löhning
Corinna
C
Rauchenberger
Robert
R
Reiffert
Silke
S
Thomassen-Wolf
Elisabeth
E
Zahn
Stefan
S
Leyer
Sigmar
S
Schier
Eva M
EM
Zahradnik
Angelika
A
Brunner
Christoph
C
Lobenwein
Kurt
K
Rattel
Benno
B
Stanglmaier
Michael
M
Hallek
Michael
M
Wing
Mark
M
Anderson
Steve
S
Dunn
Matt
M
Kretzschmar
Titus
T
Tesar
Michael
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D000915:Antibody Affinity; D000970:Antineoplastic Agents / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis; D006684:HLA-DR Antigens / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007167:Immunotherapy; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008223:Lymphoma / Q000473:pathology* / Q000503:physiopathology; D008252:Macaca fascicularis; D051379:Mice; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D006684:HLA-DR Antigens; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins