Preclinical studies combining bispecific antibodies with cytokine-stimulated effector cells for immunotherapy of renal cell carcinoma.
BACKGROUND
Bispecific antibodies--consisting of a F(ab')-fragment derived from a monoclonal antibody against a tumor epitope as well as of another antibody against a cytotoxic trigger molecule on immune effector cells--can improve the effectiveness of antibody-based tumor therapy.


METHODS
We used bispecific antibodies with one specifity against the EGF-receptor, which is overexpressed on the majority of renal cell carcinomas, and another specifity against Fc receptors on human leukocytes (Fc gamma RI/CD64; Fc gamma RIII/CD16 and Fc alpha RI/CD89). As source of effector cells, whole blood from patients treated with G-CSF, GM-CSF or IL2/IFN-alpha was used in 51Cr- release assays using various renal cancer cell lines as tumor targets. Further experiments with Percoll-isolated granulocytes or mononuclear cells from the same donors were performed in order to identify the active effector cell populations.


RESULTS
Compared with conventional monoclonal EGF-R directed antibodies (murine IgG2a, humanized IgG1), bispecific antibodies induced significantly enhanced cytotoxicity. Highest amounts of tumor cell killing were observed using whole blood from patients treated with G-CSF or GM-CSF in combination with an [Fc alpha RI x EGF-R] bispecific antibody. Under these conditions, granulocytes constituted the most active effector cell population.


CONCLUSIONS
The combination of myeloid growth factors and bispecific antibodies offer a promising new approach for the treatment of advanced renal cell carcinoma.
Elsässer
D
D
Department of Urology, Erlangen University of Erlangen-Nuremberg, Germany. david.elsaesser@rzmail.uni-erlangen.de
Stadick
H
H
Stark
S
S
Van de Winkel
J G
JG
Gramatzki
M
M
Schrott
K M
KM
Valerius
T
T
Schafhauser
W
W
D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D066246:ErbB Receptors / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D007376:Interleukin-2 / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D011961:Receptors, Fc / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D015703:Antigens, CD; D000970:Antineoplastic Agents; C036832:Fc(alpha) receptor; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D011961:Receptors, Fc; D017452:Receptors, IgG; D011994:Recombinant Proteins; D066246:ErbB Receptors