Antibody-directed effector cell therapy of tumors: analysis and optimization using a physiologically based pharmacokinetic model.
The failure of the cellular immune response to stop solid tumor growth has been the subject of much research. Although the mechanisms for tumor evasion of immune response are poorly understood, one viable explanation is that tumor-killing lymphocytes cannot reach the tumor cells in sufficient quantity to keep the tumor in check. Recently, the use of bifunctional antibodies (BFAs) has been proposed as a way to direct immune cells to the tumor: one arm of the antibody is specific for a known tumor-associated antigen and the other for a lymphocyte marker such as CD3. Injecting this BFA should presumably result in cross-linking of lymphocytes (either endogenous or adoptively transferred) with tumor cells, thereby enhancing therapy. Results from such an approach, however, are often disappointing--frequently there is no benefit gained by using the BFA. We have analyzed the retargeting of endogenous effector cells by BFA using a physiologically based whole-body pharmacokinetic model that accounts for interactions between all relevant species in the various organs and tumor. Our results suggest that the design of the BFA is critical and the binding constants of the antigen and lymphocyte binding epitopes need to be optimized for successful therapy.
Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Stuart W
SW
Friedrich
Stephany C
SC
Lin
Brian R
BR
Stoll
Laurence T
LT
Baxter
Lance L
LL
Munn
Rakesh K
RK
Jain
D000818:Animals; D018033:Antibodies, Bispecific / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000628:therapy*; D009928:Organ Specificity; D013045:Species Specificity
D018033:Antibodies, Bispecific; D000912:Antibodies, Neoplasm; D017252:CD3 Complex; D009363:Neoplasm Proteins