title: Improving the efficacy of Photoimmunotherapy (PIT) using a cocktail of antibody conjugates in a multiple antigen tumor model.
abstract: Tumors are characterized by a high degree of diversity and heterogeneity in receptor expression. Monoclonal antibodies (mAbs) are an established therapeutic method of targeting cell surface receptors. However, high affinity antibodies targeting highly expressed receptors are often prevented from distributing evenly throughout the tumor due to the "binding site barrier" whereby antibody is trapped peripherally before it can reach deeper into the tumor that leads inhomogeneous micro-distribution. When employing armed antibodies it is important that the toxin (in this case, phototoxin) be distributed evenly to more effectively treat the cancer. By adding an additional antibody conjugate, targeting a secondary, unsaturated receptor with lower expression, a more uniform distribution of the phototoxin can be achieved. In this study, panitumumab (Pan) and basiliximab (Bas) were conjugated with the phthalocyanine dye, IRDye700DX (IR700). Upon exposure to near infrared light, these armed antibodies produce rapid cell death only when bound to their respective receptors, a treatment termed photo-immunotherapy (PIT). ATAC4 cells which demonstrate high expression of human epidermal growth factor receptor (EGFR) and low expression of interleukin-2 receptor-alpha (CD25) were treated by PIT using a cocktail of Pan-IR700 and Bas-IR700. An in vivo study showed that the cocktail Pan-Bas-IR700 resulted in significantly reduced tumor growth and prolonged survival in ATAC4 tumor-bearing mice compared with either Pan-IR700 or Bas-IR700 alone. In conclusion, a cocktail injection of two different antibody-IR700 conjugates created a more homogeneous microdistribution of antibody-conjugates resulting in enhanced therapeutic effects after PIT, compared to the use of either antibody-IR700 conjugate.
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda Maryland 20892, United States.
authors.forename: Takahito
authors.initials: T
authors.lastname: Nakajima
authors.forename: Kohei
authors.initials: K
authors.lastname: Sano
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.forename: Hisataka
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077552:Basiliximab; D002232:Carbocyanines / Q000627:therapeutic use; D016923:Cell Death; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D000922:Immunotoxins / Q000627:therapeutic use*; D007259:Infrared Rays / Q000627:therapeutic use; D051379:Mice; D009369:Neoplasms / Q000628:therapy*; D009943:Organophosphorus Compounds / Q000627:therapeutic use; D000077544:Panitumumab; D010789:Phototherapy / Q000379:methods*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002232:Carbocyanines; C525731:IRD 700; D000922:Immunotoxins; D009943:Organophosphorus Compounds; D011993:Recombinant Fusion Proteins; D000077544:Panitumumab; D000077552:Basiliximab
keywords: binding site barrier; cocktail; micro-distribution; monoclonal antibody; photoimmunotherapy