Molecular engineering of anti-CEA (carcinoembryonic antigen) antibodies will be undertaken in a effort to increase their utility in radioimmunotherapy and radioimmunoimaging of adenocarcinomas. Three critical areas in which protein engineering can improve the overall quality and performance of radiolabeled antibodies will be investigated. First, despite the reduction in immunogenicity achieved by production of chimeric T84.66 during the previous project period, in clinical therapy trials a substantial fraction of patients have demonstrated human anti- chimeric antibodies (HACA). Thus, further humanization of the antibody variable regions is of high priority. T84.66 will be humanized using a resurfacing approach: the interior of the Fy will be retained and selected surface residues will be mutagenized to matched conserved surface residues in human antibodies. Thus approach has a high likelihood of retaining the high affinity and specificity of the parental antibody, while reduced immunogenicity will allow administration of multiple doses in clinical trials. Secondly, development of site-specific conjugation of antibodies will allow precise control over the location and extent of radiolabeling, resulting in reproducible production of radioimmunoconjugates with high immunoreactivity and low immunogenicity. Unique cysteine residues (providing reactive thiol groups) or N-linked glycosylation sites (to provide reactive aldehyde groups following periodate oxidation) will be introduced into the CH3 domain of a VL-V H - CH3 """"""""minibody"""""""" previously shown to demonstrate excellent xenograft targeting. these minibodies will be conjugated using novel bifunctional chelating agents developed in project 3. Thirdly, fusion to bioactive peptides or antigen-binding domains will be investigated as a means to increase tumor accretion of radiolabeled antibodies. These will include: an anti-CEA-gamma-IFN fusion to locally increase CEA antigen expression in the tumor; an anti-CEA-IL-2 fusion to locally increase vascular permeability at the tumor site; and a bispecific anti-CEA-anti-TAG72 antibody fragment to increase overall uptake in tumors with heterogeneous expression of both antigens. Preadministration of the antibody-cytokine fusions should enhance tumor uptake of subsequently administered radiolabeled antibodies. Tumor targeting by the bispecific fragment will be compared with the corresponding monospecific agent. This combined multidisciplinary approach should yield radioimmunoconjugates with greatly improved efficacy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
City of Hope National Medical Center
United States
Zip Code
Sta Maria, Naomi S; Barnes, Samuel R; Weist, Michael R et al. (2015) Low Dose Focused Ultrasound Induces Enhanced Tumor Accumulation of Natural Killer Cells. PLoS One 10:e0142767
Kwok, Cheuk S; Frankel, Paul H; Lopatin, George et al. (2014) Using a single parameter to describe time-activity curves. Cancer Biother Radiopharm 29:83-6
Yazaki, Paul J; Lee, Brian; Channappa, Divya et al. (2013) A series of anti-CEA/anti-DOTA bispecific antibody formats evaluated for pre-targeting: comparison of tumor uptake and blood clearance. Protein Eng Des Sel 26:187-93
Ng, Thomas S C; Wert, David; Sohi, Hargun et al. (2013) Serial diffusion MRI to monitor and model treatment response of the targeted nanotherapy CRLX101. Clin Cancer Res 19:2518-27
Specks, Ulrich; Ikle, David; Stone, John H (2013) Induction regimens for ANCA-Associated Vasculitis. N Engl J Med 369:1865-6
Fonge, Humphrey; Leyton, Jeffrey V (2013) Positron emission tomographic imaging of iodine 124 anti-prostate stem cell antigen-engineered antibody fragments in LAPC-9 tumor-bearing severe combined immunodeficiency mice. Mol Imaging 12:191-202
Povoski, Stephen P; Davis, Paul D; Colcher, David et al. (2013) Single molecular weight discrete PEG compounds: emerging roles in molecular diagnostics, imaging and therapeutics. Expert Rev Mol Diagn 13:315-9
Somlo, George; Spielberger, Ricardo; Frankel, Paul et al. (2011) Total marrow irradiation: a new ablative regimen as part of tandem autologous stem cell transplantation for patients with multiple myeloma. Clin Cancer Res 17:174-82
Barat, Bhaswati; Kenanova, Vania E; Olafsen, Tove et al. (2011) Evaluation of two internalizing carcinoembryonic antigen reporter genes for molecular imaging. Mol Imaging Biol 13:526-535
Gagnon, Pete; Cheung, Chia-Wei; Lepin, Eric J et al. (2010) Minibodies and Multimodal Chromatography Methods: A Convergence of Challenge and Opportunity. Bioprocess Int 8:26-35

Showing the most recent 10 out of 112 publications