Due to their recent demonstration of efficacy in a number of malignancies, monoclonal antibodies (MAb) are becoming increasingly important in cancer therapy. Most efforts to develop new antibody-based molecules are focused on identifying those with the highest possible affinity for the tumor antigen. Using small, single- chain Fv (scFv) molecules that ranged in affinity for the same epitope of HER2 from 1x10-7 M to 1x10-11 M. We showed that high affinity may impair the ability of an antibody to penetrate into a solid tumor, leading to perivascular localization and potential suboptimal therapeutic efficacy. This work validated a "Binding Site Barrier" hypothesis posed by Weinstein that stated that antibodies of very high affinity would be limited in their ability to penetrate solid tumors. A limitation of our earlier work was that scFv are rapidly eliminated from the circulation, thus limiting the ability to study tumor penetration over time. We have recently generated full-length IgG versions of the scFv molecules described above and are in the position to elucidate the role of affinity in tumor targeting and penetration and determine the mechanisms underlying this process. Preliminary data indicate that high affinity also detracts from tumor targeting and penetration of Ig. The hypotheses underlying this proposal are that 1) IgG molecules with very high affinity for tumor antigen will demonstrate a reduced ability to penetrate into solid tumors, 2) a major mechanism behind the restricted penetration of high affinity antibodies into solid tumors is the internalization and degradation by tumor cells and 3) lower affinity IgG molecules may be superior to higher affinity antibodies in mediating anti-tumor effects. We will evaluate the roles of binding affinity, antigen shedding, antigen/MAb internalization and normal tissue antigen expression on the tumor targeting and tumor penetration of anti-HER2 MAbs. We will also determine if changes in affinity, and the attendant impacts on tumor targeting and penetration, influence the anti-tumor efficacy of unconjugated anti-tumor MAbs, thereby providing information that can help guide future rational development of anti-tumor MAbs. This research is directly relevant to public health, as it will guide the development of new antibodies for the treatment of cancer. Learning how the binding strength (affinity) of an antibody for its target on the tumor cell surface affects the ability of the antibody to move into the tumor and kill tumor cells will allow us to create more effective antibody-based treatments for cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118159-05
Application #
8013826
Study Section
Special Emphasis Panel (ZRG1-CII-M (01))
Program Officer
Muszynski, Karen
Project Start
2007-02-05
Project End
2013-12-31
Budget Start
2011-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$305,975
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
073724262
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Balachandran, Siddharth; Adams, Gregory P (2013) Interferon-γ-induced necrosis: an antitumor biotherapeutic perspective. J Interferon Cytokine Res 33:171-80
Zhou, Yu; Goenaga, Anne-Laure; Harms, Brian D et al. (2012) Impact of intrinsic affinity on functional binding and biological activity of EGFR antibodies. Mol Cancer Ther 11:1467-76
Cao, Yu; Marks, James D; Huang, Qian et al. (2012) Single-chain antibody-based immunotoxins targeting Her2/neu: design optimization and impact of affinity on antitumor efficacy and off-target toxicity. Mol Cancer Ther 11:143-53
Loo, LiNa; Capobianco, Joseph A; Wu, Wei et al. (2011) Highly sensitive detection of HER2 extracellular domain in the serum of breast cancer patients by piezoelectric microcantilevers. Anal Chem 83:3392-7
Loo, Lina; Wu, Wei; Shih, Wan Y et al. (2011) A Rapid Method to Regenerate Piezoelectric Microcantilever Sensors (PEMS). Sensors (Basel) 11:5520-5528
Rudnick, Stephen I; Lou, Jianlong; Shaller, Calvin C et al. (2011) Influence of affinity and antigen internalization on the uptake and penetration of Anti-HER2 antibodies in solid tumors. Cancer Res 71:2250-9
Rudnick, Stephen I; Adams, Gregory P (2009) Affinity and avidity in antibody-based tumor targeting. Cancer Biother Radiopharm 24:155-61
Loo, LiNa; Robinson, Matthew K; Adams, Gregory P (2008) Antibody engineering principles and applications. Cancer J 14:149-53