INTERNALIZING HUMAN MONOCLONAL ANTIBODIES FOR PROSTATE CANCER
ABSTRACT:
UCSF researchers have developed a panel of human monoclonal antibodies (mAb) that bind specifically to and penetrate prostate cancer cells by receptor-mediated endocytosis. These antibodies specifically recognize hormone refractory cell lines, deliver therapeutic payloads specifically to tumor cells, and stain tumor cells immunohistochemically. Several of these antibodies also show direct in vivo anti-tumor activity..
DESCRIPTION:
The identification of tumor-specific cell surface antigens is a critical step towards the development of targeted therapeutics for cancer. For prostate carcinoma and hormone-refractory prostate carcinoma in particular, there are few known specific cell surface markers. UCSF investigators generated a panel of 93 prostate cancer-specific mAbs that trigger receptor endocytosis, and 70 of these bind to hormone-refractory prostate cancer cells. The majority of these newly identified antibodies display binding patterns that are different from the few known tumor antibodies. Because these internalizing antibodies enter into cells via endocytosis, they can be used for efficient delivery of anti-tumor drugs to the cytosol. In addition, a number of these mAbs inhibit tumor cell growth in vivo and thus also have potential therapeutic utility as naked mAbs.
Table 1: Partial characterization of antibodies:
Antibody |
Target |
Immuno-histochemistry |
Internalization/Drug delivery |
Direct anti-cancer activity |
H3 or 585II41 |
CD166 (aka MEMD, ALCAM) |
Stained tumor in frozen tissue slides. Some minor normal tissue staining. |
Internalizes. H3-targeted immunoliposomes delivered a panel of small molecular drugs to prostate cancer cells in vitro. |
Immunoliposomal topotecan is effective in killing prostate cancer cells in vitro.
Naked H3 IgG does not cause tumor inhibition in vitro. |
M10A12 |
ICAM-1 |
Stained prostate cancer metastasized into the kidney |
Internalizes |
M10A12 binds to a neutralizing epitope of ICAM-1 based on a competition study with a known neutralizing murine mAb (BBIG-I1). Preliminary in vivo study showed that M10A12 inhibited growth of hormone-refractory prostate cancer cells grafted under the renal capsules of nude mice, although the results are inconclusive for tumor cells grafted subcutaneously. |
A33 |
Under study |
Stained prostate cancer metastasized into the kidney |
Internalizes |
N.A. |
UA20 |
Under study |
Selected by LCM on prostate cancer tissues. Very low cross-reactivity with normal tissue. Stained tumor intensely in paraffin-embedded and frozen tissue slides. In vivo imaging studies have shown specific tumor uptake in xenograft models. |
Internalizes. UA20-targeted fluorescently-labeled immunoliposomes were delivered specifically to prostate cancer cells. |
N.A. |
MIIG12 |
|
Stained prostate cancer metastasized into the kidney; low binding to most of normal tissues studied. |
Internalizes |
N.A. |
C10 |
|
Stained prostate cancer metastasized into the kidney; low binding to normal tissues except for the kidney. |
Internalizes and C10-targeted fluorescently-labeled immunoliposomes were delivered specifically to prostate cancer cells. |
N.A. |
UA8 |
|
Selected by LCM on prostate cancer tissues. Bind to primary and metastatic prostate tumors, PIN and to a lesser degree normal prostate glands. |
|
|
Applications
These mAbs have the potential to be used
- for the development of prostate cancer therapeutics that combine a direct anti-proliferative effect with intracellular drug delivery;
- for cancer diagnostics;
- for identifying novel tumor antigens.
Advantages
These new mAbs provide the basis for the development of new and potentially more effective anti-cancer therapies.
Publications.
- “Anti-CD166 single chain antibody-mediated intracellular delivery of liposomal drugs to prostate cancer cells.” Roth A, Drummond DC, Conrad F, Hayes ME, Kirpotin DB, Benz CC, Marks JD, Liu B. Mol Cancer Ther. 2007 Oct;6(10):2737-46.
- “Recombinant full-length human IgG1s targeting hormone-refractory prostate cancer.” Liu B, Conrad F, Roth A, Drummond DC, Simko JP, Marks JD. J Mol Med. 2007 Oct;85(10):1113-23. Epub 2007 Jun 7.
- “Mapping tumor epitope space by direct selection of single-chain Fv antibody libraries on prostate cancer cells.” Liu B, Conrad F, Cooperberg MR, Kirpotin DB, Marks JD. Cancer Res. 2004 Jan 15;64(2):704-10.
- “Identification of clinically significant tumor antigens by selecting phage antibody library on tumor cells in situ using laser capture microdissection.” Ruan W, Sassoon A, An F, Simko JP, Liu B. Mol Cell Proteomics. 2006 Dec;5(12):2364-73. Epub 2006 Sep 18.
Patents
- US patent application 11/021,438, Publication number: 20050186214, “Prostate cancer specific internalizing human antibodies.”
- Other pending patent applications available under confidentiality agreement.
If you would like to receive further information about
this technology and potential licensing opportunities, please contact:
Sunita Rajdev, Ph.D.
Senior Licensing Officer
(415) 353-4470 phone
(415) 348-1579 fax
Sunita.rajdev@ucsf.edu
Reference: OTM Cases #2004-A39 and SF2008-024
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