In vivo cell surface engineering

a cell surface and in vivo technology, applied in the field of in vivo cell surface engineering, can solve the problems of less than satisfactory clinical response, inability to achieve satisfactory clinical response, and inability to achieve satisfactory clinical response, and achieve the effect of reducing the size of the tumor

Inactive Publication Date: 2007-07-26
UNIV OF LOUISVILLE RES FOUND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Approaching cancer treatment with surgery, chemotherapy and radiotherapy is commonly used but these approaches are appreciated to lack tumor specificity, resulting in adverse side effects and less than satisfactory clinical responses.
However, this approach may be undermined if the cancer cells no longer express the particular antigen and / or if the tumor is able to suppress or tolerize the immune response.
Several hurdles are associated with this approach, such as the need for a considerable tumor mass to prepare the vaccine, difficulties associated with the genetic manipulation of primary tumor cells, and the very long amount of time (weeks to months) required for vaccine preparation for gene therapy based approaches.

Method used

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  • In vivo cell surface engineering
  • In vivo cell surface engineering
  • In vivo cell surface engineering

Examples

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example 1

[0143] Results herein demonstrate that (1) tumor and primary cells can effectively be biotinylated under physiological conditions and biotin persists on the cell surface for weeks; (2) biotinylated cells can be engineered with several fusion proteins that then persist on the cell surface in vivo for extended periods of time (days to weeks); (3) subcutaneous injection of live LLC or A20 tumor cells causes solid tumors in syngeneic mice. The data show that tumors can be engineered in vivo for the display of CD80.

A. Cell Surface Modification

[0144] A series of studies was performed using EZ-Link™ Sulfo-NHS-LC-Biotin derivative from Pierce Biotechnology, Inc. (Rockford, Ill.) to establish biotinylation conditions that do not compromise the viability and functions of the cells. Biotinylation in the range of 5-50 μM satisfied these criteria and provided an effective platform for the optimum display of exogenous proteins. Yolcu et al., 2002, Immunity, 17:795-808.

[0145] To assess the kin...

example 2

[0166] This Example describes the engineering of tumor surfaces in vivo for effective and durable display of a combination of two or more immune co-stimulatory polypeptides, such as two or more of LIGHT, CD80, 4-1BBL, CD40L, OX40L, PD-L1 and GL50 polypeptides.

A. Biotinylation

[0167] An effectivce biotin dose for the biotinylation of tumor cells in vivo and the kinetics of biotin persistence on the surface of such tumor cells can be determined. An effective level of biotin conjugation in vivo can be defined as (i) biotinylation of >50% of tumor cells; (ii) biotin persistence on the surface of at least 50% of the tumor cells initially positive for biotin 5 days post-biotinylation, wherein the mean fluorescence intensity of the biotin positive cells is >70; and (iii) no detectable toxicity for either the tumor or the patient.

[0168] Doses of biotin that satisfy these criteria should permit display of >100,000 immune co-stimulatory fusion protein molecules per tumor cell immediately a...

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Abstract

The present invention provides methods and compositions for the in vivo engineering of cell surfaces, such as tumor cell surfaces, with one or more immune co-stimulatory polypeptides. The methods, compositions and engineered cells are useful, for example, to stimulate an immune response against the cells. When the engineered cell surfaces are tumor cell surfaces, the methods, compositions and engineered cells are useful for improving a patient's immune response against the cancer and for reducing tumor size and inhibiting tumor growth.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] The present application claims the benefit of the filing dates of the following U.S. provisional applications: 60 / 748,177 (filed Dec. 8, 2005); 60 / 771,179 (filed Feb. 6, 2006); 60 / 799,643 (filed May 12, 2006); and 60 / 863,173 (filed Oct. 27, 2006). Each of the foregoing applications is incorporated by reference herein in its entirety.FIELD OF THE INVENTION [0002] The present invention generally relates to methods for in vivo engineering of cell surfaces by displaying one or more exogenous immunostimulatory molecules thereon, for the purposes of stimulating an immune response against the cells. Compositions for effecting the engineering also are provided. BACKGROUND OF THE INVENTION [0003] Approaches directed to boosting a host's immune response to address diseases and conditions characterized by a deficiency in immunity or resolvable by a more aggressive immune response have been extensively described. An exemplary such disease or condit...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00C12N5/08C12N15/09
CPCC07K14/70532C12N2760/16134C12N5/0012C07K14/70575C12N2710/20034A61K39/0011A61K45/06A61K47/4833A61K47/48353A61K2039/5152A61K2039/5154A61K2039/5158A61K2039/55516A61K2039/6031B82Y5/00A61K38/00A61K39/12A61K2039/585A61K2039/625A61K2300/00A61K47/646A61K47/665A61P31/00A61P31/04A61P31/12A61P31/14A61P33/00A61P35/00A61P37/04Y02A50/30A61K47/50C07K14/705
Inventor SHIRWAN, HAVALELPEK, KUTLU G.YOLCU, ESMA S.
Owner UNIV OF LOUISVILLE RES FOUND INC
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