Transgenic mice expressing human cd20

Inactive Publication Date: 2006-08-10
GENENTECH INC
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  • Description
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Benefits of technology

[0011] The animals of the present invention are also useful for assessing the toxicity of anti-CD20 therapeutics by administration to the presently described transgenic animals. Treatment specificity, toxicity and efficacy can also be determined by comparison of the agent's effect with that in a wild-type animal or untreated transgenic animal.
[0012] A non-human transgenic animal of the present invention can further provide an indication of the safety of a particular agent for administration to a human. For example, a humanized antibody or other agent can be administered to the transgenic animal and any toxic or adverse effects as a result of the administration of the agent to the animal can be monitored or identified as an indicatio

Problems solved by technology

These anti-CD20 antibodies specifically bind to the CD20 cell surface antigen of both normal and malignant B cells, leading to the destruction and deplet

Method used

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  • Transgenic mice expressing human cd20
  • Transgenic mice expressing human cd20
  • Transgenic mice expressing human cd20

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0130] This example describes generation of human CD20 BAC transgenic (Tg+) mice and a study of the effects of anti-human CD20 antibody treatment in the hCD20+ mice.

[0131] Human CD20 transgenic mice were generated using CITB Human BAC-D-Clone No. 117H19 from Invitrogen. (Invitrogen, Carlsbad, Calif.) DNA encoding human CD20 was isolated from human lymphocytes and was sent to Invitrogen. Invitrogen tested the DNA against the filters with the clones from the human BAC library and identified clone 117H19. Previous attempts to generate transgenic mice expressing human CD20 were not successful, possibly due in part to the failure to include sufficient transcriptional control regions in the transgene construct. Transgenic mice were generated by micro injecting a human CD20 BAC construct prepared with clone 117H19 into a fertilized egg of FVB inbred strain of mice. The fertilized eggs were incubated for 1-7 days and then were implanted into surrogate mice. Mice were screened based on the ...

example 2

[0143] This example demonstrates the synergy between anti-CD20 mAb and BR3 antagonist treatments for B cell modulation / depletion. BR3-Fc is an immunoadhesin having the extracellular domain of human BR3 fused to constant domain of an immunoglobulin sequence in this case, human IgG1.

[0144] Human CD20 transgenic mice expressing (designated as hCD20+ mice) were treated with intraperitoneal injections of anti-CD20 mAb (single injection of 100 micrograms on day 9), BR3-Fc (100 micrograms every other day from days 1 through 12), or the combination of anti-CD20 mAb and BR3-Fc. Each group consisted of 4 mice. Two days following the last injection, the mice were sacrificed and analyzed for hCD20+ B cells. FACS analysis of spleen, blood, lymph node and Peyer's Patches were analyzed for B cell markers (CD21+CD23+).

[0145] The results indicate that anti-CD20 mAb therapy depleted >99% of the mature circulating B cells in the blood and lymph nodes and BR3-Fc treatment decreased mature circulating...

example 3

[0148] In this experiment, it was demonstrated that natural killer cells play a role in anti-CD20 mAb mediated B cell depletion.

[0149] Hybridoma clone, which produces PK-136 mAb (specific against mouse NK1.1), was obtained from ATCC. Four groups of human CD20 transgenic mice were injected ip with control mAb, PK-136, anti-CD20 mAb and the combination of PK-136 / anti-CD20, respectively. Doses of ip were as follows:

[0150] control mAb: 200 ug / ip, 3 ip / week, for 1 week

[0151] PK-136: 200 ug / ip, 3 ip / week, for 1 week

[0152] anti-CD20 mAb: 10 ug / ip, single dose

[0153] Lymphocytes from peripheral blood, lymph nodes and spleen were analyzed 3 days after anti-CD20 mAb ip. Data is expressed as mean+ / −standard error, with n=8.

[0154] The results indicated that treatment with PK-136 resulted in an approximately 80% to 90% reduction in NK cell population among the tissues examined (liver, spleen and blood) (FIG. 19). In the absence of majority of NK cells, 2H7 mediated B cell depletion is less ...

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Abstract

The present invention generally relates to non-human transgenic animals expressing human cellular markers, including CD20 and methods for using the animals to identify agents that are effective to deplete cells bearing human CD20. The transgenic animals are also useful to test safety and efficacy of anti-CD20 therapies.

Description

[0001] This application is being filed as a PCT International Patent Application in the name of Genentech, Inc., a U.S. national corporation and resident, (Applicant for all countries except US); Andrew Chee-Yuen Chan, a U.S. citizen and resident (Applicant for US only); Qian Gong, a Chinese citizen and U.S. resident (Applicant for US only); and Flavius Martin, a Romanian citizen and U.S. resident (Applicant for US only), on 11 Dec. 2003, designating all countries and claiming priority to U.S. provisional application Ser. No. 60 / 434,115, filed Dec. 16, 2002, and U.S. provisional application Ser. No. 60 / 476,481, filed Jun. 5, 2003 which are hereby incorporated by reference.BACKGROUND OF THE INVENTION [0002] T and B cells both comprise cell surface proteins that can be utilized as markers for differentiation and identification. One such human B cell marker is the human B lymphocyte-restricted differentiation antigen Bp35, also known as “CD20”. CD20 is expressed during early pre-B cell...

Claims

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Application Information

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IPC IPC(8): A01K67/027A01KA01K67/033A61K49/00C07K14/705C12N5/06C12N15/00C12N15/09C12N15/85C12P21/00C12Q1/00G01N33/00
CPCA01K67/0275A01K2207/15A01K2217/00A01K2217/05A01K2227/105A01K2267/0331A01K2267/0381A61K39/39558A61K49/0008A61K2039/505A61K2039/507C07K14/70535C07K14/70596C07K16/2803C07K16/2887C12N15/8509A61K2300/00A61P35/00A01K67/027C12N15/09G01N33/00
Inventor CHAN, ANDREW CHEE-YUENGONG, GIANMARTIN, FLAVIUS
Owner GENENTECH INC
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