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Anti-OX40 antibodies and methods of using the same

An antibody and sequence technology, applied in the field of regulation of OX40 receptor activation, can solve the problems of little known molecular signals and elusive signals

Inactive Publication Date: 2013-07-24
BOARD OF RGT THE UNIV OF TEXAS SYST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Although the molecular signals leading to Tr1 cells have been studied, little is known about the molecular signals that inversely regulate the generation of these cells
Although immunosuppressive drugs, cytokines, co-stimulatory molecules, and DCs have been implicated in the induction of Tr1 cells, the signals that counter-regulate Tr1 cells remain elusive

Method used

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  • Anti-OX40 antibodies and methods of using the same
  • Anti-OX40 antibodies and methods of using the same
  • Anti-OX40 antibodies and methods of using the same

Examples

Experimental program
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Effect test

Embodiment I

[0206] Chimeric and humanized 106-222 IgG1 / κ mAbs (Ch222 and Hu222, respectively) were purified from the culture supernatants of the corresponding NSO stable transfectants using protein A columns as described in Appendices A and B . Hu222 was eluted from the column in two different ways. Briefly, Hu222 lot I was eluted with low pH buffer and lot II with Pierce's Gentle Ag / Ab elution buffer. Yield of Hu222 is better when eluted with lower pH buffer. Ch222 was eluted from the column with Gentle Ag / Ab Elution Buffer.

[0207] Purified Hu222 batches I and II antibodies were characterized by SDS-PAGE along with mouse 106-222 according to standard procedures. 5 μg of each antibody was analyzed under reducing conditions. Such as Figure 21 As shown, the Hu222 Lot I and II antibodies each consist of a heavy chain with a molecular weight of about 50 kD and a light chain with a molecular weight of about 25 kD. The purity of the Hu222 Lot I and II antibodies was shown to be over 95%....

Embodiment II

[0235] Purification of Ch119-122 and Hu119-122 Antibodies

[0236] The chimeric 119-122 IgG1 / κ monoclonal antibody (Ch119) was purified from the culture supernatant of the corresponding NSO stable transfectants (clone G11) grown on Hybridoma-SFM medium (Invitrogen) using a protein A column. After elution with Pierce's Gentle Ag / Ab Elution Buffer, Ch119 was buffer exchanged into PBS by gel filtration followed by dialysis. The concentration of Ch119 was 0.21 mg / ml.

[0237] Humanized 119-122 IgG1 / κ monoclonal antibody (Hu119) was purified from the culture supernatant of the corresponding NSO stable transfectants (clone 2F5) grown on Hybridoma-SFM medium (Invitrogen) using a protein A column. Hu106-222 was eluted from the column with a low pH buffer, neutralized with 1M Tris-HCl (pH 8.0) and dialyzed against PBS. The concentration of Hu122 was 1.6 mg / ml.

[0238] Purified Hu106-222 was characterized by SDS-PAGE along with mouse 119-122 according to standard procedures. 5 μg o...

Embodiment III

[0243] To assess the ability of our humanized anti-human OX40 antibody to enhance T cell proliferation, we used anti-CD3-coated CD32-L cells and freshly sorted naive CD4 + T cells were subjected to proliferation assays. Figure 27 Humanized anti-human OX40 mAb clone 119-122 (Hu122) and its FcR-binding mutant antibody (Hu122-AA) were shown to enhance naive CD4 +T cell proliferation. Compared with the parental mouse anti-human OX40 mAb (Mouse122), Hu122 produced better T cell stimulatory activity ( Figure 27 ).

[0244] FcR-binding mutant humanized anti-human OX40 mAb clone 106-222 (Hu222-AA) and chimeric anti-human OX40 mAb clone 106-222 (Ch222) enhance anti-CD3-stimulated naive CD4 + T cell proliferation. These antibodies have similar stimulatory activity compared to the parental mouse anti-human OX40 mAb (Mouse106-222). However, the fully humanized anti-human OX40Ab, Hu106, did not enhance T cell proliferation ( Figure 28 ).

[0245] To evaluate the blocking of CD4 b...

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Abstract

Human antibodies, preferably recombinant human antibodies, both humanized and chimeric, which specifically bind to human OX40 are disclosed. Preferred antibodies have high affinity for OX40 receptor and activate the receptor in vitro and in vivo. The antibody can be a full-length antibody or an antigen-binding portion thereof. The antibodies, or antibody portions, are useful for modulating receptor activity, e.g., in a human subject suffering from a disorder in which OX40 activity is detrimental. Nucleic acids, vectors and host cells for expressing the recombinant human antibodies are provided, and methods of synthesizing the recombinant human antibodies, are also provided.

Description

technical field [0001] The present invention relates generally to the modulation of OX40 receptor activation, and more specifically, to modulation of the OX40 receptor to inhibit the production of interleukin 10 (IL-10) by CD4 + Type 1 regulatory T cells ("Tr1 cells") and express Foxp3 + Regulatory T cells (sometimes referred to herein as "Foxp3 + The immunosuppressive function of T-reg” cells) and from CD4 + Cells or naive cells produce Trl cells and IL-10 production. [0002] Cross References to Related Applications [0003] This application claims priority to US Patent Application Serial No. 61 / 375,999, filed August 23, 2010, and US Patent Application Serial No. 61 / 380,827, filed September 8, 2010. Both applications are incorporated herein by reference. [0004] Statement Regarding Federally Sponsored Research or Development [0005] This application was made with government support under grants R01 AI061645-01, R01 AI062888-01, and U19 AI071130-01 awarded by the N...

Claims

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Application Information

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IPC IPC(8): C07K16/28C12N15/13A61K39/395A61P35/00
CPCC07K2317/75A61K2039/505C07K16/2878C07K2317/74C07K2317/24A61P35/00A61K39/395C07K16/28A61P37/00A61P37/02C07K2317/56C07K2317/565C07K7/06
Inventor 刘勇军邬揭新劳拉·博韦尔鹤下直也J·云·曹尚卡尔·库马尔
Owner BOARD OF RGT THE UNIV OF TEXAS SYST
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