Anti-human 4-1 bb antibodies and use thereof
An antibody and antigen technology, applied in the direction of antibodies, antibody medical components, anti-animal/human immunoglobulins, etc., can solve the problems of pain and medical expenses, such as reduced quality of life of cancer patients and their families
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Embodiment 1
[0231] Example 1 - Preparation of humanized anti-human 4-1BB antibody
[0232] This example describes the generation of exemplary anti-human 4-1BB antibodies with improved affinity compared to the reference 94G1 antibody. 94G1 was produced by humanizing the mouse anti-human 4-1BB antibody (BBK 4) as described in Son et al. J. Immunol. Methods (2004) 286:187-201, which is incorporated herein by reference in its entirety. Also used herein is the H4-1BB antigen (accession number: KCTC 0952BP), which is specifically isolated from activated T cells (eg, an activated T cell line) and has not been identified from unstimulated T cells. For example, the H4-1BB antigen can be isolated from T cells that have been matured by phorbol myristate acetate (PMA), ionotoxin, concanavalin A, or anti-CD3i, the H4 The -1BB antigen is 1.4 kb in size and 60% homologous to mouse 4-1BB (Garni-Wagner et al., Cellular Immunology (1996) 169:91-98, which is hereby incorporated by reference in its entirety...
Embodiment 2
[0268] Example 2 - Characterization of humanized anti-human 4-1BB antibodies
[0269] 2.1 Determination of the binding epitope of the anti-human 4-1BB antibody
[0270] It is recognized herein that the humanized anti-human 4-1BB antibodies provided herein can be used for 4-1BB co-stimulation. Therapeutic applications of the antibodies herein may include promoting anti-cancer immunity and / or anti-viral immunity. However, for clinical applications, it is important to identify which portion of human 4-1BB is recognized by and / or reacts with (ie, binding epitope) an anti-humanized 4-1BB antibody. 4-1BB antibodies that recognize different epitopes of the 4-1BB molecule have been identified, and these antibodies have been shown to have diverse clinical effects (see, e.g., Kwon et al. Eur. J. Immunogenetics (2002) 29:449-452, by reference incorporated into this article in its entirety). Epitope mapping includes methods for identifying molecular determinants of antibody-antigen rec...
Embodiment 3
[0294] Example 3 - In Vitro Potency Analysis of Humanized Anti-Human 4-1BB Antibodies
[0295] Anti-4-1BB antibodies have previously been demonstrated to activate CD8 + The co-stimulatory molecule 4-1BB expressed in T cells provides signaling stimulus to activate CD8 + T cells, induce proliferation and increase T H Type 1 cytokine expression. In this example, the humanized anti-4-1BB antibody described in Example 1 was detected to induce CD8 + T cell proliferation and T H Activity of type 1 cytokine expression.
[0296] 3.1 Exemplary anti-human 4-1BB antibodies induce CD8 + Cell Proliferation of T Cells
[0297] To assess CD8 + Proliferation of T cells, cells were stained with WST-1 (water soluble tetrazolium salt), which is a cell proliferation reagent. Preparation of WST-1-labeled CD8 + T cells were activated with 0.5 μg / ml anti-CD3 antibody. activated CD8 + T cells were treated with 1.0 μg / ml of iso-type control antibody, mouse BBK-4 antibody, reference 94G1 anti...
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