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    Anti-PCSK9 antibodies with pH dependent antigen binding
    7.
    发明授权
    Anti-PCSK9 antibodies with pH dependent antigen binding 有权
    具有pH依赖性抗原结合的抗PCSK9抗体

    公开(公告)号：US09029515B2

    公开(公告)日：2015-05-12

    申请号：US13045345

    申请日：2011-03-10

    申请人： Jaume Pons ,  Jeffrey Raymond Chabot ,  Javier Fernando Chaparro Riggers ,  Bruce Charles Gomes ,  Hong Liang ,  Kapil Mayawala ,  Jerome Thomas Mettetal, II ,  Arvind Rajpal ,  David Louis Shelton

    发明人： Jaume Pons ,  Jeffrey Raymond Chabot ,  Javier Fernando Chaparro Riggers ,  Bruce Charles Gomes ,  Hong Liang ,  Kapil Mayawala ,  Jerome Thomas Mettetal, II ,  Arvind Rajpal ,  David Louis Shelton

    IPC分类号： C07K16/00 ,  C07K16/40 ,  C07K16/42

    CPC分类号： C07K16/4291 ,  C07K16/28 ,  C07K16/40 ,  C07K2317/56 ,  C07K2317/565 ,  C07K2317/70 ,  C07K2317/732 ,  C07K2317/734 ,  C07K2317/76 ,  C07K2317/92 ,  C07K2317/94 ,  C07K2319/21

    摘要： The present invention relates to antibodies with pH dependent binding to its antigen such that the affinity for antigen binding at physiological pH (i.e., pH 7.4) is greater than at endosomal pH (i.e., pH 6.0 or 5.5). In other words, the KD or koff ratio at pH 5.5/pH 7.4 or at pH 6.0/pH 7.4 is more than, or ranges between, 2, 3, 4, 8, 10, 16, 20, 30, 40, or 100 or more. Such pH dependent antibodies preferentially dissociate from the antigen in the endosome. This can increase antibody half life, as compared to antibodies with equivalent KDs at pH 7.4 but with no pH dependent binding, when the antigen is one that undergoes antigen-mediated clearance (e.g., PCSK9). Antibodies with pH dependent binding can decrease total antigen half life when the antigen undergoes reduced clearance when bound to antibody (e.g., IL6). Antibodies with pH dependent binding can also prolong the decrease in antigen which is not antibody-bound. This can be important when antagonizing a target antigen typically present at high levels (e.g., IgE, DKK1, C5 and SOST). In addition, such antibodies can increase antigen half life when the antigen is a receptor and the receptor has increased clearance when bound to antibody (e.g., GMCSF receptor).

    摘要翻译： 本发明涉及与其抗原具有pH依赖性结合的抗体，使得在生理pH（即pH 7.4）下抗原结合的亲和力大于内体pH（即pH6.0或5.5）时的亲和力。 换句话说，pH5.5 / pH7.4或pH6.0 / pH7.4下的KD或koff比大于或等于2,3,4,8,10,16,20,30,40或100 或者更多。 这种pH依赖性抗体优先从内体中的抗原解离。 与抗原为经过抗原介导的清除（例如，PCSK9）的抗原相比，与具有pH 7.4但具有pH依赖性结合的等效KD的抗体相比，可以增加抗体半衰期。 当与抗体（例如IL6）结合时，当抗原经历减少的清除时，具有pH依赖性结合的抗体可降低总抗原半衰期。 具有pH依赖性结合的抗体也可以延长不抗体结合的抗原的降低。 当拮抗通常以高水平存在的靶抗原（例如IgE，DKK1，C5和SOST）时，这可能是重要的。 此外，当抗原是受体时，这种抗体可增加抗原半衰期，并且当与抗体（例如，GMCSF受体）结合时，该受体具有增加的清除能力。