Pons, Jaume,Chabot, Jeffrey Raymond,Chaparro Riggers, Javier Fernando,Gomes, Bruce Charles,Liang, Hong,Mayawala, Kapil,Merretal II, Jerome Thomas,Rajpal, Arvind,Shelton, David Louis
申请号：
AU2013204981
公开号：
AU2013204981A1
申请日:
2013.04.12
申请国别(地区):
AU
年份:
2013
代理人:
摘要：
#$%^&*AU2013204981A120130516.pdf#####H:irklntenvoven\NRPortb\DCC\RBR\5074674_ 1.DOC-12/04/2013 Abstract 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/ 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 10 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 15 a receptor and the receptor has increased clearance when bound to antibody (e.g, GMCSF receptor).WO 2011/111007 PCT/IB2011/050989 8/16 FIGURE 7A 120 -9- Control IgG 10 mpk 0 -V- 5A1 0-hu frame 1 Ompk E -i- 5A10.B8 1mpk -A- 5A10.B8 3mpk +- 5A10.B8 1Ompk a) =0 80 0 -I- 10i 0 20 40 60 80 Days post injection FIGURE 7B 120 -e- Control IgG 10 mpk -w- 5A1 0-hu frame 1 Ompk E0 -.- 5L1721 H23_6H3 1mpk O -A- 5L1 721 H23_6H3 3mpk + -5L1721H23 6H3 10mpk 0 0 0 20 40 60 80 Days post injection
