The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions.
The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions.
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DOI：
10.1007/s00262-018-2160-x
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Li K
中科院分区：
文献类型：
--
作者：
Zhang T;Song X;Xu L;Ma J;Zhang Y;Gong W;Zhang Y;Zhou X;Wang Z;Wang Y;Shi Y;Bai H;Liu N;Yang X;Cui X;Cao Y;Liu Q;Song J;Li Y;Tang Z;Guo M;Wang L;Li K
针对PD-1的抗体已被证明在某些癌症类型中具有持久的抗癌活性。然而，抗PD-1抗体在许多情况下不太有效或无效，这可能归因于多种抑制性受体的共表达或肿瘤微环境中免疫抑制细胞的存在。临床研究中使用的大多数抗PD-1抗体是具有S228 P突变的IgG 4同种型（IgG 4S 228 P）。抗PD-1 IgG 4S 228 P抗体与Fc γ受体（Fcγ R）相互作用的功能影响尚不清楚。为了评估效果，我们产生了一对抗PD-1抗体：BGB-A317/IgG 4S 228 P和BGB-A317/IgG 4变体（缩写为BGB-A317），具有相同的可变区，但具有两个不同的IgG 4 Fc铰链序列。这两种抗体在与PD-1的结合方面没有显著差异。然而，BGB-A317/IgG 4S 228 P以高亲和力与人FcγRI结合，并介导PD-1与FcγRI之间的交联。而BGB-A317两者都没有。进一步的基于细胞的测定显示，这种交联可以将抗PD-1抗体的功能从阻断逆转为活化。更重要的是，交联诱导FcγRI+巨噬细胞吞噬PD-1+ T细胞。在移植同种异体人癌细胞和PBMC的小鼠模型中，BGB-A317显示出显著的肿瘤生长抑制作用，而BGB-A317/IgG 4S 228 P无此类抑制作用。免疫组织化学研究显示，在BGB-A317/IgG 4S 228 P处理组中，FcγRI+鼠巨噬细胞浸润与肿瘤内CD 8 +PD-1+人T细胞密度呈负相关。这些证据表明FcγRI+结合和交联对抗PD-1抗体介导的抗癌活性具有负面影响。本文的在线版本（10.1007/s 00262 -018-2160-x）包含补充材料，可供授权用户使用。
Antibodies targeting PD-1 have been demonstrated durable anti-cancer activity in certain cancer types. However, the anti-PD-1 antibodies are less or not efficacious in many situations, which might be attributed to co-expression of multiple inhibitory receptors or presence of immunosuppressive cells in the tumor microenvironment. Most of the anti-PD-1 antibodies used in clinical studies are of IgG4 isotype with the S228P mutation (IgG4S228P). The functional impact by the interaction of anti-PD-1 IgG4S228P antibody with Fc gamma receptors (FcγRs) is poorly understood. To assess the effects, we generated a pair of anti-PD-1 antibodies: BGB-A317/IgG4S228P and BGB-A317/IgG4-variant (abbreviated as BGB-A317), with the same variable regions but two different IgG4 Fc-hinge sequences. There was no significant difference between these two antibodies in binding to PD-1. However, BGB-A317/IgG4S228P binds to human FcγRI with high affinity and mediates crosslinking between PD-1 and FcγRI. In contrast, BGB-A317 does neither. Further cell-based assays showed that such crosslinking could reverse the function of an anti-PD-1 antibody from blocking to activating. More importantly, the crosslinking induces FcγRI+ macrophages to phagocytose PD-1+ T cells. In a mouse model transplanted with allogeneic human cancer cells and PBMCs, BGB-A317 showed significant tumor growth inhibition, whereas BGB-A317/IgG4S228P had no such inhibition. Immunohistochemistry study revealed an inverse correlation between FcγRI+ murine macrophage infiltration and the density of CD8+PD-1+ human T cells within tumors in the BGB-A317/IgG4S228P-treated group. These evidences suggested that FcγRI+ binding and crosslinking had negative impact on the anti-PD-1 antibody-mediated anti-cancer activity. The online version of this article (10.1007/s00262-018-2160-x) contains supplementary material, which is available to authorized users.
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影响因子：
7.3
作者：
Gillis C;Gouel-Chéron A;Jönsson F;Bruhns P
通讯作者：
Bruhns P
影响因子：
20.3
作者：
Dai X;Jayapal M;Tay HK;Reghunathan R;Lin G;Too CT;Lim YT;Chan SH;Kemeny DM;Floto RA;Smith KG;Melendez AJ;MacAry PA
通讯作者：
MacAry PA
影响因子：
5.3
作者：
Kinder, Michelle;Greenplate, Allison R.;Brezski, Randall J.
通讯作者：
Brezski, Randall J.
影响因子：
4.6
作者：
Isaacs, JD;Wing, MG;Waldmann, H
通讯作者：
Waldmann, H
影响因子：
32.4
作者：
Noy, Roy;Pollard, Jeffrey W.
通讯作者：
Pollard, Jeffrey W.