Diabody-based recombinant formats of humanized IgG-like bispecific antibody with effective retargeting, of lymphocytes to tumor cells
Diabody-based recombinant formats of humanized IgG-like bispecific antibody with effective retargeting, of lymphocytes to tumor cells
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DOI：
10.1097/cji.0b013e3181849071
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发表时间：
2008-10-01
影响因子：
3.9
通讯作者：
Kumagai, Izumi
中科院分区：
文献类型：
--
作者：
Asano, Ryutaro;Kawaguchi, Hiroko;Kumagai, Izumi
最近，重组抗体已被分解成抗原结合区，并重建成多价高亲和格式。这些新的结构设计有望改善体内药代动力学和临床使用的疗效。在此，我们设计了有效的重组双特异性抗体（BsAb）格式，该格式基于人源化双特异性抗体hEx3，具有表皮生长因子受体和CD3重靶向。从hEx3（或其单链形式，hEx3- scdb）和人类Fc区设计的双特异性和二价IgG样抗体与每个靶细胞的结合比单价糖尿病格式更强，并且它们的亲和力与相应的亲本IgG相同。构建的igg样bsab的二价效应导致细胞毒性是单价抗体的10倍，并且Fc部分的融合通过诱导抗体依赖性细胞毒性对外周血单核细胞产生强烈的细胞毒性。igg样bsab的生长抑制作用优于被批准的治疗性抗体西妥昔单抗，后者识别相同的表皮生长因子受体抗原，即使使用外周血单个核细胞作为效应细胞。因此，我们证明了自下而上构建igg样bsab对hEx3的作用有关键的改善；在过继性免疫治疗中，没有补充分子的单一治疗可能会诱导抗体依赖性细胞毒性。
Recently, recombinant antibodies have been dissected into antigen-binding regions and rebuilt into multivalent high-avidity formats. These new structural designs are expected to improve in vivo pharmacokinetics and efficacy in clinical use. Here, we designed effective recombinant bispecific antibody (BsAb) formats based on hEx3, a humanized bispecific diabody with epidermal growth factor receptor and CD3 retargeting. The bispecific and bivalent IgG-like antibodies engineered from hEx3 (or its single-chain form, hEx3-scDb) and the human Fc region showed stronger binding to each target cell than did monovalent diabody formats, and their affinity was identical to that of the corresponding parent IgG. The bivalent effect of the constructed IgG-like BsAbs resulted in cell cytotoxicity 10 times that of monovalent diabodies, and further, the fusion of Fc portion contributed intense cytotoxicity in peripheral blood mononuclear cells by the induction of the anti body-dependent cellular cytotoxicity. The growth-inhibition effects of IgG-like BsAbs were superior to those of the approved therapeutic antibody cetuximab, which recognizes the same epidermal growth factor receptor antigen, even when peripheral blood mononuclear cells were used as effector cells. We thus demonstrated a critical improvement in the effect of hEx3 by the bottom-up construction of IgG-like BsAbs; in adoptive immunotherapy, monotherapy without supplemental molecules may be able to induce antibody-dependent cellular cytotoxicity.