A CDR-grafted (humanized) domain-deleted antitumor antibody.
A CDR-grafted (humanized) domain-deleted antitumor antibody.
复制标题
一种 CDR 移植（人源化）结构域缺失的抗肿瘤抗体。
DOI：
10.1089/cbr.1997.12.305
复制
发表时间：
1997
影响因子：
3.4
通讯作者：
P. Hand
中科院分区：
文献类型：
--
作者：
D. C. Slavin;S. Kashmiri;Hyun;D. Milenic;D. Poole;Eric Bernon;J. Schlom;P. Hand
虽然一些针对肿瘤相关抗原的鼠源性单抗在临床试验中表现出了良好的肿瘤靶向性，但放射性标记单抗用于诊断和治疗的应用受到两个因素的阻碍：(A)宿主抗免疫球蛋白(Ig)反应的诱导和(B)未结合的放射性标记单抗的缓慢血浆清除，导致用于治疗的骨髓毒性，以及用于诊断应用的单抗给药和肿瘤检测之间的长时间间隔。这份报告描述了第一个具有减少或消除上述两个问题的性质的重组Ig的开发：互补决定区(CDR)嫁接的CH2结构域缺失的人源化(CH2)单抗(增量CH2)。选择用于工程的单抗是CC49，它针对的是一种名为Tag-72的肿瘤抗原，该抗原在大多数结直肠癌、胃癌、乳腺癌、卵巢癌、前列腺癌、胰腺癌和肺癌上都有表达。在固相竞争放射免疫分析中，HuCC49βCH2单抗可完全抑制鼠(U)CC49和HuCC49与TAG-72的结合。相对亲和常数分别为5.1×10(-9)、2.1×10(-9)和2.3×10(-9)。静脉注射后，131I-HuCC49βCH2的血浆清除速度明显快于完整的125I-HuCC49。或者IP。裸鼠给药(p(2)0.05)。荷人结肠癌裸鼠静脉注射后的生物分布研究。或者IP。131I-HuCC49 Delta CH2和125I-HuCC49 Delta CH2在正常组织中的注射剂量(%ID/g)显著低于131I-HuCC49 Delta CH2。这反映在用HuCC49 Delta CH2观察到的大多数正常组织的显著较高的放射定位指数(肿瘤中的%ID/g除以正常组织中的%ID/g)(p(2)0.05)。在SCID小鼠中，HuCC49-CH2和HuCC49-CH2的血浆清除率差异更为明显，已被证明是研究人类免疫球蛋白代谢的合适模型。因此，这些研究描述了重组免疫球蛋白分子的开发，它第一次结合了1)比完整的人源化免疫球蛋白分子更快清除血液的特性--而不会失去抗原结合亲和力--以及2)降低了在患者中引发人抗鼠抗体(HAMA)反应的可能性。这些研究还证明了HuCC49三角洲CH2对I.P.的潜在用途。以及静脉注射。TAG-72阳性肿瘤患者的放射免疫诊断与治疗
While several murine monoclonal antibodies (MAbs) directed against carcinoma associated antigens have shown excellent tumor targeting properties in clinical trials, the use of radiolabeled MAbs for both diagnostic and therapeutic applications has been hindered by two factors: (a) the induction of host anti-immunoglobulin (Ig) responses and (b) slow plasma clearance of unbound radiolabeled MAb, resulting in bone marrow toxicity for therapeutic application, and long intervals between MAb administration and tumor detection for diagnostic applications. This report describes the development of the first recombinant Ig with properties designed to reduce or eliminate both of the above problems: a complementarity determining region (CDR)-grafted humanized (Hu) MAb with a CH2 domain deletion (delta CH2). The MAb chosen for engineering was CC49, which is directed against a pancarcinoma antigen designated TAG-72 that is expressed on the majority of colorectal, gastric, breast, ovarian, prostate, pancreatic and lung carcinomas. When characterized for antigen binding in solid phase competition radioimmunoassays, the HuCC49 delta CH2 MAb completely inhibited the binding of murine (mu) CC49 and HuCC49 for TAG-72. The relative affinity constants (Ka) of MAbs HuCC49 delta CH2, HuCC49 and muCC49 were 5.1 x 10(-9), 2.1 x 10(-9) and 2.3 x 10(-9), respectively. The plasma clearance of 131I-HuCC49 delta CH2 was significantly faster than that of intact 125I-HuCC49 after either i.v. or i.p. administration in athymic mice (p(2)0.05). Biodistribution studies in athymic mice bearing human colon carcinoma xenografts after i.v. or i.p. administration of 131I-HuCC49 delta CH2 and 125I-HuCC49 demonstrated the efficient tumor localization and substantially lower percent of the injected dose (%ID/g) of the HuCC49 delta CH2 in normal tissues. This is reflected in the significantly higher radiolocalization indices (%ID/g in tumor divided by %ID/g in normal tissue) observed with the HuCC49 delta CH2 for most normal tissues tested (p(2)0.05). The differential between the rate of plasma clearance of HuCC49 delta CH2 and HuCC49 was even more pronounced in SCID mice, which have been shown to be an appropriate model to study the metabolism of human IgG. These studies thus describe the development of a recombinant Ig molecule which, for the first time, combines 1) the properties of more rapid blood clearance than an intact humanized Ig molecule--without loss of antigen binding affinity--and 2) reduced potential for eliciting a human anti-murine antibody (HAMA) response in patients. These studies also demonstrate the potential utility of HuCC49 delta CH2 for i.p. as well as i.v. radioimmunodiagnosis and radioimmunotherapy in patients with TAG-72 positive tumors.
影响因子：
2.7
作者：
Miller Ad;Rosman Gj
通讯作者：
Miller Ad;Rosman Gj
131I-嵌合小鼠/人 B72.3（人 γ 4）单克隆抗体在人体内的药代动力学和免疫反应。
影响因子：
11.2
作者：
Khazaeli,MB;Saleh,MN;Liu,TP;Meredith,RF;Wheeler,RH;Baker,TS;King,D;Secher,D;Allen,L;Rogers,K
通讯作者：
Rogers,K