Bagshawe K D, Springer C J, Searle F, Antoniw P, Sharma S K, Melton R G, Sherwood R F
Department of Medical Oncology, Charing Cross Hospital, London, UK.
Br J Cancer. 1988 Dec;58(6):700-3. doi: 10.1038/bjc.1988.293.
Attempts to improve the selectivity of anti-cancer agents by conjugating them to antibodies directed at tumour associated antigens have demonstrated tumour localisation but only limited therapeutic success. We report here the advantage of a 2-stage approach in which the first component combines the selective delivery of antibody with a capability to generate a cytotoxic agent from a second subsequently administered component. A bacterial enzyme, carboxypeptidase G2 (CPG2) was conjugated with F(ab')2 fragment of a monoclonal antibody directed at beta subunit of human chorionic gonadotrophin (beta-hCG) and injected into nude mice bearing hCG producing CC3 xenografts of human choriocarcinoma. Time was allowed for the conjugate to localise at tumour sites and clear from blood before injecting para-N-bis (2-chloroethyl) aminobenzoylglutamic acid. Cleavage of the glutamic acid moiety from this molecule by CPG2 released a benzoic acid mustard. Growth of the tumour which is resistant to conventional chemotherapy was markedly depressed by a single course of treatment. This demonstrates for the first time the potential of an antibody directed enzyme to activate an alkylating agent and to eradicate an established human cancer xenograft.
通过将抗癌剂与针对肿瘤相关抗原的抗体偶联来提高其选择性的尝试已证明可实现肿瘤定位，但治疗成功有限。我们在此报告一种两阶段方法的优势，其中第一组分将抗体的选择性递送与从随后施用的第二组分产生细胞毒性剂的能力相结合。将一种细菌酶羧肽酶G2（CPG2）与人绒毛膜促性腺激素β亚基（β-hCG）单克隆抗体的F(ab')2片段偶联，并注射到携带产生hCG的人绒毛膜癌CC3异种移植瘤的裸鼠体内。在注射对-N-双（2-氯乙基）氨基苯甲酰谷氨酸之前，让偶联物在肿瘤部位定位并从血液中清除。CPG2从该分子上切割谷氨酸部分，释放出苯甲酸氮芥。对传统化疗耐药的肿瘤生长通过单一疗程的治疗明显受到抑制。这首次证明了抗体导向酶激活烷化剂并根除已建立的人癌异种移植瘤的潜力。
