TARGETED CELLULAR TOXICITY OF SCCL CELLS

描述：(申请人描述)肺小细胞癌 (SCCL)约占所有肺癌的15%至25%。这个 SCCL的预后仍然很差。超过40,000例SCCL病例是 确诊后，美国有超过3.5万人死于这种疾病 每年。虽然化疗是SCCL的主要治疗方法，但许多 化疗药物的组合已经在临床上进行了试验，没有 长期存活率有了很大提高。我们开发了一部小说 专为治疗SCCL而设计的双特异性免疫结合物。目标定位 癌细胞上的结构对癌细胞的整体活性很重要 免疫结合物。我们选择以受体为靶点 蛙毒素样多肽。蛙形素是一种由14个氨基酸组成的多肽， 最初从青蛙Bombina Bombina的皮肤中分离出来。哺乳动物 蛙皮素的类似物，胃泌素释放肽(GRP)已被证明 含有一个羧基末端七肽序列，该序列与 蛙乙素。大多数人SCCL细胞系产生GRP，并表达 BN/GRP的高亲和力受体。我们推断这些细胞表面 GRP受体，并在大多数SCCL细胞上表达，但仅在 很少在正常组织上，可能是特定的理想靶点 免疫疗法。因此，我们开发了一种新的免疫治疗方法。 通过在BN样多肽和AFP之间制备免疫结合物来对抗SCCL 抗免疫球蛋白受体的单抗 (FcGammaRI)，表达于正常单核细胞、巨噬细胞和 中性粒细胞。我们假设免疫结合物能够 将单核细胞定向至SCCL细胞并诱导特异性抗体依赖 对SCCL细胞的细胞介导的细胞毒作用(ADCC)。我们的初步数据 表明mAb22结合物可以诱导高水平的ADCC (抗FcGammaRI)和蛙素受体激动剂Lys3-BN肽。我们 建议研制针对BN/GRP受体的免疫结合物 抗FcGammaRI(CD64)单抗的临床应用。我们建议 启动Lys3-mAb22免疫结合物的I期临床试验 以确定这一新药物的安全性和活性 治疗试剂。这些研究将决定一部小说的潜力 SCCL的免疫治疗形式，以改善治疗结果。

DESCRIPTION: (Applicant's Description) Small cell carcinoma of the lung (SCCL) accounts for about 15 percent to 25 percent of all lung cancers. The prognosis for SCCL remains poor. More than 40,000 cases of SCCL are diagnosed and over 35,000 people die of this disease in the United States per year. While chemotherapy is the mainstay of treatment for SCCL, many combinations of chemotherapeutic agents have been tried clinically without much improvement in the long-term survival rate. We have developed a novel bispecific immunoconjugate designed for the therapy of SCCL. The targeting structure on the cancer cell is important to the overall activity of the immunoconjugate. We have chosen to target the receptor for the bombesin-like peptides. Bombesin is a 14-amino acid peptide which was initially isolated from the skin of the frog Bombina bombina. The mammalian analogue of bombesin, gastrin-releasing peptide (GRP) has been shown to contain a carboxy-terminal heptapeptide sequence identical to that of bombesin. The majority of human SCCL cell lines produce GRP, and express high-affinity receptors for BN/GRP. We reasoned that these cell surface receptors for GRP, and expressed on the majority of SCCL cells but only rarely on normal tissues, might serve as ideal targets for specific immunotherapy. Thus, we have developed a novel approach for immunotherapy against SCCL by making an immunoconjugate between a BN-like peptide and a monoclonal antibody (mAb) against the receptor for immuno-globulin (FcgammaRI) which is expressed on normal monocytes, macrophages, and neutrophils. We hypothesized that the immunoconjugates would be able to direct monocytes towards SCCL cells and elicit a specific antibody-dependent cell-mediated cytotoxicity (ADCC) against SCCL cells. Our preliminary data show that high-levels of ADCC can be elicited with a conjugate of mAb 22 (anti-FcgammaRI) and the peptide Lys3-BN, a bombesin-receptor agonist. We propose to develop this immunoconjugate directed to the BN/GRP receptor using mAb to FcgammaRI (CD64) for clinical application. We propose to initiate a phase I clinical trial of the Lys3-mAb22 immunoconjugate in patients with SCCL to determine the safety and activity of this new therapeutic reagent. These study will determine the potential for a novel form of immunotherapy for SCCL to improve treatment outcomes.