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%。 的 SCCL的预后仍然很差。 超过40，000例SCCL病例 在美国有超过35，000人被确诊死于这种疾病 每一年。 虽然化疗是SCCL治疗的主要手段，但许多 已经在临床上尝试了化学治疗剂的组合， 长期存活率有很大提高。 我们已经开发出一种新颖 本发明涉及设计用于治疗SCCL的双特异性免疫缀合物。 靶向 癌细胞上的结构对癌细胞的整体活性是重要的。 免疫缀合物。 我们选择靶向受体， 蛙皮素样肽。 蛙皮素是一种由14个氨基酸组成的肽， 最初是从铃蟾的皮肤中分离出来的。 哺乳动物 蛙皮素类似物胃泌素释放肽（GRP）已被证明 含有与以下序列相同的羧基末端七肽序列 铃蟾肽 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 很少在正常组织上，可能是特异性的理想靶点。 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样肽和免疫缀合物之间制备针对SCCL的免疫缀合物， 抗免疫球蛋白受体单克隆抗体 （Fc γ RI），其在正常单核细胞、巨噬细胞上表达， 中性粒细胞 我们假设免疫结合物能够 将单核细胞导向SCCL细胞，并引发特异性抗体依赖性 细胞介导的细胞毒性（ADCC）。 我们的初步数据 显示用mAb 22缀合物可以引发高水平的ADCC （抗Fc γ RI）和肽Lys 3-BN（铃蟾肽受体激动剂）。 我们 我建议开发这种针对BN/GRP受体的免疫缀合物 利用抗Fc γ RI（CD 64）的mAb进行临床应用。 我们建议 启动Lys 3-mAb 22免疫偶联物的I期临床试验 患者SCCL，以确定这种新的安全性和活性 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.