Characterization of human antibodies to sialyl-Lewis A (sLeA) derived from patien

描述（由申请人提供）：碳水化合物抗原sialyl-Lewis a （sLea）在胃肠道上皮肿瘤、乳腺癌细胞和小细胞肺癌细胞中广泛表达，但在正常组织中表达极低或根本不表达。sLea作为上皮白细胞粘附分子的配体，在淋巴结受累较大的患者中观察到sLea的高表达。由于sLea的过表达似乎是许多肿瘤细胞侵袭和转移的关键事件，并且表达sLea的肿瘤细胞对抗体介导的裂解机制高度敏感，因此sLea在最小疾病环境下为肿瘤治疗提供了一个有吸引力的分子靶点。MSKCC是唯一被证明能够使用其独特的结合疫苗在癌症患者中持续诱导针对神经节苷脂和糖脂类（包括sLea）的抗体的中心。MabVax抗体生成技术旨在利用体内免疫的人的b淋巴细胞来挽救因疫苗接种而产生的人单克隆抗体。我们最初提议的目标已经实现：在乳腺癌患者中开展了sLea-KLH疫苗的试点试验。利用MabVax全人单克隆抗体生成技术对两例sLea高效价反应患者的血液标本进行处理，生成了对sLea具有高亲和力和特异性的人单克隆抗体。其中两种抗体，一种IgG抗体和一种IgM抗体，被证明对sLea阳性癌细胞具有有效的效应功能，并且都已转化为功能齐全的人重组抗体。所提出的工作旨在建立选定抗体候选物体内功效的初步证据，并进一步推进最有效的抗体进入临床前开发。这包括扩大重组人单抗的生产，以提高抗体产量，并在小鼠异种肿瘤激发模型中测试人单抗。长期目标是为进一步开发和商业化努力选择一种临床候选抗体。由于sLea是广泛表达的，主要候选抗体最终可能在每年发生的一半以上的新癌症病例中找到用途。

DESCRIPTION (provided by applicant): The carbohydrate antigen sialyl-Lewis a (sLea) is widely expressed on epithelial tumors of the gastrointestinal tract, on breast cancer cells, and also on small cell lung cancer cells but is expressed minimally or not at all on normal tissues. sLea serves as a ligand for epithelial leukocyte adhesion molecules and higher expression of sLea was observed in patients with greater node involvement. Since over-expression of sLea appears to be a key event in invasion and metastasis of many tumor cells and tumor cells expressing sLea are highly susceptible to antibody mediated lysis mechanisms, sLea presents an attractive molecular target for tumor therapy in a minimal disease setting. MSKCC is the only center with the demonstrated ability to consistently induce antibodies against gangliosides and glycolipids including sLea in cancer patients using its unique conjugate vaccines. The MabVax antibody generation technology is designed to utilize B-lymphocytes from in vivo immunized humans to rescue human monoclonal antibodies generated in response to the vaccination. The goals of our initial proposal have been achieved: A pilot trial with the sLea-KLH vaccine in breast cancer patients was initiated. Blood specimens from two patients with high titer responses against sLea have been processed utilizing the MabVax fully human mAb generating technologies, and HumAbs with high affinity and specificity for sLea have been generated. Two of the antibodies, one IgG and one IgM, were shown to possess potent effecter functions against sLea positive cancer cells and both have been converted to fully functional human recombinant antibodies. The proposed work is designed to establish initial proof of in vivo efficacy of the selected antibody candidates, and to advance the most efficacious antibodies further into preclinical development. This includes scaling up recombinant HumAb production, to improve antibody yield, and testing the HumAbs in mouse xenogeneic tumor challenge models. The long-term goal is to select a clinical candidate antibody for further development and commercialization efforts. Since sLea is widely expressed, the lead candidate antibody could eventually find utility in more than half of the new cancer cases occurring each year. PUBLIC HEALTH RELEVANCE: Administered antibodies and antibodies induced by vaccines are well suited for eradication of free circulating tumor cells and micrometastasis. Administered human monoclonal antibodies have additional advantages: Higher concentrations with predictable pharmacodynamic properties are achievable and effector functions can be selectively altered, so eradication of early established metastasis might become more feasible. If antibodies of efficient titer and effector functions against the cell surface antigens most dominant on cancers of the colon and breast (such as sLea) can be safely administered, this would dramatically change our approach to treating the cancer patient. Establishment of new metastasis would no longer be possible so aggressive local therapies including surgery or radiation therapy might result in long term control of even metastatic cancers.