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

描述（由申请人提供）：糖抗原唾液酸-路易斯a（sLea）在胃肠道上皮肿瘤、乳腺癌细胞以及小细胞肺癌细胞上广泛表达，但在正常组织上表达最低或根本不表达。sLea作为上皮白细胞粘附分子的配体，并且在淋巴结受累较大的患者中观察到sLea的较高表达。由于sLea的过表达似乎是许多肿瘤细胞的侵袭和转移中的关键事件，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呈现了在最小疾病环境中用于肿瘤治疗的有吸引力的分子靶标。MSKCC是唯一一个证明有能力使用其独特的结合疫苗在癌症患者中持续诱导抗神经节苷脂和糖脂（包括sLea）抗体的中心。MabVax抗体生成技术旨在利用体内免疫人的B淋巴细胞来拯救疫苗接种后产生的人单克隆抗体。我们最初提案的目标已经实现：在乳腺癌患者中启动了sLea-KLH疫苗的试点试验。使用MabVax全人源mAb生成技术处理了来自两名对sLea具有高滴度应答的患者的血液标本，并生成了对sLea具有高亲和力和特异性的HumAb。两种抗体，一种IgG和一种IgM，显示具有针对sLea阳性癌细胞的有效效应子功能，并且两者都已转化为全功能的人重组抗体。所提出的工作旨在建立所选抗体候选物的体内功效的初步证据，并将最有效的抗体进一步推进临床前开发。这包括按比例增加重组HumAb生产，以提高抗体产量，并在小鼠异种肿瘤攻击模型中测试HumAb。长期目标是选择临床候选抗体用于进一步开发和商业化工作。由于sLea广泛表达，主要候选抗体最终可能会在每年发生的一半以上的新癌症病例中发挥作用。 公共卫生相关性：施用抗体和疫苗诱导的抗体非常适合于根除游离循环肿瘤细胞和微转移。施用人单克隆抗体具有额外的优点：可实现具有可预测药效学特性的更高浓度，并且可以选择性地改变效应器功能，因此根除早期建立的转移可能变得更加可行。如果可以安全地施用针对结肠癌和乳腺癌（如sLea）上最主要的细胞表面抗原的有效滴度和效应子功能的抗体，这将极大地改变我们治疗癌症患者的方法。新转移的建立将不再可能，因此包括手术或放射治疗在内的积极局部治疗可能导致甚至转移性癌症的长期控制。

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.