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

源自患者的唾液酸-刘易斯 A (sLeA) 人抗体的表征

• 批准号: 8119141
• 负责人: Wolfgang W Scholz
• 金额: $ 56.91万
• 依托单位: MABVAX THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-12 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119141
• 关键词: Affinity; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Binding; Biological Assay; Blood; Blood specimen; Breast; Breast Cancer Cell; Cancer Patient; Cancer Vaccines; Carbohydrates; Cell surface; Clinical; Colon Carcinoma; Conjugate Vaccines; Cytolysis; Development; Disadvantaged; Disease; Disseminated Malignant Neoplasm; Drug Formulations; Epithelial; Event; Gangliosides; Gastrointestinal Neoplasms; Generations; Glycolipids; Glycoproteins; Goals; Human; Immune response; Immunoglobulin G; Immunoglobulin M; In Vitro; Individual; Keyhole Limpet Hemocyanin; Lead; Leukocyte Adhesion Molecules; Leukocyte-Adhesion Receptors; Licensing; Ligands; Local Therapy; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Measures; Mediating; Membrane; Memorial Sloan-Kettering Cancer Center; Micrometastasis; Modeling; Molecular Target; Mus; Neoplasm Metastasis; Neuroblastoma; Normal tissue morphology; Operative Surgical Procedures; Patients; Pharmacodynamics; Phase; Principal Investigator; Process; Production; Property; Radiation therapy; Recombinant Antibody; Recombinants; Rights; Series; Small Business Technology Transfer Research; Specificity; Surface Antigens; Surface of the Prostate; Technology; Test Result; Testing; Therapeutic; Toxicology; Vaccination; Vaccines; Work; anti-IgM; cancer cell; cancer type; cell bank; commercialization; design; glycosylation; human monoclonal antibodies; improved; in vivo; lung small cell carcinoma; malignant breast neoplasm; meetings; melanoma; neoplastic cell; overexpression; pilot trial; pre-clinical; programs; public health relevance; response; safety testing; sarcoma; scale up; sialyl Lewis a; stable cell line; tumor

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.

描述（由申请人提供）：碳水化合物抗原唾液酸-Lewis 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，但在胃肠道上皮肿瘤细胞上表达极少或根本不表达。正常组织。 sLea 作为上皮白细胞粘附分子的配体，在淋巴结受累较多的患者中观察到 sLea 的表达较高。由于 sLea 的过度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 为最小疾病环境下的肿瘤治疗提供了一个有吸引力的分子靶点。 MSKCC 是唯一一家被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针对神经节苷脂和糖脂（包括 sLea）的抗体的中心。 MabVax 抗体生成技术旨在利用体内免疫人类的 B 淋巴细胞来拯救因疫苗接种而产生的人类单克隆抗体。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。利用 MabVax 全人单克隆抗体生成技术处理了两名对 sLea 具有高滴度反应的患者的血液样本，并生成了对 sLea 具有高亲和力和特异性的 HumAb。其中两种抗体，一种 IgG 和一种 IgM，被证明对 sLea 阳性癌细胞具有有效的效应功能，并且两种抗体都已转化为全功能的人类重组抗体。拟议的工作旨在建立所选候选抗体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。这包括扩大重组 HumAb 的生产，以提高抗体产量，以及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进行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在每年超过一半的新癌症病例中发挥作用。 公共卫生相关性：施用的抗体和疫苗诱导的抗体非常适合根除游离循环肿瘤细胞和微转移。施用人单克隆抗体具有其他优点：可以实现具有可预测的药效特性的更高浓度，并且可以选择性地改变效应器功能，因此根除早期已形成的转移可能变得更加可行。如果能够安全地施用针对结肠癌和乳腺癌中最主要的细胞表面抗原（例如 sLea）的有效滴度和效应功能的抗体，这将极大地改变我们治疗癌症患者的方法。不再可能出现新的转移，因此包括手术或放射治疗在内的积极的局部治疗可能会导致转移性癌症的长期控制。