Human Monoclonal Antibodies from Immunized Patient Lymphocytes

来自免疫患者淋巴细胞的人单克隆抗体

• 批准号: 7405003
• 负责人: PHILIP O. LIVINGSTON
• 金额: $ 19.78万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405003
• 关键词: Affinity; Antibodies; Antibody Formation; Antibody Specificity; Antigens; B-Lymphocytes; Blood specimen; Breast; Cancer Patient; Cancer Vaccines; Cell Line; Cell surface; Cells; Clinical; Collaborations; Colon Carcinoma; Conjugate Vaccines; Cytolysis; Development; Disseminated Malignant Neoplasm; Environment; Epithelial; Gangliosides; Hemocyanin; Human; Hybridomas; Immune; Immunization; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Variable Region; Legal patent; Leukocyte-Adhesion Receptors; Licensing; Ligands; Light; Local Therapy; Lung; Lymphocyte; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Memorial Sloan-Kettering Cancer Center; Micrometastasis; Modeling; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Neuroblastoma; Operative Surgical Procedures; Patients; Peripheral Blood Lymphocyte; Phase; Phase I Clinical Trials; Production; Purpose; Radiation therapy; Rights; SCID Mice; Series; Small Business Technology Transfer Research; Surface Antigens; Surface of the Prostate; Technology; Technology Transfer; Test Result; Testing; Therapeutic; Vaccination; Vaccines; base; cancer type; human monoclonal antibodies; human tissue; improved; in vivo; malignant breast neoplasm; melanoma; neoplastic cell; programs; sarcoma; scale up; tumor

DESCRIPTION (provided by applicant): This Phase I STTR application is to support the development of a panel of human monoclonal antibodies (HmAbs) against sLea (also known as CA 19.9), a ganglioside extensively expressed at the cell surface of colon cancers but also the majority of breast cancers. sLea is highly susceptible as a target for lysis by antibody directed mechanisms and since sLea serves as a ligand for epithelial leukocyte adhesion molecule, sLea antibodies may also have direct impact on metastatic potential. MSKCC is the only center with the demonstrated ability to consistently induce antibodies against gangliosides such as sLea in cancer patients using its unique conjugate vaccines. MabVax is the only company currently using B- lymphocytes from in vivo immunized humans to obtain human mAbs. The MabVax Technology transfers PBL from immune human donors to SCID mice for further expansion, prepares hybridomas using human lymphocytes from selected SCID mice, and finally clones the heavy and light chain variable regions into CHO-K1 cells for expansion, selection and scale up. Initial induction in the human tissue environment (decreasing the chance of generating self reacting monoclonal antibodies), high affinity due to repeated immunizations in vivo and maintenance of the original heavy and light chain pairing are the major advantages of the MabVax Technology. If impact of treatment on clinical course is to be tested with human mAbs against sLea, an MSKCC-MabVax collaboration will be required. Establishment of multiple such CHO-K1 cell lines against sLea will be the starting point for a subsequent Phase 2 STTR application. The focus of the Phase 2 application will be scaling up HmAb production; further improving antibody yield, affinity and possibly effector functions; and testing the resulting HmAbs in mouse xenogeneic tumor challenge models. Administered antibodies and antibodies induced by vaccines are well suited for eradication of free circulating tumor cells and micrometastasis. Administered monoclonal antibodies may have the additional advantage due to higher concentrations and selected effector functions of being able to eradicate early established metastasis as well. If antibodies of efficient titer and effector functions can be administered against the cell surface antigens most dominant on cancers of the colon and breast (such as sLea), 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）：此I期STTR应用是为了支持针对SLEA（也称为Ca 19.9）的人类单克隆抗体（HMABS）的开发，这是一种在结肠癌的细胞表面上广泛表达的神经节蛋白，但也大多数乳腺癌。 SLEA高度易于通过抗体定向机制裂解的靶标，并且由于SLEA充当上皮白细胞粘附分子的配体，因此SLEA抗体也可能对转移性潜力有直接影响。 MSKCC是使用其独特的共轭疫苗在癌症患者中持续诱导诸如SLEA之类的神经节剂的抗体能力的唯一中心。 Mabvax是当前使用体内免疫人类的B-淋巴细胞以获得人物单元单元的唯一一家公司。 Mabvax技术将PBL从免疫供体转移到SCID小鼠以进一步扩展，使用来自选定的SCID小鼠的人淋巴细胞制备杂交瘤，最后克隆重链和轻链可变区域中的CHO-K1细胞以扩展，选择和扩展。人体组织环境的初步诱导（减少产生自反应抗体的机会），由于体内反复的免疫和维持原始重链和轻链配对而导致的高亲和力是Mabvax技术的主要优势。如果要用人MAB对SLEA进行治疗对临床过程的影响，则需要进行MSKCC-Mabvax协作。建立多个针对SLEA的CHO-K1细胞系将是随后的2阶段STTR应用的起点。第2阶段应用的重点将扩大HMAB生产；进一步改善抗体产量，亲和力和可能的效应功能；并在小鼠异构肿瘤挑战模型中测试所得的HMAB。疫苗诱导的抗体和抗体非常适合根除自由循环的肿瘤细胞和微量含量。施用的单克隆抗体可能具有较高的浓度以及能够消除早期已建立的转移的选定效应函数，因此具有额外的优势。如果可以针对结肠和乳腺癌最大的细胞表面抗原施用有效滴度和效应子功能的抗体（例如SLEA），这将极大地改变我们治疗癌症患者的方法。建立新的转移将不再是可能的，因此包括手术或放射治疗在内的积极局部疗法可能会长期控制转移性癌症。