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）：该 I 期 STTR 申请旨在支持开发一组针对 sLea（也称为 CA 19.9）的人单克隆抗体 (HmAb)，sLea 是一种神经节苷脂，广泛表达于结肠癌和大多数乳腺癌的细胞表面。 sLea 非常容易成为抗体定向机制裂解的靶标，并且由于 sLea 作为上皮白细胞粘附分子的配体，因此 sLea 抗体也可能对转移潜力产生直接影响。 MSKCC 是唯一一家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（例如 sLea）抗体的中心。 MabVax 是目前唯一一家使用来自体内免疫人体的 B 淋巴细胞来获得人 mAb 的公司。 MabVax技术将来自免疫人类供体的PBL转移至SCID小鼠以进一步扩增，使用来自选定SCID小鼠的人淋巴细胞制备杂交瘤，最后将重链和轻链可变区克隆到CHO-K1细胞中以进行扩增、选择和放大。在人体组织环境中进行初始诱导（减少产生自反应单克隆抗体的机会）、体内重复免疫带来的高亲和力以及维持原始重链和轻链配对是 MabVax 技术的主要优势。如果要使用针对 sLea 的人类单克隆抗体来测试治疗对临床过程的影响，则需要 MSKCC-MabVax 合作。针对 sLea 的多个此类 CHO-K1 细胞系的建立将是后续 2 期 STTR 应用的起点。第二阶段应用的重点将是扩大 HmAb 的生产；进一步提高抗体产量、亲和力以及可能的效应功能；并在小鼠异种肿瘤攻击模型中测试所得的 HmAb。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。施用的单克隆抗体可能具有额外的优势，因为它具有更高的浓度和选择性的效应功能，也能够根除早期形成的转移。如果可以针对结肠癌和乳腺癌中最主要的细胞表面抗原（例如 sLea）施用具有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。