Human Monoclonal Antibodies from Immunized Patient Lymphocytes

描述(由申请人提供)：这项第一阶段的STTR申请是为了支持一组针对Slea(也称为CA19.9)的人源性单抗(HmAbbs)的开发，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作为抗体导向机制的溶解靶点是高度敏感的，由于SLEA是上皮性白细胞黏附分子的配基，SLEA抗体也可能对转移潜能有直接影响。MSKCC是唯一一个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抗神经节苷脂抗体(如Slea)的中心。MabVax是目前唯一一家使用体内免疫人类的B淋巴细胞来获得人类单抗的公司。MabVax技术将免疫人类捐赠者的PBL转移到SCID小鼠进行进一步扩增，使用选定的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细胞中进行扩增、选择和放大。MabVax技术的主要优势是在人体组织环境中进行初始诱导(减少产生自反应单抗的机会)、体内反复免疫所产生的高亲和力以及保持原始的重链和轻链配对。如果要用人类抗Slea单抗测试治疗对临床病程的影响，则需要MSKCC-MabVax合作。针对SleA建立多个这样的CHO-K1细胞系将是后续阶段2 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、亲和力和可能的效应功能；以及在小鼠异种肿瘤挑战模型中测试由此产生的HmAbs。注射抗体和疫苗诱导的抗体非常适合于根除自由循环的肿瘤细胞和微转移。给予单抗可能具有额外的优势，因为较高的浓度和选定的效应器功能能够消除早期建立的转移以及。如果能够针对结肠癌和乳腺癌最主要的细胞表面抗原(如Slea)注射高效滴度和效应器功能的抗体，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可能，所以积极的局部治疗，包括手术或放射治疗，可能导致甚至转移癌的长期控制。

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.