Mizrahi Rena A, Lin Wendy Y, Gras Ashley, Niedecken Ariel R, Wagner Ellen K, Keating Sheila M, Ikon Nikita, Manickam Vishal A, Asensio Michael A, Leong Jackson, Medina-Cucurella Angelica V, Benzie Emily, Carter Kyle P, Chiang Yao, Edgar Robert C, Leong Renee, Lim Yoong Wearn, Simons Jan Fredrik, Spindler Matthew J, Stadtmiller Kacy, Wayham Nicholas, Büscher Dirk, Terencio Jose Vicente, Germanio Clara Di, Chamow Steven M, Olson Charles, Pino Paula A, Park Jun-Gyu, Hicks Amberlee, Ye Chengjin, Garcia-Vilanova Andreu, Martinez-Sobrido Luis, Torrelles Jordi B, Johnson David S, Adler Adam S
GigaGen, Inc., South San Francisco, CA 94080, USA.
Alira Health, Inc., Framingham, MA 01702, USA.
Pathogens. 2022 Jul 19;11(7):806. doi: 10.3390/pathogens11070806.
Conventionally, hyperimmune globulin drugs manufactured from pooled immunoglobulins from vaccinated or convalescent donors have been used in treating infections where no treatment is available. This is especially important where multi-epitope neutralization is required to prevent the development of immune-evading viral mutants that can emerge upon treatment with monoclonal antibodies. Using microfluidics, flow sorting, and a targeted integration cell line, a first-in-class recombinant hyperimmune globulin therapeutic against SARS-CoV-2 (GIGA-2050) was generated. Using processes similar to conventional monoclonal antibody manufacturing, GIGA-2050, comprising 12,500 antibodies, was scaled-up for clinical manufacturing and multiple development/tox lots were assessed for consistency. Antibody sequence diversity, cell growth, productivity, and product quality were assessed across different manufacturing sites and production scales. GIGA-2050 was purified and tested for good laboratory procedures (GLP) toxicology, pharmacokinetics, and in vivo efficacy against natural SARS-CoV-2 infection in mice. The GIGA-2050 master cell bank was highly stable, producing material at consistent yield and product quality up to >70 generations. Good manufacturing practices (GMP) and development batches of GIGA-2050 showed consistent product quality, impurity clearance, potency, and protection in an in vivo efficacy model. Nonhuman primate toxicology and pharmacokinetics studies suggest that GIGA-2050 is safe and has a half-life similar to other recombinant human IgG1 antibodies. These results supported a successful investigational new drug application for GIGA-2050. This study demonstrates that a new class of drugs, recombinant hyperimmune globulins, can be manufactured consistently at the clinical scale and presents a new approach to treating infectious diseases that targets multiple epitopes of a virus.
传统上，由接种疫苗或康复供体的混合免疫球蛋白制成的高免疫球蛋白药物已被用于治疗无可用治疗方法的感染。在需要多表位中和以防止在用单克隆抗体治疗时出现免疫逃逸病毒突变体的情况下，这一点尤为重要。利用微流体技术、流式分选和靶向整合细胞系，生成了一种针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的一流重组高免疫球蛋白疗法（GIGA-2050）。使用与传统单克隆抗体制备类似的工艺，对包含12500种抗体的GIGA-2050进行了临床生产放大，并对多个研发/毒理批次进行了一致性评估。在不同的生产地点和生产规模下，评估了抗体序列多样性、细胞生长、生产力和产品质量。对GIGA-2050进行了纯化，并对其进行了良好实验室规范（GLP）毒理学、药代动力学以及针对小鼠自然SARS-CoV-2感染的体内疗效测试。GIGA-2050主细胞库高度稳定，在超过70代的时间里，以一致的产量和产品质量生产材料。GIGA-2050的良好生产规范（GMP）批次和研发批次在体内疗效模型中显示出一致的产品质量、杂质清除率、效价和保护作用。非人类灵长类动物毒理学和药代动力学研究表明，GIGA-2050是安全的，其半衰期与其他重组人IgG1抗体相似。这些结果支持了GIGA-2050成功的研究性新药申请。这项研究表明，一类新型药物，即重组高免疫球蛋白，可以在临床规模上持续生产，并为治疗针对病毒多个表位的传染病提供了一种新方法。
