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    • 48. 发明申请
    • STRUCTURAL VARIANTS OF ANTIBODIES FOR IMPROVED THERAPEUTIC CHARACTERISTICS
    • 用于改善治疗特征的抗体的结构变体
    • WO2010011697A1
    • 2010-01-28
    • PCT/US2009/051321
    • 2009-07-21
    • IMMUNOMEDICS INC.GOLDENBERG, David, M.CHANG, Chien-HsingHANSEN, Hans, J.
    • GOLDENBERG, David, M.CHANG, Chien-HsingHANSEN, Hans, J.
    • A61K39/395C07K16/18
    • C07K16/2887A61K2039/505A61K2039/545C07K2317/24C07K2317/565C07K2317/732C07K2317/734
    • The present invention provides substituted humanized, chimeric or human anti-CD20 antibodies or antigen binding fragments thereof and bispecific antibodies or fusion proteins comprising the substituted antibodies or antigen binding fragments thereof. The antibodies, fusion proteins or fragments are useful for treatment of B-cell disorders, such as B-cell malignancies and autoimmune diseases, as well as GVHD, organ transplant rejection, and hemolytic anemia and cryoglobulinemia. Amino acid substitutions, particularly substitution of an aspartate residue at Kabat position 101 of CDR3 V H (CDRH3), result in improved therapeutic properties, such as decreased dissociation rates, improved CDC activity, improved apoptosis, improved B-cell depletion and improved therapeutic efficacy at very low dosages. Veltuzumab, a humanized anti-CD20 antibody that incorporates such sequence variations, exhibits improved therapeutic efficacy compared to similar antibodies of different CDRH3 sequence, allowing therapeutic effect at dosages as low as 200 mg or less, more preferably 100 mg or less, more preferably 80 mg or less, more preferably 50 mg or less, most preferably 30 mg or less of naked antibody when administered i.v. or s.c.
    • 本发明提供取代的人源化,嵌合或人抗CD20抗体或其抗原结合片段和包含取代的抗体或其抗原结合片段的双特异性抗体或融合蛋白。 抗体,融合蛋白或片段可用于治疗B细胞病变,如B细胞恶性肿瘤和自身免疫性疾病,以及GVHD,器官移植排斥,溶血性贫血和冷球蛋白血症。 氨基酸取代,特别是取代CDR3 VH(CDRH3)Kabat 101位天冬氨酸残基导致改善的治疗性质,例如降低的解离速率,改善的CDC活性,改善的细胞凋亡,改善的B细胞消耗和改善的治疗功效 非常低的剂量 Veltuzumab是与不同CDRH3序列的相似抗体相比具有改善的治疗效果的,具有这种序列变异性的人源化抗-CD20抗体,其能够以低至200mg或更低,更优选为100mg或更少,更优选为80mg mg或更少,更优选50mg或更少,最优选30mg或更少的裸抗体 或s.c.