Talacotuzumab

Talacotuzumab (JNJ 56022473; CSL 362) is an IgG1-type fully humanized, CD123-neutralizing monoclonal antibody containing a modified Fc structure. Talacotuzumab has KDs of 0.43 nM, 188 nM, 46 nM, 16.8 nM for CD123, CD32b/c, CD16-158F, CD16-158V, respectively. Talacotuzumab inhibits IL-3 binding to CD123, antagonizing IL-3 signaling in target cells. Talacotuzumab has mutated the Fc region to increase affinity for CD16 (FcγRIIIa), thereby enhancing antibody-dependent cell-mediated cytotoxicity (ADCC). Talacotuzumab is highly effective in vivo reducing leukemic cell growth in acute myeloid leukemia (AML) xenograft mouse models[1][2][3][4].

Research Areas >> Cancer

Signaling Pathways >> Immunology/Inflammation >> Interleukin Related

塔妥珠单抗 (JNJ 56022473; CSL 362) 强烈介导 TF-1 细胞的抗体依赖性细胞介导的细胞毒性 (ADCC)，IC50 为 5 ng/ml (33 pM)[1]。 塔妥珠单抗(1 μg/ml; 预处理 24 小时) 抑制 SLE 供体和健康供体浆细胞样树突状细胞和嗜碱性粒细胞中 TLR7 刺激(咪喹莫特; HY-B0180; 0.5 μM; 6 天) 和 TLR9 刺激 (CpG C; 0.5 μM; 6 天) IFN-α 的产生，而 TLR4 刺激 (LPS; HY-D1056; 10 μg/ml) 的产生没有显着减少。Talacotuzumab 通过耗尽浆细胞样树突状细胞 (pDC) 来抑制 TLR7 和 TLR9 诱导的浆母细胞扩增和增殖[2]。

塔妥珠单抗 (JNJ 56022473; CSL 362; 300 μg; 腹腔注射; 每周三次持续 5 周) 与同种型对照相比，在急性髓性白血病小鼠异种移植物中导致肿瘤生长显着延迟[1]。 塔妥珠单抗 (1, 10, 30 mg/kg; 皮下注射; 单次注射) 在幼稚食蟹猴中以 1、10、30 mg/kg 的剂量在 48 小时时的最大血清浓度分别为 12、190 和 380 μg/ml[2]。 塔妥珠单抗 3 周可显着减少血液、脾脏和肝脏中 AML-5、-16 和 -17 的植入，但仅对雌性 OD/SCID 小鼠骨髓中的 AML-17 显着有效[3 ]。 Animal Model: Nonobese diabetic/severe combined immunodeficiency mice injected intravenously AML xenograft cells (AML-5)[1] Dosage: 300 μg Administration: IP; thrice weekly for 5 weeks Result: Resulted in a significant delay in tumor growth compared with an isotype control.

[1]. S J Busfield, et al. Targeting of acute myeloid leukemia in vitro and in vivo with an anti-CD123 mAb engineered for optimal ADCC. Leukemia. 2014 Nov;28(11):2213-21.  

[2]. Shereen Oon, et al. A cytotoxic anti-IL-3Rα antibody targets key cells and cytokines implicated in systemic lupus erythematosus. JCI Insight. 2016 May 5;1(6):e86131.  

[3]. Erwin M Lee, et al. Efficacy of an Fc-modified anti-CD123 antibody (CSL362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice. Haematologica. 2015 Jul;100(7):914-26.  

[4]. L H Xie, et al. CD123 target validation and preclinical evaluation of ADCC activity of anti-CD123 antibody CSL362 in combination with NKs from AML patients in remission. Blood Cancer J. 2017 Jun 2;7(6):e567.