摘要:靶向flt3的TriTACs是治疗急性髓系白血病的T细胞接合物

R. Austin, W. Aaron, Manasi Barath, Evan C. Callihan, Scott Gatto, Golzar Hemmati, C. Law, D. LemonBryan, J. O'rear, Purbasa Patnaik, Morgan Thompson, Lihn To, H. Wesche, Kevin Wright, Yinghua Xiao, Stephen Yu, Timothy Z. Yu
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引用次数: 0

摘要

FLT3 (fms相关受体酪氨酸激酶3)是一种在造血干细胞和祖细胞群中表达的细胞表面蛋白1。FLT3 RNA在超过95%的急性髓性白血病(AML)样本中过表达2,并且在25%至35%的AML样本中发现FLT3突变1。到2020年,美国预计将有19,940例新的AML病例和11180例AML相关死亡,这表明需要更好的治疗方法来治疗这种疾病。考虑到FLT3在AML中的表达频率和患者未满足的医疗需求,FLT3代表了AML中T细胞重定向免疫治疗的一个有吸引力的靶点。FLT3靶向三特异性T细胞激活构建体(FLT3 TriTACs)旨在同时激活靶AML细胞上的FLT3和T细胞上的CD3,导致T细胞活化、增殖和AML细胞裂解。FLT3 TriTACs是一种约53 kDa的分子,由三个结合域组成:与人FLT3结合的n端单链抗体(sdAb),与人血清白蛋白(HSA)结合以延长半衰期的中间sdAb,以及与T细胞受体(TCR) CD3e结合的c端单链Fv (scFv)。这些分子的生物物理分析表明它们是稳定的,单体含量高。TriTACs与人和食蟹猴FLT3、CD3e和白蛋白结合,具有相似的亲和力。流式细胞术分析了来自各种正常供体的T细胞和FLT3阳性和FLT3阴性肿瘤细胞系,证实FLT3 TriTACs与细胞表面表达的靶标结合。FLT3 TriTACs在体外诱导表达FLT3的AML细胞系的有效杀伤。在来自正常人供体的T细胞、靶肿瘤细胞和HSA的共培养中,这些TriTACs介导了剂量依赖性和flt3依赖性的细胞毒性。表达食蟹FLT3的细胞系也很容易被带有FLT3 TriTACs的T细胞杀死。将介绍FLT3 TriTACs在体外、小鼠肿瘤模型和食蟹猴药代动力学研究中的临床前评估。引用1。Kazi和Ronnstrand, 2019。物理启示录99:1433-1466。2. 数据由TCGA研究网络生成:https://www.cancer.gov/tcga。3.Howlader et al. 2020。癌症统计回顾,1975-2017。引文格式:Richard J. Austin, Wade H. Aaron, Manasi Barath, Evan Callihan, Scott Gatto, Golzar Hemmati, Che-Leung Law, Bryan D. Lemon, Jessica O9Rear, Purbasa Patnaik, Morgan Thompson, Lihn To, Holger Wesche, Kevin Wright, Yinghua Xiao, Stephen Yu, Timothy Z. Yu。靶向flt3的TriTACs是治疗急性髓系白血病的T细胞接合物[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要第913期。
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Abstract 913: FLT3-targeting TriTACs are T cell engagers for treatment of acute myeloid leukemia
FLT3 (fms related receptor tyrosine kinase 3) is a cell surface protein expressed in hematopoietic stem and progenitor cell populations1. FLT3 RNA is overexpressed in greater than 95% of acute myeloid leukemia (AML) samples2, and FLT3 mutations are found in 25% to 35% of AML samples1. In 2020 in the United States, an estimated 19,940 new AML cases and 11,180 AML-related deaths are expected3, exemplifying that better therapies are needed to treat this disease. Given the frequency of FLT3 expression in AML and unmet medical need for patients, FLT3 represents an attractive target for T cell-redirecting immunotherapy in AML. FLT3-targeting Tri-specific T cell Activating Constructs (FLT3 TriTACs) are designed to simultaneously engage FLT3 on a target AML cell and CD3 on a T cell, resulting in T cell activation, proliferation, and lysis of the AML cell. FLT3 TriTACs are ~53 kDa molecules that consist of three binding domains: an N-terminal single domain antibody (sdAb) that binds to human FLT3, a middle sdAb that binds to human serum albumin (HSA) to extend the half-life, and a C-terminal single chain Fv (scFv) that binds to CD3e of the T cell receptor (TCR). Biophysical analyses of these molecules indicate they are stable with high monomer content. FLT3 TriTACs bind to human and cynomolgus monkey FLT3, CD3e and albumin with similar affinities. Flow cytometry analysis of T cells from various normal donors and a panel of FLT3-positive and FLT3-negative tumor cell lines confirmed binding of FLT3 TriTACs to their targets expressed on the cell surface. FLT3 TriTACs induce potent killing of FLT3-expressing AML cell lines in vitro. In co-cultures of T cells from normal human donors, target tumor cells, and HSA, these TriTACs mediated dose-dependent and FLT3-dependent cytotoxicity. Cell lines engineered to express cynomolgus FLT3 were also readily killed by T cells with FLT3 TriTACs. Preclinical evaluation of FLT3 TriTACs in vitro, in mouse tumor models, and cynomolgus monkey pharmacokinetic studies will be presented. References 1. Kazi and Ronnstrand. 2019. Physiol Rev. 99:1433-1466. 2. Data generated by the TCGA Research Network: https://www.cancer.gov/tcga. 3. Howlader et al. 2020. SEER Cancer Statistics Review, 1975-2017. Citation Format: Richard J. Austin, Wade H. Aaron, Manasi Barath, Evan Callihan, Scott Gatto, Golzar Hemmati, Che-Leung Law, Bryan D. Lemon, Jessica O9Rear, Purbasa Patnaik, Morgan Thompson, Lihn To, Holger Wesche, Kevin Wright, Yinghua Xiao, Stephen Yu, Timothy Z. Yu. FLT3-targeting TriTACs are T cell engagers for treatment of acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 913.
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