Alligator Bioscience AB, Medicon Village, Scheelevägen 2, 223 81, Lund, Sweden.
J Immunother Cancer. 2019 Apr 11;7(1):103. doi: 10.1186/s40425-019-0570-8.
The CTLA-4 blocking antibody ipilimumab has demonstrated substantial and durable effects in patients with melanoma. While CTLA-4 therapy, both as monotherapy and in combination with PD-1 targeting therapies, has great potential in many indications, the toxicities of the current treatment regimens may limit their use. Thus, there is a medical need for new CTLA-4 targeting therapies with improved benefit-risk profile.
ATOR-1015 is a human CTLA-4 x OX40 targeting IgG1 bispecific antibody generated by linking an optimized version of the Ig-like V-type domain of human CD86, a natural CTLA-4 ligand, to an agonistic OX40 antibody. In vitro evaluation of T-cell activation and T regulatory cell (Treg) depletion was performed using purified cells from healthy human donors or cell lines. In vivo anti-tumor responses were studied using human OX40 transgenic (knock-in) mice with established syngeneic tumors. Tumors and spleens from treated mice were analyzed for CD8 T cell and Treg frequencies, T-cell activation markers and tumor localization using flow cytometry.
ATOR-1015 induces T-cell activation and Treg depletion in vitro. Treatment with ATOR-1015 reduces tumor growth and improves survival in several syngeneic tumor models, including bladder, colon and pancreas cancer models. It is further demonstrated that ATOR-1015 induces tumor-specific and long-term immunological memory and enhances the response to PD-1 inhibition. Moreover, ATOR-1015 localizes to the tumor area where it reduces the frequency of Tregs and increases the number and activation of CD8 T cells.
By targeting CTLA-4 and OX40 simultaneously, ATOR-1015 is directed to the tumor area where it induces enhanced immune activation, and thus has the potential to be a next generation CTLA-4 targeting therapy with improved clinical efficacy and reduced toxicity. ATOR-1015 is also expected to act synergistically with anti-PD-1/PD-L1 therapy. The pre-clinical data support clinical development of ATOR-1015, and a first-in-human trial has started (NCT03782467).
CTLA-4 阻断抗体伊匹单抗已在黑色素瘤患者中显示出显著且持久的疗效。虽然 CTLA-4 疗法（无论是单药治疗还是与 PD-1 靶向疗法联合使用）在许多适应症中都具有巨大的潜力，但目前治疗方案的毒性可能会限制其应用。因此，需要开发具有更好获益风险比的新型 CTLA-4 靶向疗法。
ATOR-1015 是一种人 CTLA-4×OX40 靶向 IgG1 双特异性抗体，通过将人 CD86 的优化 Ig 样 V 型结构域（CTLA-4 的天然配体）与激动性 OX40 抗体相连而产生。使用来自健康人类供体或细胞系的纯化细胞体外评估 T 细胞激活和 T 调节细胞（Treg）耗竭。使用已建立同源肿瘤的人 OX40 转基因（嵌合）小鼠研究体内抗肿瘤反应。使用流式细胞术分析来自治疗小鼠的肿瘤和脾脏中的 CD8 T 细胞和 Treg 频率、T 细胞激活标志物和肿瘤定位。
ATOR-1015 在体外诱导 T 细胞激活和 Treg 耗竭。ATOR-1015 治疗可减少几种同源肿瘤模型（包括膀胱癌、结肠癌和胰腺癌模型）的肿瘤生长并改善生存。进一步表明，ATOR-1015 诱导肿瘤特异性和长期免疫记忆，并增强对 PD-1 抑制的反应。此外，ATOR-1015 定位于肿瘤区域，在该区域减少 Treg 的频率并增加 CD8 T 细胞的数量和激活。
通过同时靶向 CTLA-4 和 OX40，ATOR-1015 被引导至肿瘤区域，在该区域诱导增强的免疫激活，因此有可能成为一种具有改善的临床疗效和降低毒性的下一代 CTLA-4 靶向疗法。ATOR-1015 也有望与抗 PD-1/PD-L1 治疗协同作用。临床前数据支持 ATOR-1015 的临床开发，一项首次人体试验已经开始（NCT03782467）。
