CD20 Tcb (RG6026)，一种用于治疗 B 细胞恶性肿瘤的新型“2:1”T 细胞双特异性抗体,Blood

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CD20 Tcb (RG6026)，一种用于治疗 B 细胞恶性肿瘤的新型“2:1”T 细胞双特异性抗体
Blood ( IF 21.0 ) Pub Date : 2016-12-02 , DOI: 10.1182/blood.v128.22.1836.1836
Marina Bacac ₁ , Pablo Umaña ₁ , Sylvia Herter ₁ , Sara Colombetti ₁ , Johannes Sam ₁ , Marine Le Clech ₁ , Anne Freimoser-Grundschober ₁ , Marine Richard ₁ , Valeria Nicolini ₁ , Christian Gerdes ₁ , Laurent Lariviere ₂ , Christiane Neumann ₁ , Christian Klein ₁

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尽管随着抗 CD20 单克隆抗体疗法的引入，治疗选择最近取得了进展，但大约 50% 的非霍奇金淋巴瘤 (NHL) 患者无法对标准护理 (SOC) 治疗产生持久反应。因此，在该适应症中仍然需要更安全和更有效的抗癌疗法。T 细胞双特异性抗体 (TCB) 代表了一类新的疾病靶向剂，可促进患者自身 T 细胞的激活以攻击和杀死癌细胞。CD20 TCB 是一种新的双特异性抗体，具有 IgG 样药代动力学特性，与其他 T 细胞结合双特异性抗体分子形式相比，其独特的“2:1”结构导致增加的肿瘤抗原亲和力、T 细胞活化和肿瘤细胞杀伤。该分子包含两个 CD20 结合 Fab（源自 II 型 CD20 IgG1 obinutuzumab）、一个 CD3e 结合 Fab（通过短的柔性接头与其中一个 CD20 Fab 融合）和一个工程化的异二聚体 Fc 区，与 FcgR 的结合完全消失和 C1q。在体外，CD20 TCB 显示出剂量依赖性地诱导肿瘤溶解，EC50 值范围为 0.05 - 3.1 pM。与具有传统的“1:1”基于 IgG 的格式（即，一个 CD20 的结合域和一个用于 CD20 的结合域和一个CD3）。CD20 TCB 介导的肿瘤溶解导致 T 细胞活化、增殖和细胞因子释放，肿瘤溶解后程序性死亡 1 (PD-1)/程序性死亡配体 1 (PD-L1) 轴上调。CD20 TCB 在 NHL 和 CLL 患者（n = 17）的全骨髓穿刺样本中也显示出有效的离体活性。这种原发肿瘤样本保留了天然肿瘤微环境，并且在本研究中具有较低的效应细胞与靶细胞比率，范围为 0.02 至 0.8（平均值为 0.3）。CD20 TCB 活性始终优于“1:1”CD20 TCB 的活性，并且表现出更快、更深刻和更有效的 B 细胞消耗，EC50 值范围为 0.002 至 2.7 nM。在体内，CD20 TCB 在干细胞人源化小鼠的异种移植模型中显示出有效的抗肿瘤活性，并诱导大的侵袭性 WSU-DLCL2 淋巴瘤肿瘤消退（0.5 mg/kg，每周给药）。除了肿瘤消退，CD20 TCB 治疗导致在首次给药后 24 小时内快速完全消除外周血 B 细胞（0.05、0.15 和 0.5 mg/kg，每周给药），并完全消除脾脏、骨髓和淋巴结中的 B 细胞两次执政后。B 细胞耗竭与外周血中 T 细胞计数的短暂减少和首次给药后 24 小时细胞因子释放达到峰值平行，随后快速恢复并在治疗后 72 小时恢复到基线水平。CD20 TCB 介导的肿瘤生长抑制伴随着肿瘤内 T 细胞浸润的增加、T 细胞上的 PD-1 受体和肿瘤中的 PD-L1 的上调。CD20 TCB 与 PD-L1 阻断抗体的联合研究导致了更深刻和更快的肿瘤生长抑制。综合起来，临床前数据表明，CD20 TCB 是一种新型分化的 CD20 靶向 T 细胞双特异性抗体，具有良好的抗肿瘤活性和修饰肿瘤微环境的能力。与具有传统“1:1”IgG 格式的其他 CD20 TCB 相比，CD20 TCB 始终表现出卓越的效力。这转化为体外、离体和体内的卓越功效，这是增加“1:1”TCB 剂量无法比拟的。该分子现在计划于 2016 年 12 月开始临床试验。披露 Bacac:Roche：就业、股权、专利和特许权使用费。Umana:Roche：就业、股权、专利和特许权使用费。Herter:Roche：就业、专利和特许权使用费。Colombetti：罗氏：就业。山姆：罗氏：就业。Le Clech：罗氏：就业。Freimoser-Grundschober:Roche: 就业。理查德：罗氏：就业。Nicolini：罗氏：就业。Gerdes：罗氏：就业。拉里维埃：罗氏：就业。诺依曼：罗氏：就业。克莱因：罗氏：就业、专利和特许权使用费。

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CD20 Tcb (RG6026), a Novel "2:1" T Cell Bispecific Antibody for the Treatment of B Cell Malignancies

Despite the recent advancements in treatment options with the introduction of anti-CD20 monoclonal antibody therapy, approximately 50% of patients with non-Hodgkin9s lymphomas (NHL) will not sustain a durable response to standard of care (SOC) treatment. Thus, there remains a continuous need for safer and more effective anti-cancer therapies in this indication. T-cell bispecific antibodies (TCBs) represent a new class of disease targeting agents shown to promote the activation of a patient9s own T cells to attack and kill cancer cells. CD20 TCB is a new bispecific antibody with IgG-like pharmacokinetic properties whose unique "2:1" structure leads to increased tumor antigen avidity, T cell activation, and tumor cell killing, as compared to other T cell engaging bispecific antibody molecular formats. The molecule comprises two CD20 binding Fabs (derived from the Type II CD20 IgG1 obinutuzumab), one CD3e binding Fab (fused to one of the CD20 Fabs via a short flexible linker), and an engineered, heterodimeric Fc region with completely abolished binding to FcgRs and C1q. In vitro, CD20 TCB was shown to dose-dependently induce tumor lysis with EC50 values in the range of 0.05 - 3.1 pM. The "2:1"format of CD20 TCB was shown to confer superior potency (up to 10 - 1000x) when compared to CD20 TCBs having the conventional "1:1" IgG-based format (i.e., one binding domain for CD20 and one for CD3). CD20 TCB-mediated tumor lysis resulted in T-cell activation, proliferation and cytokine release with up-regulation of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis upon tumor lysis. CD20 TCB also demonstrated potent ex vivo activity in whole bone marrow aspirate samples of NHL and CLL patients (n=17). Such primary tumor samples preserve the native tumor microenvironment and bear low effector to target cell ratios ranging in this study from 0.02 to 0.8 (average value 0.3). CD20 TCB activity was consistently superior to that of the "1:1" CD20 TCB and demonstrated faster, more profound and more potent B cell depletion with EC50 values ranging from 0.002 to 2.7 nM. In vivo, CD20 TCB displayed potent anti-tumor activity in xenograft models in stem cell humanized mice and induced regression of large, aggressive WSU-DLCL2 lymphoma tumors (0.5 mg/kg, weekly administration). In addition to tumor regression, CD20 TCB treatment led to fast and complete elimination of peripheral blood B cells within 24 h after the first administration (0.05, 0.15 and 0.5 mg/kg, weekly administration) and to a complete elimination of B cells in spleen, bone marrow and lymph nodes after two administrations. B cell depletion was paralleled by transient decrease of T-cell counts in the peripheral blood and by the peak of cytokine release 24 h after the first administration, followed by rapid recovery and return to baseline levels at 72 h post treatment. Tumor growth inhibition mediated by CD20 TCB was accompanied by increase in intra-tumor T-cell infiltration, up-regulation of PD-1 receptor on T cells and PD-L1 in the tumor. Combination studies of CD20 TCB with PD-L1 blocking antibody led to more profound and faster tumor growth inhibition. Taken together, the preclinical data show that CD20 TCB is a novel differentiated CD20-targeting T cell bispecific antibody with promising anti-tumor activity and the ability to modify the tumor microenvironment. CD20 TCB consistently demonstrated superior potency compared to other CD20 TCBs with a conventional "1:1" IgG format. This translated into superior efficacy in vitro, ex-vivo and in vivo, which could not be matched by increasing doses of the "1:1" TCBs. The molecule is now scheduled to start clinical trial by December 2016. Disclosures Bacac:Roche: Employment, Equity Ownership, Patents & Royalties. Umana:Roche: Employment, Equity Ownership, Patents & Royalties. Herter:Roche: Employment, Patents & Royalties. Colombetti:Roche: Employment. Sam:Roche: Employment. Le Clech:Roche: Employment. Freimoser-Grundschober:Roche: Employment. Richard:Roche: Employment. Nicolini:Roche: Employment. Gerdes:Roche: Employment. Lariviere:Roche: Employment. Neumann:Roche: Employment. Klein:Roche: Employment, Patents & Royalties.

更新日期：2016-12-02

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