Targeting lymphoma with modular anti-idiotype peptibodies

目前治疗非霍奇金淋巴瘤(NHL)的方法最初对大多数患者有效，但结果是 在反复使用的疗效和累积毒性降低以及大多数患者复发和 屈从于进行性疾病(1)。一种利用新的作用机制的更有针对性的疗法将 这是一种受欢迎的补充，可用于管理这种疾病的治疗方法。 大多数NHL肿瘤起源于B细胞的克隆性群体。互补性 表面免疫球蛋白受体的决定区域(CDR)，也称为独特型，几乎是相同的 在B细胞淋巴瘤的所有恶性细胞上，并且与非恶性B细胞上存在的独特型不同。 因此，独特型是一种真正的肿瘤特异性表面标志物，是靶向癌症治疗的一个有吸引力的候选者。 抗独特型抗体已被证明可以诱导患者淋巴瘤的完全消退(3)。但 由于每个患者癌症的独特型是独一无二的，这种治疗方法需要产生一种 为每个患者定制的单抗-这一要求提高了技术和实践障碍， 禁止这种方法的广泛翻译。 我们正在开发一种针对独特型的方法，这种方法可能更适合规模化。短肽 独特型的靶向亲和力可以通过高通量筛选来鉴定，快速生产和 通过自动化固相合成，成本低廉，并可在体外直接诱导淋巴瘤细胞凋亡 (4、5)。尽管这些多肽在动物模型中似乎是劣质药物，但将它们贴在氨基末端 通过延长其药代动力学半衰期和通过 通过激活天然免疫效应机制增强其抗肿瘤作用。自.以来 患者特有的部分将是一个短的合成肽，生物Fc结构域将在 对于所有患者来说，这种方法可能比生产独特的生物克隆更实用 每个病人的抗体。 我们假设这种半合成的结构，我们称之为“模块多肽”，将是 足以在小鼠模型系统中清除人淋巴瘤异种移植瘤。

Current therapies for non-hodgkin lymphoma (NHL) are initially effective for most patients but result in diminished efficacy and cumulative toxicity with repeated use and the majority of patients relapse and succumb to progressive disease (1). A more targeted therapy that utilizes a novel mechanism of action would be a welcome addition to the arsenal of therapies available for management of this disease. The majority of NHL tumors arise from a clonal population of B-cells. The complementarity determining region (CDR) of the surface immunoglobulin receptor, also known as idiotype, is nearly identical on all malignant cells in B-cell lymphomas and is distinct from the idiotype present on non-malignant B-cells. Thus, idiotype is a true tumor-specific surface marker and an attractive candidate for targeted cancer therapy. Antibodies against idiotype have been shown to induce complete regression of lymphoma in patients (3). But since the idiotype on each patient's cancer is unique, this therapeutic approach requires the generation of a custom monoclonal antibody for each patient - a requirement that raises technical and practical barriers that prohibit the widespread translation of this approach. We are developing a method of targeting idiotype that may be more practical to scale. Short peptides with targeted affinity for idiotype can be identified by high throughput screens, produced rapidly and inexpensively by automated solid-phase synthesis, and can directly induce apoptosis of lymphoma cells in-vitro (4, 5). Although these peptides appear to be poor drugs in animal models, affixing them to the amino terminus of an IgG Fc domain might improve their potency by extending their pharmacokinetic half-life and by augmenting their anti-tumor effect through activation of innate immune effector mechanisms. Since the patient-specific portion would be a short synthetic peptide and the biologic Fc domain would be produced in bulk for all patients, this approach may be more practical than producing a unique biologic monoclonal antibody for each patient. We hypothesize that this semi-synthetic construct, that we term a "modular peptibody", will be sufficient for lymphoma tumor clearance of a human lymphoma xenograft in a murine model system.