Exploring CD38 molecular biology and imaging in multiple myeloma pathogenesis

多发性骨髓瘤（MM）是第二常见的年龄相关的血液恶性肿瘤，估计 每年有30，000例新病例和13，000例死亡。前期难治性疾病的患者进展迅速， 进入缓解期的患者最终死于复发性疾病。为了提高患者生存率，临床医生 需要为复发性和难治性MM患者选择有效和持久的治疗方法。抗体 (Ab)基于靶向分化簇38（CD 38）的治疗， 在MM细胞中表达，是复发性和难治性MM患者的有希望的疗法。目前，有三个 MM患者临床中的CD 38靶向单克隆抗体（mAb）、达雷妥尤单抗、isatuximab和莫尔-202。 这些抗体安全、耐受性良好，在约30%的骨髓瘤患者中显示出显著疗效。尚不清楚 为什么大多数剩余的患者对CD 38靶向mAb治疗没有反应，以及为什么有这样的 患者之间的差异。在功能上，CD 38是一种多效性抗原，其充当酶以及免疫调节剂。 受体的CD 38的胞外酶组分负责烟酰胺的代谢 腺嘌呤二核苷酸（NAD）与下游Ca 2+信号分子的相互作用。越来越多的证据表明， MM细胞中CD 38靶向治疗反应的变化可能在很大程度上归因于其NAD的变化。 酶活性在这里，我们认为，虽然CD 38表达是重要的，监测CD 38酶， 与时空成像一致的活动是将MM反应与CD 38靶向治疗联系起来的关键。我们 我建议使用正电子发射断层扫描（PET）来解决这个问题，PET是一种强大的分子成像技术。 成像工具，可以直接应用于定量受体表达和功能活性在体内，非- 破坏性的纵向的我们已经表明，MM细胞上CD 38抗原的PET成像是可行的， 放射性标记的CD 38 mAb达雷妥尤单抗。然而，这种方法的局限性在于Ab不适合于 由于其生物半衰期长，因此可用于纵向成像研究。基于高亲和力肽的小分子 成像剂可以有效地克服这些局限性，因为它们被肿瘤组织迅速吸收， 在体内迅速从非靶器官清除。尽管需求未得到满足，但缺乏CD 38 针对MM的基于小分子肽的PET探针。使用创新的噬菌体展示技术，我们将 开发新的基于CD 38靶向肽的PET成像探针，其对酶促活化的CD 38具有特异性 构象此外，在高度相关的生物系统中，我们也将评估分子途径 作为空间关系，支配MM相关的CD 38表达。具体目标是：（1）目标1a。识别 并验证CD 38靶向治疗前后CD 38表达和酶活性的变化， MM的人小鼠模型。基于PET成像评价时空CD 38表达。（二） 目标2.开发、评估和优化新型高亲和力CD 38靶向肽PET探针。 总之，目前的提案是创新的，具有潜在的临床变革性，因为它旨在确定 对抗CD 38单克隆免疫治疗最敏感和最耐药的MM患者。

Multiple myeloma (MM) is the 2nd most common, age related, hematological malignancy with an estimated 30,000 new cases and 13,000 deaths per year. Patients with upfront refractory disease progress fast, and those that enter remission eventually die as a consequence of relapsed disease. To increase patient survival, clinicians need new ways of selecting effective and durable therapies for relapsed and refractory MM patients. Antibody (Ab) based treatments that target cluster of differentiation 38 (CD38), a transmembrane protein consistently expressed in MM cells, is a promising therapy for relapsed and refractory MM patients. Currently, there are three CD38 targeted monoclonal Abs (mAbs) in the clinic for MM patients, daratumumab, isatuximab and MOR-202. These Abs are safe, well tolerated and show remarkable efficacy in ~30% of myeloma patients. It is unknown why the majority of remaining patients do not respond to CD38 targeted mAb therapy and why there is such variability between patients. Functionally, CD38 is a pleiotropic antigen that acts as an enzyme as well as a receptor. The extracellular enzymatic component of CD38 is responsible for the metabolism of nicotinamide adenine dinucleotide (NAD) to downstream Ca2+ signaling molecules. There is growing evidence that variability in CD38 targeted therapy response in MM cells could in large part be contributed to the changes in its NAD enzymatic activity. Here, we posit that while CD38 expression is important, the monitoring of CD38 enzymatic activity in concert with spatiotemporal imaging is key to linking MM response to CD38 targeted therapies. We propose to address this question using Positron Emission Tomography (PET), which is a powerful molecular imaging tool that can be directly applied to quantify receptor expression and functional activity in vivo, non- destructively and longitudinally. We have shown that PET imaging of CD38 antigen on MM cells is feasible using the radiolabeled CD38 mAb daratumumab. A limitation of this approach however is that Abs are not suited for longitudinal imaging studies due to their long biological half-life. High-affinity peptide based small molecule imaging agents can effectively overcome these limitations since they are rapidly taken up by tumor tissue while being promptly cleared from non-target organs in vivo. Despite the unmet need, there is a paucity of CD38 targeted small molecule peptide based PET probes for MM. Using innovative phage display technology, we will develop new CD38 targeted peptide-based PET imaging probes that are specific for enzymatically activate CD38 conformation. Furthermore, in highly relevant biological systems, we will evaluate molecular pathways as well as spatial relationships that govern MM-associated CD38 expression. The specific aims are: (1) Aim 1a. Identify and validate changes in CD38 expression and enzymatic activity before and after CD38 targeted therapies in human mouse models of MM. Aim 1b. Evaluate spatiotemporal CD38 expression based on PET imaging. (2) Aim 2. Develop, evaluate and optimize novel high affinity CD38 targeted peptide PET probes. In summary, the current proposal is innovative and potentially clinically transformative since it seeks to identify those MM patients who are most sensitive and most resistant to anti-CD38 monoclonal immunotherapy.