Production of chimeric monoclonal antibodies to Pim1, a novel therapeutic target for cancer treatment

几乎六分之一的男性会在一生中患上前列腺癌。每年大约有10,000名澳大利亚男性被诊断出患有前列腺癌，超过2,500人死于这种疾病，使前列腺癌成为仅次于肺癌的第二大男性癌症死亡原因。在过去的十年里，前列腺癌的研究取得了令人鼓舞的进展。然而，5年生存率仍然很低。迫切需要开发治疗这种疾病的新方法。最近出现了一个令人兴奋的原理，使用单克隆抗体（Mab），如赫赛汀（一种人源抗her2 Mab），现在被广泛用于治疗乳腺癌。我们制备了2个针对Pim1的单抗，在小鼠前列腺癌模型中显著抑制前列腺癌细胞的生长。遗传射线和免疫组化染色显示，Pim1在90%以上的前列腺癌中过表达，但在正常前列腺中不表达或表达较少，是一种新型的癌蛋白，是治疗前列腺癌的生物标志物。Pim1在细胞存活、增殖和转移中起重要作用。Pim1是一个新的靶点，抗Pim1单克隆抗体可能对人类癌症的治疗有价值。然而，由于人体内会产生抗小鼠抗体反应，小鼠单抗不能在人体内重复使用，而且小鼠单抗会迅速退出循环，这极大地限制了单抗的治疗潜力。幸运的是，这个问题可以通过使用混合嵌合抗体来克服。在本研究中，我们将使用嵌合技术将抗pim1单抗人源化，并在体外和小鼠模型中进行临床前研究。我们有专利来保护我们的发现，我们有信心为未来的临床试验生产鼠-人嵌合单克隆抗体，因为我们有适当的知识和技术。我们对未来的临床试验也很乐观，因为我们有商业化的经验。

Almost one in six men will develop prostate cancer during his lifetime. Every year, around 10,000 Australian men are diagnosed and more than 2,500 die of the disease, making prostate cancer the second largest cause of male cancer deaths after lung cancer. The research progress made on prostate cancer over the past 10 years has been encouraging. However the five-year survival rate remains low. There is a vital need to develop new methods to treat this disease. An exciting principle has emerged recently with the use of monoclonal antibodies (Mabs) such as Herceptin (a humanised anti-HER2 Mab), which is now being widely used to treat breast cancer. We produced 2 Mabs to Pim1, which significantly inhibited prostate cancer cell growth in mouse prostate cancer model. Pim1 is a novel oncoprotein, a biomarker for the treatment of prostate cancer as it overexpresses in more than 90% of prostate cancer, but not or less expressed in normal prostate, demonstrated by genearrays and immunohistochemical staining. Pim1 plays an important role in cell survival, proliferation and metastasis. Pim1 is a novel target, and the anti-Pim1 Mabs may be of value for the cancer therapy in humans. However, the murine Mab can not be repeatedly used in human because human would produce anti-mouse antibody response, and the murine Mab would be rapidly removed from circulation, which will greatly limit the therapeutic potential of the Mabs. Fortunately, the problem can be overcome by the use of hybrid chimeric antibodies. In this study, we are going to use chimeric technology to humanise the anti-Pim1 Mab and test them in vitro and in mouse model for the preclinical studies. We have had patent to protect our finding, and we are confident to produce mouse-human chimeric Mab for the future clinical trial as we have proper knowledge, techniques. We are also optimic for the future clinical trial as we have the experiences on commercialisation.