A Technology Platform for Next Generation VNAR Based Oncology Medicines

“尽管癌症患者的预后有了显著改善，但仍有35%的患者会死于这种疾病。一线化疗治疗通常依赖于快速生长的癌症的敏感性，其比“正常”健康细胞更容易受到毒性剂的影响。这种治疗令人不快的副作用以及不良的预后意味着迫切需要新的靶向治疗方法来改善患者的健康。迄今为止的发展包括将药物靶向递送到癌细胞，作为限制对健康组织的毒副作用的一种方式。基于单克隆抗体的靶向治疗已经取得了一些成功。然而，它们的“杀伤力”对较大的实体瘤可能无效。为了提高它们的效力，肿瘤靶向抗体已经与高效细胞毒性药物结合，并且抗体已经被改造成同时靶向两种不同的癌症蛋白质，以提高肿瘤选择性。虽然这些抗体药物缀合物（ADC）和双特异性抗体方法显示出前景，但抗体的大尺寸和复杂性限制了它们的肿瘤穿透能力和工程化治疗改进的能力。此外，制造成本和脱靶副作用仍然是这些药剂的显著问题。因此，使用具有改善的肿瘤渗透性、增加的稳定性和较小的毒性的“较小”蛋白质治疗剂的下一代方法具有很大的前景。该项目的目的是建立一个平台技术，用于加速开发和优化基于鲨鱼中发现的抗体样单域受体（VNARs）的新型肿瘤药物鲨鱼VNAR结构域是动物界中最小的天然存在的抗原结合结构域，并且它们的性质对于癌症治疗是潜在有利的。在Almac Discovery和Elasmogen之间的初步合作中，我们已经证明可以产生针对肿瘤靶点的高亲和力VNAR，并且可以使用Almac Discovery开发的生物缀合技术对这些VNAR进行位点特异性修饰。目的是通过结合Elasmogen在VNAR蛋白产生和筛选方面的专业知识，Almac Discovery在蛋白质工程和肿瘤药物发现方面的专业知识。其理念是开发一个模块化的VNAR“即插即用”平台，以加速创新VNAR癌症药物的开发。成功开发一种平台技术，可以克服全长抗体的局限性，快速提供VNAR治疗候选药物，提高疗效，将使这些下一代方法的全部潜力得以实现，并显着改善人类健康。"

"Despite marked improvements in outcomes for cancer patients, 35% will succumb to the disease. First line chemotherapy treatments generally rely on the sensitivity of fast-growing cancers being more susceptible to toxic agents than ""normal"" healthy cells. The unpleasant side-effects of this treatment, together with a poor prognosis means there is an urgent need for new targeted therapeutics to improve patient health. Developments to-date have included the targeted delivery of drugs to cancer cells as a way of limiting toxic side effects on healthy tissues. Targeted therapies based on monoclonal antibodies have been used with some success. However, their ""killing power"" can be ineffective against larger solid tumours.To ramp-up their potency, tumour targeting antibodies have been conjugated with highly potent cytotoxic drugs, and antibodies have been engineered that simultaneously target two different cancer proteins in order to improve tumour selectivity. Whilst these antibody drug conjugates (ADCs) and bi-specific antibody approaches show promise, the large size and complexity of antibodies limits their tumour penetrating ability and the ability to engineer therapeutic improvements. Furthermore, the cost of manufacture and off-target side effects are still significant problems for these agents. Consequently, next generation approaches using 'smaller' protein therapeutics with improved tumour penetration, increased stability and less toxicity hold great promise.To meet this challenge, the aim of this project is to build a platform technology for the accelerated development and optimisation of novel oncology medicines based on antibody-like single domain receptors found in sharks (VNARs).Shark VNAR domains are the smallest naturally occurring antigen binding domain in the animal kingdom and their properties are potentially advantageous for cancer therapy. In an initial collaboration between Almac Discovery and Elasmogen, we have shown that high affinity VNARs can be generated to an oncology target and that these VNARs can be site-specifically modified using a bio-conjugation technology developed by Almac Discovery.The aim is to build on this initial proof-of-concept research by combining Elasmogen's expertise in the generation and screening of VNAR proteins, with Almac Discovery's expertise in protein engineering and oncology drug discovery. The idea is to develop a modular VNAR ""plug-and-play"" platform for the accelerated development of innovative VNAR cancer drugs.Successful development of a platform technology that can overcome the limitations of full-length antibodies, and rapidly deliver VNAR therapeutic candidates with improved efficacy, will enable the full potential of these next-generation approaches to be realised and significantly improve human health."