Development of therapeutic monoclonal antibody to the bioactive lipid lysophospha

开发针对生物活性脂质溶血蛋白的治疗性单克隆抗体

• 批准号: 7749454
• 负责人: ROSALIA Gerarda MATTEO
• 金额: $ 13.95万
• 依托单位: LPATH THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7749454
• 关键词: Affect; Angiogenic Factor; Antibodies; Apoptosis; Apoptotic; Applications Grants; Ascites; Back; Benign; Biological; Bladder; Blood Vessels; Brain; Cancer Biology; Cancer Patient; Cell Line; Cell Proliferation; Cells; Choroidal Neovascularization; Clinical; Conditioned Culture Media; Cutaneous Melanoma; Data; Development; Diagnosis; Disease; Dose; Drops; Drug Kinetics; Edg-7 Receptor; Edg4 Protein; Enzymes; Epithelium; Extracellular Matrix; Goals; Growth; Growth Factor Receptors; Human; IL8 gene; Incidence; Interleukin-6; Interleukin-8; Kidney; Lead; Lipids; Liquid substance; Liver; Lysophosphatidic Acid Receptors; Lysophospholipids; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Metalloproteases; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Multiple Myeloma; Mus; Mutation; Neoplasm Metastasis; Non-Hodgkin' s Lymphoma; Oncogenes; Ovarian; Paclitaxel; Pancreas; Pathology; Patients; Peritoneal Fluid; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Porifera; Positioning Attribute; Pre-Clinical Model; Production; Quality of life; Relapse; Reporting; Research; Resistance; Safety; Serum; Signal Transduction; Small Business Innovation Research Grant; Societies; Staging; Survival Rate; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; Thyroid Gland; Time; Toxicology; Treatment Protocols; Tumor Volume; Tumor Weights; Up-Regulation; Update; Vascular Endothelial Growth Factors; base; cancer cell; cancer therapy; cell stroma; cellular targeting; chemotherapeutic agent; commercialization; cytokine; design; drug candidate; drug discovery; effective therapy; efficacy testing; extracellular; feeding; humanized monoclonal antibodies; improved; in vitro Assay; in vivo; leukemia; lysophosphatidic acid; matrigel; melanoma; mortality; neoplastic cell; neovascularization; novel; novel therapeutics; ovarian neoplasm; overexpression; public health relevance; response; standard care; trend; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Ovarian cancer is associated with a poor overall survival due to the advanced stage of the disease at the time of diagnosis and the high incidence of acquired resistance to standard treatments. Identification of the major determinants of ovarian cancer progression and the development of more efficacious treatments still remain challenging. Lysophosphatidic acid (LPA) has been associated with multiple aspects of ovarian cancer biology including malignant transformation of ovarian epithelium, tumor progression and metastasis. In ovarian tumorigenesis, LPA receptors profiling changes dramatically and the aberrant overexpression of two of those ones, LPA2 and LPA3, is associated to the passage from the benign to the malignant stage of the pathology. LPA induces VEGF upregulation, activation of metalloproteinases (MMP), overexpression of growth factor receptors, and production of both pro-angiogenic and pro-metastatic cytokines such as interleukin-8 (IL-8) and interleukin-6 (IL-6). LPA not only modulates tumor cell responses but also influences cellular and molecular cross- talk among cancer cells, stroma, vascular and extracellular matrix components present in the tumor microenvironment. LPA is elevated in sera and ascites fluid of patients with early and late stage disease. Based on this evidence, LPA and its signaling network represent attractive molecular and cellular targets for rational drug discovery in the treatment of ovarian cancer. We have developed a humanized monoclonal antibody that specifically recognizes LPA, designated as LT3015, and neutralizes biological actions of the lipids on its cognate GPCRs. We hypothesize that our anti-LPA antibody could be used as a molecular sponge to selectively absorb LPA, thus lowering the effective extracellular levels of this tumorigenic, pro-angiogenic and metastatic agent in the tumor microenvironment. It is anticipated that neutralizing LPA would result in the reduction of tumor weights and metastatic potential as well as blocking the neovascularization that would otherwise feed the growing tumor. We also hypothesize that the ability of LPA to protect cells from apoptosis could be reversed by the anti-LPA mAb, thus increasing the efficacy of standard pro-apoptotic chemotherapeutic agents. Preliminary studies with the murine anti-LPA antibody, Lpathomab, have shown efficacy tested in a panel of relevant in vitro assays using the ovarian cell line SKOV3. Lpathomab blocked tumor cell migration and invasion triggered by LPA, reduced cytokines release in tumor conditioned media, and blocked LPA mediated protection from apoptosis triggered by the chemotherapeutic drug, taxol. More importantly, Lpathomab retarded the progression of orthotopically placed SKOV3 tumor cells, reduced neovascularization in two classical angiogenic models (Matrigel plug and choroid neovascularization models) and showed preliminary anti-metastatic activity when tested in the B16-F10 melanoma metastasis model. For this proposal, we intend to demonstrate the efficacy of the humanized anti-LPA mAb, designated as LT3015, alone and in combination with the standard chemotherapeutic agent, Taxol, in a murine model of human ovarian cancer (SKOV3). We will determine the optimal dosing regimen for LT3015 to inhibit ovarian cancer progression as well as ovarian tumor metastasis by using a well established LPA2 receptor overexpressing-SKOV3 metastasis model. In moving towards commercialization of LT3015, we will perform toxicology and pharmacokinetics studies to determine the suitability of LT3015 as a clinical drug candidate. In view of these results, we hypothesize that the anti-LPA antibody-based neutralization of LPA may offer the potential to augment the efficacy of current ovarian cancer therapy by blocking the growth-promoting, angiogenic and metastatic effects of LPA generated either by ovarian cancer cells or the tumor microenvironment. PUBLIC HEALTH RELEVANCE: Cancer is a devastating disease, with the second highest mortality in the US. As described in the Cancer Trends Report update 2007, the incidences of cancers such as liver, pancreas, kidney, thyroid, brain, bladder and skin melanoma as well as new cases of non-Hodgkin lymphoma, leukemia, myeloma, and childhood cancers have continue to rise in past years. Late state of disease at the first diagnosis, resistance to standard treatment, relapsing cases and, finally, tumor metastasis represent the major problems occurring in the treatment of cancer patients. In particular, once the disease becomes metastatic, survival rates drop significantly due to a lack of effective therapy. Thus, urgent needs exist for novel anti-cancer therapies that will improve quality of life as well as offering a potential cure. Discovering the major determinants in cancer progression for the development of more efficacious therapies is therefore extremely important to society.

说明(申请人提供)：卵巢癌患者在确诊时处于晚期，总体存活率较低，且对标准治疗的获得性抵抗力较高。确定卵巢癌进展的主要决定因素和开发更有效的治疗方法仍然具有挑战性。溶血磷脂酸(LPA)与卵巢癌生物学的多个方面有关，包括卵巢上皮细胞的恶性转化、肿瘤的进展和转移。在卵巢肿瘤的发生过程中，LPA受体的构型发生了显著变化，其中两种受体LPA2和LPA3的异常过表达与卵巢肿瘤从良性向恶性转化有关。LPA可诱导血管内皮生长因子表达上调，金属蛋白酶激活，生长因子受体过度表达，促进血管生成和转移的细胞因子的产生，如白介素8和白介素6。LPA不仅调节肿瘤细胞的反应，还影响肿瘤微环境中存在的癌细胞、间质、血管和细胞外基质成分之间的细胞和分子串扰。LPA在早期和晚期疾病患者的血清和腹水中升高。基于这一证据，LPA及其信号网络是治疗卵巢癌的合理药物发现的有吸引力的分子和细胞靶点。我们已经开发出一种人源化的单抗，它能特异性识别LPA，命名为LT3015，并中和脂类对其同源GPCRs的生物学作用。我们假设我们的抗LPA抗体可以作为分子海绵选择性地吸收LPA，从而降低这种致癌、促血管生成和转移因子在肿瘤微环境中的有效细胞外水平。预计中和LPA将导致肿瘤重量和转移潜能的减少，并阻止新生血管的形成，否则将滋养不断生长的肿瘤。我们还假设，LPA保护细胞免受凋亡的能力可以被抗LPA单抗逆转，从而增加标准促凋亡化疗药物的疗效。对小鼠抗LPA抗体Lpathomab的初步研究表明，在使用卵巢细胞株SKOV3进行的一系列相关体外测试中，该抗体具有疗效。Lpathomab阻断了LPA引发的肿瘤细胞迁移和侵袭，减少了肿瘤条件培养液中细胞因子的释放，并阻断了LPA对化疗药物紫杉醇引发的细胞凋亡的保护作用。更重要的是，Lpathomab延缓了原位放置的SKOV3肿瘤细胞的进展，减少了两种经典血管生成模型(Matrigel Plug和脉络膜新生血管模型)中的新生血管，并在B16-F10黑色素瘤转移模型中显示出初步的抗转移活性。对于这项建议，我们打算证明人源化的抗LPA单抗，命名为LT3015，单独和联合标准化疗药物紫杉醇，在人卵巢癌小鼠模型(SKOV3)中的疗效。我们将利用LPA2受体过度表达-SKOV3转移模型来确定LT3015抑制卵巢癌进展和卵巢肿瘤转移的最佳给药方案。在LT3015走向商业化的过程中，我们将进行毒理学和药代动力学研究，以确定LT3015是否适合作为临床候选药物。鉴于这些结果，我们推测，基于抗LPA抗体的LPA中和可能通过阻断LPA在卵巢癌细胞或肿瘤微环境中产生的促进生长、血管生成和转移的作用来提高当前卵巢癌治疗的疗效。与公共健康相关：癌症是一种毁灭性的疾病，死亡率在美国排名第二。如《癌症趋势报告》2007年更新版所述，过去几年，肝癌、胰腺癌、肾癌、甲状腺癌、脑黑色素瘤、膀胱癌和皮肤黑色素瘤等癌症的发病率以及非霍奇金淋巴瘤、白血病、骨髓瘤和儿童癌症的新病例持续上升。在癌症患者的治疗中，初诊时疾病的晚期状态、对标准治疗的抵抗力、复发病例以及最后的肿瘤转移是主要问题。特别是，一旦疾病转移，由于缺乏有效的治疗，存活率会显著下降。因此，迫切需要新的抗癌疗法，既能提高生活质量，又能提供潜在的治疗方法。因此，发现癌症进展的主要决定因素，以开发更有效的治疗方法，对社会极其重要。