Characterization of a GPCR-blocking antibody for the treatment of breast cancer.

用于治疗乳腺癌的 GPCR 阻断抗体的表征。

• 批准号: 8199615
• 负责人: Garret Guenther
• 金额: $ 16.7万
• 依托单位: EXPRESSION DRUG DESIGNS, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8199615
• 关键词: Acute; Affect; Affinity; American; Animals; Antibodies; Antineoplastic Agents; Binding; Biochemical; Biological; Biological Assay; Biological Availability; Blocking Antibodies; Blood; Blood Vessels; Bradycardia; Breast Cancer Cell; Breast Cancer Treatment; Cardiac; Cardiotoxicity; Cardiovascular system; Cause of Death; Cell Surface Receptors; Cell Survival; Cell physiology; Cells; Data; Development; Diagnosis; Disease; Dose; Drug Delivery Systems; Drug Design; Drug Kinetics; Drug resistance; Enzyme-Linked Immunosorbent Assay; Family; Family member; Funding; Future; G-Protein-Coupled Receptors; Goals; Growth; H218 Protein; Human; In Vitro; Individual; Inhibitory Concentration 50; Life; Ligands; Lipids; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediating; Methods; Monitor; Monoclonal Antibodies; Mus; Nutrient; Oxygen; Pathologic Neovascularization; Pharmaceutical Preparations; Phase; Process; Property; Receptor Activation; Reporting; Request for Applications; Research; Resistance; Role; Safety; Screening procedure; Serum; Signal Transduction; Small Business Innovation Research Grant; Specificity; Staging; Therapeutic; TimeLine; Tissues; Validation; Woman; Work; Xenograft procedure; aptamer; cancer cell; chemotherapy; design; drug development; edg-1 Protein; extracellular; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; hormone therapy; improved; in vivo; insight; killings; malignant breast neoplasm; migration; mortality; novel; outcome forecast; pre-clinical; preclinical study; prevent; receptor; response; small molecule; sphingosine 1-phosphate; success; tumor; tumor growth; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): G protein-coupled receptors (GPCRs) represent a diverse family of cell surface receptors that mediate important biological responses in nearly all cells. These responses include proliferation, migration, tissue invasion, and cell survival. As such, this large, ~700 member family represents the most attractive single family of drug targets for a variety of diseases including cancer. A great deal of work has been performed in an effort to generate specific pharmacologic antagonists for individual family members, but the success of this approach has been limited by their structural similarity. This has made it difficult to produce suitably selective compounds that are not complicated by off-target effects. One approach that offers the potential for unparalleled specificity is the development of monoclonal antibodies. However, GPCRs have historically been considered intractable to antibody antagonism due to poor antigenicity of critical, exposed, extracellular motifs that must be targeted to block receptor activation. Breast cancer is a physically and emotionally devastating diagnosis affecting over 2.3 million Americans living with the disease and killing over 100 women each day. Although the prognosis for this disease is gradually improving with the continued development of antineoplastic drugs, hormonal therapies, and targeted therapies, many aggressive forms of breast cancer are resistant to chemotherapy and result in a 10% mortality rate within 5 years of diagnosis. A compound known as sphingosine 1-phosphate (S1P) may be a major determinant of the aggressiveness and drug resistance of breast cancer. S1P is a small molecule normally present in high concentrations in the blood that accelerates the progression of breast cancer. It does this by promoting the growth and spreading of cancer cells and by stimulating the formation of new blood vessels, thereby increasing the supply of oxygen and nutrients to the tumor. Evidence suggests that these actions are largely the result of the stimulation of a cognate GPCR for S1P called S1P3. Since S1P has been shown to promote growth of breast cancer cells, and since it causes blood vessels to grow uncontrollably in tumors, it is likely that blocking S1P3 will inhibit the growth of most forms of breast cancer. Animal studies suggest that loss of this receptor is not associated with undesirable effects, providing evidence for the safety of this approach. Until recently, however, there were no reports of any specific antagonists for S1P3. Our previous work (1R43CA132400) resulted in the development of a monoclonal antibody that specifically recognizes S1P3 and blocks its activation. Since this is the first-reported antibody to block a non-cytokine GPCR, it represents a breakthrough in antibody drug development. The goals of this project are to 1) quantitatively validate the functional efficacy of this antibody, and 2) demonstrate its activity and bioavailability in vivo. PUBLIC HEALTH RELEVANCE: Breast cancer is the second most common form of cancer in women causing the death of over 35,000 Americans each year. The proposed research will characterize a new drug developed at Expression Drug Designs that interrupts cellular processes known to promote growth of breast tumors, thus limiting cancer growth. Completion of the proposed project will determine if this new drug is likely to be effective in treating breast tumors.

描述(申请人提供)：G蛋白偶联受体(GPCRs)代表一个不同的细胞表面受体家族，在几乎所有细胞中介导重要的生物反应。这些反应包括增殖、迁移、组织侵袭和细胞存活。因此，这个拥有约700名成员的大家族代表着最具吸引力的单一药物靶标家族，可用于治疗包括癌症在内的各种疾病。人们已经做了大量的工作来为个别家庭成员产生特定的药理拮抗剂，但这种方法的成功受到它们结构相似性的限制。这使得生产不受靶外效应影响的具有适当选择性的化合物变得困难。一种提供无与伦比的特异性的方法是开发单抗。然而，GPCRs历来被认为对抗体拮抗很困难，因为关键的、暴露的细胞外基序的抗原性很差，必须以此为靶点来阻断受体的激活。乳腺癌是一种身体和情感上的毁灭性诊断，每天影响着230多万患有这种疾病的美国人，并导致100多名妇女死亡。尽管随着抗肿瘤药物、激素治疗和靶向治疗的不断发展，乳腺癌的预后正在逐渐改善，但许多侵袭性形式的乳腺癌对化疗具有耐药性，并导致在确诊后5年内死亡率达到10%。一种被称为1-磷酸鞘氨醇(S1P)的化合物可能是乳腺癌侵袭性和耐药性的主要决定因素。S1P是一种小分子，通常存在于血液中，浓度很高，会加速乳腺癌的发展。它通过促进癌细胞的生长和扩散，刺激新血管的形成，从而增加肿瘤的氧气和营养物质的供应来做到这一点。有证据表明，这些行为在很大程度上是被称为S1P3的S1P的同源GPCR刺激的结果。由于S1P已被证明可以促进乳腺癌细胞的生长，而且由于它导致肿瘤中的血管无法控制地生长，因此阻断S1P3很可能会抑制大多数形式的乳腺癌的生长。动物研究表明，这种受体的丢失与不良影响无关，这为这种方法的安全性提供了证据。然而，直到最近，还没有关于S1P3的任何特定拮抗剂的报道。我们之前的工作(1R43CA132400)导致了一种能够特异性识别S1P3并阻断其激活的单抗的开发。由于这是第一个报告的能阻断非细胞因子gpr的抗体，它代表了抗体药物开发的一个突破。本项目的目标是1)定量验证该抗体的功能效力，2)在体内证明其活性和生物利用度。 与公共健康相关：乳腺癌是女性第二常见的癌症，每年导致超过3.5万美国人死亡。这项拟议的研究将描述Expression药物设计公司开发的一种新药的特征，这种新药可以干扰已知的促进乳腺癌生长的细胞过程，从而限制癌症的生长。拟议项目的完成将决定这种新药是否可能在治疗乳腺肿瘤方面有效。