Inhibition of heteromeric erbB kinases

异聚 erbB 激酶的抑制

• 批准号: 8245001
• 负责人: MARK I GREENE
• 金额: $ 33.85万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245001
• 关键词: Affinity; Antibodies; Binding; Biological; Cancer cell line; Cell Line; Cells; Clinical; Clinical Research; Complementarity Determining Regions; Complex; Coupling; Cyclic Peptides; Cysteine-Rich Domain; Development; Dimerization; Disease; ERBB2 gene; ERBB3 gene; Engineering; Epidermal Growth Factor Receptor; Epitopes; Family; Fc Immunoglobulins; Fc Receptor; Fc domain; Future; Half-Life; Human; Immunoglobulin G; Immunoglobulin Variable Region; In Vitro; Injection of therapeutic agent; Lead; Light; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Membrane; Modeling; Monitor; Mus; Mutagenesis; Mutation; Oncogene Proteins; Oncogenic; Peptide Fragments; Peptide Receptor; Peptides; Phage Display; Phenotype; Phosphotransferases; Process; Property; Resistance; Risk; Roche brand of trastuzumab; Role; Structure; System; Therapeutic; Therapeutic antibodies; Tyrosine Kinase Inhibitor; Work; Xenograft procedure; antibody engineering; antibody-dependent cell cytotoxicity; base; cancer therapy; cell transformation; cross reactivity; design; dimer; erbB Genes; humanized antibody; improved; improved functioning; in vivo; innovation; malignant breast neoplasm; malignant phenotype; member; mimetics; neoplastic cell; new therapeutic target; novel; public health relevance; receptor; receptor binding; receptor function; small molecule; therapy resistant; tumor; tumor growth; vector

DESCRIPTION (provided by applicant): Our work has been concerned with cancer therapy that targets HER oncoproteins. Our efforts on antibody development have focused on understanding the dominant role of CDR3 heavy chain regions and cross reactivity at the atomic level. We have discovered a new antibody set, 8A4, that is cross-reactive with 2 members of the HER family and interacts even better with dimeric forms of HER2. The antibody disables the malignant phenoytpe of both EGFR transformed, HER2 transformed, and dual EGFR-HER2 heteromeric transformed cells. We will perform affinity maturation and mutation of the 8A4 antibody variable region. Since HER3 and EGFR share similar structural features, we will also examine if we can expand reactivity to HER3 epitopes through light chain mutagenesis to create a tri-reactive MAb. The Fv region of this antibody will be humanized and recombinantly expressed as an intact IgG molecule containing the human Fc region. Such a humanized antibody can be used for future clinical studies in cancers resistant to targeted therapies. HER kinase receptor switching of dimer partners occurs; and cancer resistance can emerge by sequential activities of different HER heteromeric species, HER2-HER2 and then HER2-HER3, for example; and this type of dual or tri-reactive therapeutic will limit that process. In addition, we will combine two subregions of different receptor families. We will use a fragment of human HER2 that is structurally like a CDR and link it to human Fc fragments. Our studies with HER2 receptor peptide mimetics have led to the creation of a receptor derived S22 CDR-like cyclic peptide that binds to EGFR, HER2, and HER3 ectodomains. This molecule can reverse the malignant phenotype in vitro but would require frequent injections in vivo to reduce tumor growth. To extend the therapeutic half-life of S22 CDR, we will engineer a small antibody-like form created by fusing the S22 CDR onto Fc domains. This small novel form will penetrate tumor masses efficiently. Because of its structure it should promote ADCC by preferential interactions with stimulatory Fc Receptors. This novel species should disable EGFR- HER2, HER2-HER3, or EGFR-HER3 complexes and tumor cells expressing them. These efforts are highly innovative and of moderate risk. If successful, new therapeutics for targeted therapy resistant forms of human breast cancer disease will be developed. PUBLIC HEALTH RELEVANCE: We are developing new classes of antibody therapeutics to treat breast cancers that have become resistant to therapeutics such as Herceptin or tyrosine kinase inhibitors.

描述（由申请人提供）：我们的工作一直关注针对她的癌蛋白的癌症疗法。我们在抗体开发方面的努力集中在理解CDR3重链区域的主要作用和在原子水平上的交叉反应性。我们发现了一种新的抗体集8A4，它与她的两个家庭成员进行了交叉反应，并与HER2的二聚体形式更好地互动。该抗体禁用EGFR转化，HER2转化和双EGFR-HER2异构转化细胞的恶性肿瘤。我们将执行8A4抗体可变区域的亲和力成熟和突变。由于HER3和EGFR具有相似的结构特征，因此我们还将检查是否可以通过轻链诱变对HER3表位扩大反应性，从而产生三反反应的mAb。该抗体的FV区域将被人性化并重组表示为包含人FC区域的完整IgG分子。这种人源化抗体可用于抗靶向疗法的癌症的未来临床研究。她的激酶受体转换二聚体伴侣发生。例如，通过不同异源物种HER2-HER2，然后是HER2-HER3的顺序活性，可以出现癌症的耐药性；而且这种类型的双重或三反应治疗将限制该过程。 此外，我们将结合不同受体家族的两个子区域。我们将使用像CDR一样结构上的人类HER2片段，并将其链接到人类FC碎片。我们对HER2受体肽模拟物的研究导致了受体衍生的S22 CDR样环肽的受体，该肽与EGFR，HER2和HER3胞外域结合。该分子可以在体外逆转恶性表型，但需要经常注射体内以减少肿瘤生长。为了扩展S22 CDR的治疗半衰期，我们将通过将S22 CDR融合到FC域上产生的小型抗体样形式。这种小型新型形式将有效地穿透肿瘤肿块。由于其结构，它应该通过优先与刺激FC受体相互作用来促进ADCC。这种新型物种应禁用EGFR-HER2，HER2-HER3或EGFR-HER3复合物和表达它们的肿瘤细胞。 这些努力具有高度创新性和中等风险。如果成功，将开发针对靶向治疗形式的人类乳腺癌疾病的新疗法。 公共卫生相关性：我们正在开发新的抗体疗法类别，以治疗对诸如赫赛汀或酪氨酸激酶抑制剂等治疗疗法具有抗药性的乳腺癌。