Inhibition of heteromeric erbB kinases

描述（由申请人提供）：我们的工作涉及靶向HER癌蛋白的癌症治疗。我们在抗体开发方面的努力集中在理解CDR 3重链区的主导作用和原子水平上的交叉反应性。我们已经发现了一种新的抗体集，8A 4，它与HER家族的2个成员交叉反应，并且与HER 2的二聚体形式更好地相互作用。该抗体使EGFR转化细胞、HER 2转化细胞和双重EGFR-HER 2异聚体转化细胞的恶性表型失活。我们将进行8A 4抗体可变区的亲和力成熟和突变。由于HER 3和EGFR具有相似的结构特征，我们还将检查是否可以通过轻链诱变来扩大对HER 3表位的反应性，以产生三反应性MAb。该抗体的Fv区将被人源化并重组表达为含有人Fc区的完整IgG分子。这样的人源化抗体可用于对靶向疗法有抗性的癌症的未来临床研究。HER激酶受体发生二聚体伴侣的转换;癌症抗性可以通过不同HER异聚体种类的顺序活性出现，例如HER 2-HER 2，然后HER 2-HER 3;这种类型的双重或三反应性治疗将限制该过程。 此外，我们将联合收割机两个不同受体家族的亚区。我们将使用在结构上类似于CDR的人HER 2片段并将其连接至人Fc片段。我们对HER 2受体肽模拟物的研究已经导致产生了与EGFR、HER 2和HER 3胞外域结合的受体衍生的S22 CDR样环肽。这种分子可以在体外逆转恶性表型，但需要在体内频繁注射以减少肿瘤生长。为了延长S22 CDR的治疗半衰期，我们将通过将S22 CDR融合到Fc结构域上来设计小抗体样形式。这种小的新形式将有效地穿透肿瘤块。由于其结构，它应该通过与刺激性Fc受体的优先相互作用来促进ADCC。这种新物种应使EGFR-HER 2、HER 2-HER 3或EGFR-HER 3复合物和表达它们的肿瘤细胞失活。 这些努力具有高度创新性，风险不大。如果成功，将开发出针对人类乳腺癌疾病的靶向治疗抗性形式的新疗法。 公共卫生相关性：我们正在开发新的抗体治疗药物，以治疗对赫赛汀或酪氨酸激酶抑制剂等治疗药物产生耐药性的乳腺癌。

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.