Inhibition of heteromeric erbB kinases

描述(由申请人提供)：我们的工作一直关注针对HER癌蛋白的癌症治疗。我们在抗体开发方面的努力集中在了解CDR3重链区域的主导作用和原子水平的交叉反应。我们发现了一组新的抗体，8A4，它与HER家族的两个成员发生交叉反应，并与HER2的二聚体作用更好。该抗体使EGFR转化细胞、HER2转化细胞和双EGFR-HER2异构体转化细胞的恶性表型失效。我们将对8A4抗体可变区进行亲和成熟和突变。由于HER3和EGFR具有相似的结构特征，我们还将研究是否可以通过轻链突变来扩大对HER3表位的反应性，以创建三反应单抗。该抗体的Fv区将人源化，并重组表达为包含人Fc区的完整免疫球蛋白分子。这种人源化抗体可以用于未来对靶向治疗耐药的癌症的临床研究。例如，HER2-HER2和HER2-HER3等不同的HER异构体的顺序活动可以产生癌症耐药性；这种双重或三反应的治疗将限制这一过程。此外，我们还将结合不同受体家族的两个亚区。我们将使用结构上类似CDR的人类HER2片段，并将其与人类Fc片段联系起来。我们对HER2受体多肽模拟物的研究导致了一种受体衍生的S22 CDR样环肽的产生，它与EGFR、HER2和HER3胞外结构域结合。这种分子在体外可以逆转恶性表型，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结构域上来设计一种类似抗体的小形式。这种小而新颖的形式将有效地穿透肿瘤肿块。由于它的结构，它可能通过与刺激性Fc受体的优先相互作用来促进ADCC。这种新的物种应该会使EGFR-HER2、HER2-HER3或EGFR-HER3复合体和表达它们的肿瘤细胞失效。这些努力具有很高的创新性，风险适中。如果成功，针对靶向治疗抵抗形式的人类乳腺癌疾病的新疗法将被开发出来。

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.