Rationally designed anti-HER2/neu peptide mimetic disables P185HER2/neu tyrosine kinases in vitro and in vivo.
TL;DR: A structure-based derivation of the AHNP represents a novel strategy for the design of receptor-specific tumor therapies for p185HER2/neu-expressing human cancers.
Abstract: Monoclonal antibodies specific for the p185HER2/neu growth factor receptor represent a significant advance in receptor-based therapy for p185HER2/neu-expressing human cancers. We have used a structure-based approach to develop a small (1.5 kDa) exocyclic anti-HER2/neu peptide mimic (AHNP) functionally similar to an anti-p185HER2/neu monoclonal antibody, 4D5 (Herceptin). The AHNP mimetic specifically binds to p185HER2/neu with high affinity (KD=300 nM). This results in inhibition of proliferation of p185HER2/neu-overexpressing tumor cells, and inhibition of colony formation in vitro and growth of p185HER2/neu-expressing tumors in athymic mice. In addition, the mimetic sensitizes the tumor cells to apoptosis when used in conjunction with ionizing radiation or chemotherapeutic agents. A comparison of the molar quantities of the Herceptin antibody and the AHNP mimetic required for inhibiting cell growth and anchorage-independent growth showed generally similar activities. The structure-based derivation of the AHNP represents a novel strategy for the design of receptor-specific tumor therapies.
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TL;DR: Using peptide mapping to determine 'active' antigen recognition residues, molecular modeling, and a molecular dynamics trajectory analysis, a peptide mimic of an anti-CD4 antibody is developed, containing antigen contact residues from multiple CDRs.
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TL;DR: A broad overview of signal transduction networks that are controlled by the EGFR superfamily of receptors in health and disease and its application for target-selective therapeutic intervention is given.
Abstract: Homeostasis of multicellular organisms is critically dependent on the correct interpretation of the plethora of signals which cells are exposed to during their lifespan. Various soluble factors regulate the activation state of cellular receptors which are coupled to a complex signal transduction network that ultimately generates signals defining the required biological response. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases represents both key regulators of normal cellular development as well as critical players in a variety of pathophysiological phenomena. The aim of this review is to give a broad overview of signal transduction networks that are controlled by the EGFR superfamily of receptors in health and disease and its application for target-selective therapeutic intervention. Since the EGFR and HER2 were recently identified as critical players in the transduction of signals by a variety of cell surface receptors, such as G-protein-coupled receptors and integrins, our special focus is the mechanisms and significance of the interconnectivity between heterologous signalling systems.
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TL;DR: The crystal structure of residues 1-509 of ErbB2 reveals an activated conformation similar to that of the EGFR when complexed with ligand and very different from that seen in the unactivated forms ofErbB3 or EGFR.
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TL;DR: This review describes recent advances in the use of CPPs for biological and therapeutic applications and describes the remarkable advancements these peptides have facilitated in cell biology.
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Cites background from "Rationally designed anti-HER2/neu p..."
...This mimetic binds selectively to ErbB2[88], an epidermal growth factor receptor over-expressed in 30% of breast cancers [89]....
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TL;DR: Current therapy has not yet been optimized, allowing for opportunities for optimization of the next generation of targeted therapy, particularly with regards to inhibiting heteromeric ErbB family receptor complexes.
Abstract: Understanding the genetic origin of cancer at the molecular level has facilitated the development of novel targeted therapies. Aberrant activation of the ErbB family of receptors is implicated in many human cancers and is already the target of several anticancer therapeutics. The use of mAbs specific for the extracellular domain of ErbB receptors was the first implementation of rational targeted therapy. The cytoplasmic tyrosine kinase domain is also a preferred target for small compounds that inhibit the kinase activity of these receptors. However, current therapy has not yet been optimized, allowing for opportunities for optimization of the next generation of targeted therapy, particularly with regards to inhibiting heteromeric ErbB family receptor complexes.
533 citations
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TL;DR: Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer, and had greater prognostic value than most currently used prognostic factors in lymph node-positive disease.
Abstract: The HER-2/neu oncogene is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor. This gene has been shown to be amplified in human breast cancer cell lines. In the current study, alterations of the gene in 189 primary human breast cancers were investigated. HER-2/neu was found to be amplified from 2- to greater than 20-fold in 30% of the tumors. Correlation of gene amplification with several disease parameters was evaluated. Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer. It retained its significance even when adjustments were made for other known prognostic factors. Moreover, HER-2/neu amplification had greater prognostic value than most currently used prognostic factors, including hormonal-receptor status, in lymph node-positive disease. These data indicate that this gene may play a role in the biologic behavior and/or pathogenesis of human breast cancer.
11,597 citations
TL;DR: It was shown that phenol red does not interfere with the measurements and no washing steps are required since all ingredients can be added subsequently, and Serum proteins at concentrations up to 25% have no influence on the result.
3,442 citations
TL;DR: The murine monoclonal antibody mumAb4D5, directed against human epidermal growth factor receptor 2 (p 185HER2), specifically inhibits proliferation of human tumor cells overexpressing p185HER2, but the efficacy of mumAb 4D5 in human cancer therapy is likely to be limited by a human anti-mouse antibody response and lack of effector functions.
Abstract: The murine monoclonal antibody mumAb4D5, directed against human epidermal growth factor receptor 2 (p185HER2), specifically inhibits proliferation of human tumor cells overexpressing p185HER2. However, the efficacy of mumAb4D5 in human cancer therapy is likely to be limited by a human anti-mouse antibody response and lack of effector functions. A "humanized" antibody, humAb4D5-1, containing only the antigen binding loops from mumAb4D5 and human variable region framework residues plus IgG1 constant domains was constructed. Light- and heavy-chain variable regions were simultaneously humanized in one step by "gene conversion mutagenesis" using 311-mer and 361-mer preassembled oligonucleotides, respectively. The humAb4D5-1 variant does not block the proliferation of human breast carcinoma SK-BR-3 cells, which overexpress p185HER2, despite tight antigen binding (Kd = 25 nM). One of seven additional humanized variants designed by molecular modeling (humAb4D5-8) binds the p185HER2 antigen 250-fold and 3-fold more tightly than humAb4D5-1 and mumAb4D5, respectively. In addition, humAb4D5-8 has potency comparable to the murine antibody in blocking SK-BR-3 cell proliferation. Furthermore, humAb4D5-8 is much more efficient in supporting antibody-dependent cellular cytotoxicity against SK-BR-3 cells than mumAb4D5, but it does not efficiently kill WI-38 cells, which express p185HER2 at lower levels.
2,604 citations
TL;DR: The relatively few residues that, through their packing, hydrogen bonding or the ability to assume unusual phi, psi or omega conformations, are primarily responsible for the main-chain conformations of the hypervariable regions are identified.
2,400 citations
TL;DR: Antigen-contacting propensities are presented for each antibody residue, allowing a new definition for the complementarity determining regions (CDRs) to be proposed based on observed antigen contacts.
1,900 citations