Receptor Antibodies as Novel Therapeutics for Diabetes

Ussar, Siegfried; Vienberg, Sara G.; Kahn, C. Ronald

doi:10.1126/scitranslmed.3003447

Cited by 16 publications

(15 citation statements)

References 21 publications

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“…The set of tryptic peptides bound by each individual CIMS antibody was thus detected and identified using tandem-mass spectrometry. The results showed that peptides of a median length of 10 amino acids (range [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] and with a median pI of 6.5 (range 3.8-12) were captured in a clone-dependent manner (Table I). Noteworthy, as illustrated for the CIMS-17 sister pair, the affinity (K D ) for an experimentally verified captured yeast peptide was found to be in the same range as that observed for the original selection peptide (Table I).…”

Section: Degenerate Peptide-binding Specificitymentioning

confidence: 93%

“…Protein-peptide interactions, and in particular antibody-peptide interactions, have been explored in various applications, such as biosensors, biomarkers, therapeutics, and functional modulation of proteins. [2][3][4][5][6][7] Hence, increasing our fundamental understanding of protein-peptide recognition, and having the possibility to design, control, and even predict novel protein-peptide interactions will have a significant impact on broad applications within the fields of proteomics, biology, and medicine. 2,6 Antibodies and other proteins can interact specifically with short peptide sequences in a variety of ways, and the bound peptides are frequently in an extended conformation, although they might also adopt beta-turns and alpha-helices as motifs for recognition.…”

Section: Introductionmentioning

confidence: 99%

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Epitope‐specificity of recombinant antibodies reveals promiscuous peptide‐binding properties

et al. 2012

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Protein-peptide interactions are a common occurrence and essential for numerous cellular processes, and frequently explored in broad applications within biology, medicine, and proteomics. Therefore, understanding the molecular mechanism(s) of protein-peptide recognition, specificity, and binding interactions will be essential. In this study, we report the first detailed analysis of antibody-peptide interaction characteristics, by combining large-scale experimental peptide binding data with the structural analysis of eight human recombinant antibodies and numerous peptides, targeting tryptic mammalian and eukaryote proteomes. The results consistently revealed that promiscuous peptide-binding interactions, that is, both specific and degenerate binding, were exhibited by all antibodies, and the discovery was corroborated by orthogonal data, indicating that this might be a general phenomenon for low-affinity antibodypeptide interactions. The molecular mechanism for the degenerate peptide-binding specificity appeared to be executed through the use of 2-3 semi-conserved anchor residues in the C-terminal part of the peptides, in analogue to the mechanism utilized by the major histocompatibility complex-peptide complexes. In the long-term, this knowledge will be instrumental for advancing our fundamental understanding of protein-peptide interactions, as well as for designing, generating, and applying peptide specific antibodies, or peptide-binding proteins in general, in various biotechnical and medical applications.

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Section: Degenerate Peptide-binding Specificitymentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Epitope‐specificity of recombinant antibodies reveals promiscuous peptide‐binding properties

et al. 2012

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“…IR monoclonal antibodies may represent a novel class of longacting therapeutics for regulating glucose metabolism in T2DM (Ussar et al, 2011). Monoclonal antibodies to the IR also have the potential to elicit metabolic effects while minimizing mitogenic responses.…”

Section: Introductionmentioning

confidence: 99%

Differential Pathway Coupling of the Activated Insulin Receptor Drives Signaling Selectivity by XMetA, an Allosteric Partial Agonist Antibody

Bedinger

Goldfine

Corbin

et al. 2015

J Pharmacol Exp Ther

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The monoclonal antibody XMetA is an allosteric partial agonist of the insulin receptor (IR), which activates the metabolic Akt kinase signaling pathway while having little or no effect on the mitogenic extracellular signal-regulated kinase (ERK) signaling pathway. To investigate the nature of this selective signaling, we have conducted a detailed investigation of XMetA to evaluate specific phosphorylation and activation of IR, Akt, and ERK in Chinese hamster ovary cell lines expressing either the short or long isoform of the human IR. Insulin activated both pathways, but the phosphorylation of Akt was more sensitive to the hormone than the phosphorylation of ERK. Maximally effective concentrations of XMetA elicited phosphorylation patterns similar to 40-100 pM insulin, which were sufficient for robust Akt phosphorylation, but had little effect on ERK phosphorylation. These data indicate that the preferential signaling of XMetA is due to an innate difference in pathway sensitivity of Akt versus ERK responses to IR activation and partial agonism by XMetA, rather than a separate pathwaybiased mechanism. The metabolic selectivity of partial IR agonists like XMetA, if recapitulated in vivo, may be a desirable feature of therapeutic agents designed to regulate blood glucose levels while minimizing undesirable outcomes of excessive IR mitogenic activation.

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“…3 It has been suggested that monoclonal antibodies to the insulin receptor (INSR) may be useful in various disorders of glucose metabolism including hyperglycemia and hypoglycemia. 6 We have recently produced allosteric antibodies that regulate INSR signaling by either direct activation, or positive or negative modulation. [7][8][9][10] These types of antibodies have been classified as selective INSR modulators.…”

mentioning

confidence: 99%

Selective Allosteric Antibodies to the Insulin Receptor for the Treatment of Hyperglycemic and Hypoglycemic Disorders

Issafras

Bedinger

Corbin

et al. 2014

J Diabetes Sci Technol

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Recombinant monoclonal antibodies, by blocking cellular pathways that are dysregulated, are powerful targeted therapeutics for certain severe diseases. 1-2 However, these cellular pathways, when functioning normally, also have important roles in normal physiology. Therefore successful treatment of these diseases may require modulation, rather than complete inhibition, of signaling pathways to restore a normal physiological state with a potentially low side-effect profile. Monoclonal antibodies also have the potential to treat disease states by either stimulating or enhancing biological signaling pathways. This class of antibodies has the potential to maintain the spatial and temporal aspects of endogenous ligands such as hormones, cytokines, and neurotransmitters. The site on receptors at which the endogenous ligand binds is defined as the orthosteric site (Figure 1A). Sites on the receptor at which nonligand molecules bind are termed allosteric sites. 1 Regulation of receptor activity by molecules binding to allosteric sites has been recognized as common mechanism for the control of enzyme activity and protein function. 3 We previously described a new approach to target disease using an allosteric antibody approach based on the modulation of ligand-receptor binding kinetics. 2 Both allosteric and orthosteric antibodies can induce conformational changes in receptors that may markedly activate or modulate receptor function. This approach has been previously employed to regulate receptors using small molecules. 3 Allosteric antibodies have the potential to bind and regulate receptors more selectively than orthosteric antibodies (Figure 1). This selectivity is due to lower sequence and structural homology at allosteric sites relative to orthosteric sites. 4,5 This selectivity of allosteric molecules is particularly useful for targeting closely related receptors that bind to similar natural ligands. Moreover, because of their noncompetitive nature 529886D STXXX10.

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Receptor Antibodies as Novel Therapeutics for Diabetes

Cited by 16 publications

References 21 publications

Epitope‐specificity of recombinant antibodies reveals promiscuous peptide‐binding properties

Epitope‐specificity of recombinant antibodies reveals promiscuous peptide‐binding properties

Differential Pathway Coupling of the Activated Insulin Receptor Drives Signaling Selectivity by XMetA, an Allosteric Partial Agonist Antibody

Selective Allosteric Antibodies to the Insulin Receptor for the Treatment of Hyperglycemic and Hypoglycemic Disorders

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