Human Immunodeficiency Virus Type 1-neutralizing Monoclonal Antibody 2F5 is Multispecific for Sequences Flanking the DKW Core Epitope

Menéndez, Alfredo; Chow, Keith C.; Pan, Oscar; Scott, Jamie K.

doi:10.1016/j.jmb.2004.02.051

Cited by 46 publications

(54 citation statements)

References 51 publications

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“…Fine definition of the 2F5 epitope suggests the involvement in antibody recognition of a helical stretch that follows the core epitope residues (34,36,63). It has been argued that the MAb2F5's CDR-H3 loop establishes contact with residues located further downstream within a continuous helix (25,38).…”

Section: Designation Of the Mper Peptide Containing The Complete 2f5 mentioning

confidence: 99%

“…9C). Screening of phage-displayed peptide libraries with the MAb2F5 identified Leu-669 as an almost invariant residue at the C terminus of the core epitope (63). Further competition ELISA demonstrated that the CDR-H3 loop increased binding affinity when C-terminal 672 WFNITNWLWYIK 683 residues were added to the full 656 NEQELLELDKWASLWN 681 epitope sequence (38).…”

Section: Figure 8 Recovered Responses After Vaccination With the Popmentioning

confidence: 99%

See 1 more Smart Citation

Structure and Immunogenicity of a Peptide Vaccine, Including the Complete HIV-1 gp41 2F5 Epitope

Serrano

Araujo

Apellániz

et al. 2014

Journal of Biological Chemistry

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Background: HIV-1 vaccines should elicit broadly neutralizing antibodies as the gp41 "membrane-proximal external region" targeting MAb2F5. Results: NMR disclosed unprecedented 2F5 peptide-epitope structures. Although overall conformation was preserved in different adjuvants, recovered antibodies after vaccination were functionally different. Conclusion: Membrane-inserted helical oligomers may encompass effective 2F5 peptide vaccines. Significance: Disclosing the structures that generate 2F5-like antibodies may guide future vaccine development.

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Section: Designation Of the Mper Peptide Containing The Complete 2f5 mentioning

confidence: 99%

Section: Figure 8 Recovered Responses After Vaccination With the Popmentioning

confidence: 99%

Structure and Immunogenicity of a Peptide Vaccine, Including the Complete HIV-1 gp41 2F5 Epitope

Serrano

Araujo

Apellániz

et al. 2014

Journal of Biological Chemistry

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“…multiple factors, including the nature of the displayed molecule and/or the method of its display ( Table 1). Specifically, we speculate that, as reported for other peptides, [26][27][28] the native antigenic structure of MD10 may be stabilized by the peptide bond with pVIII (since it was originally selected from a phage-displayed peptide library as a recombinant fusion to the N-terminus of pVIII); this may be particularly important for short peptides (MD10 is 6 residues long) that are less likely to adopt stable folded conformations as free peptides in solution. 29 In support of this, others have found synthetic MD10 peptide conjugated to other carrier proteins to be very poorly immunogenic.…”

Section: The Immune Response To Filamentous Phagementioning

confidence: 68%

Developing strategies to enhance and focus humoral immune responses using filamentous phage as a model antigen

et al. 2011

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Filamentous bacteriophage are commonly used as immunogenic carriers for peptides and proteins displayed on the phage surface. Previously, we showed that immunization with phage to which peptides had been chemically conjugated can elicit a focused anti-peptide antibody response compared with traditional carrier molecules bearing the same peptide, perhaps due to the low surface complexity of the phage. The regularity of its surface also gives the phage other advantages as a carrier, including immunological simplicity and thousands of well-defined sites for chemical conjugation. More recently, we showed that focusing of antibody responses against 'target' peptides was enhanced when the phage's molecular surface was simplified by removal of immunodominant B-cell epitopes present on the minor coat protein, pIII. The pIII-truncated variant elicits an antibody response that is largely restricted to the exposed N-terminus of the major coat protein, pVIII, and to phage-associated bacterial lipopolysaccharide, and a significant fraction of this response crossreacts with a 12-residue peptide covering the surface-exposed region of pVIII. This allows one to track antibody responses against the phage (and any associated haptens) as they develop over time, and characterize them using a combination of serological, flow cytometric, cellular and immunogenetic assays. The filamentous phage thus provides an excellent model system for studying various aspects of the antibody response, all with the goal of targeting antibody production against weakly immunogenic peptides, proteins and carbohydrates.

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“…Phage enzyme-linked immunosorbent assays (ELISAs) were performed as described previously (35,36). MAb 2G12 was used at 50 nM and incubated for three hours at 4°C.…”

Section: Enzyme-linked Immunosorbent Assaysmentioning

confidence: 99%

A peptide inhibitor of HIV‐1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120

Menéndez

Calarese

Stanfield³

et al. 2008

FASEB j.

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MAb 2G12 neutralizes HIV-1 by binding with high affinity to a cluster of high-mannose oligosaccharides on the envelope glycoprotein, gp120. Screening of phage-displayed peptide libraries with 2G12 identified peptides that bind specifically, with K d s ranging from 0.4 to 200 μM. The crystal structure of a 21-mer peptide ligand in complex with 2G12 Fab was determined at 2.8 Å resolution. Comparison of this structure with previous structures of 2G12-carbohydrate complexes revealed striking differences in the mechanism of 2G12 binding to peptide vs. carbohydrate. The peptide occupies a site different from, but adjacent to, the primary carbohydrate-binding site on 2G12, and makes only slightly fewer contacts to the Fab than Man 9 GlcNAc 2 (51 vs. 56, respectively). However, only two antibody contacts with the peptide are hydrogen bonds in contrast to six with Man 9 GlcNAc 2 , and only three of the antibody residues that interact with Man 9 GlcNAc 2 also contact the peptide. Thus, this mechanism of peptide binding to 2G12 does not support structural mimicry of the native carbohydrate epitope on gp120, since it neither replicates the oligosaccharide footprint on the antibody nor most of the contact residues. Moreover, 2G12.1 peptide is not an immunogenic mimic of the 2G12 epitope, since antisera produced against it did not bind gp120.-Menendez, A., Calarese, D. A., Stanfield, R. L., Chow, K. C., Scanlan, C. N., Kunert, R., Katinger, H., Burton, D. R., Wilson, I. A., Scott, J. K. A peptide inhibitor of HIV-1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptHuman monoclonal antibody (MAb) 2G12 efficiently neutralizes a broad range of HIV-1 primary isolates in vitro (1-3) and protects from in vivo viral challenge in macaques in combination with other antibodies (4-6). MAb 2G12 binds with high affinity to a unique, conserved epitope on the HIV-1 envelope that is formed by a cluster of N-linked, high-mannose glycan groups on the "silent" face of gp120 (7-10). Crystal structures of 2G12 Fab alone, and in complex with oligosaccharides Man 9 GlcNAc 2 and Manα1-2Man, revealed that two Fab monomers assemble into an interlocked, domain-swapped dimer, that forms an extensive, multivalent binding surface (11). Four Man 9 GlcNAc 2 moieties were observed bound to the Fab dimer in the crystal structure, occupying the two canonical antigen-binding sites, and two novel ones located at the assembled interface of the two interlocked V H domains. Since the identification of its epitope, MAb 2G12 has received significant attention as a template for HIV-1 vaccine development. Considerable effort has been directed at characterizing its oligosaccharide-binding profile (12)(13)(14)(15), and the generation of novel antigens in the form of synthetic oligomannoses (13,16,17) or short, synthetic glycopeptides (18-20). In an attempt to generate immunogens that elicit 2G12-like antibodies, we chose to isolate peptides t...

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Human Immunodeficiency Virus Type 1-neutralizing Monoclonal Antibody 2F5 is Multispecific for Sequences Flanking the DKW Core Epitope

Cited by 46 publications

References 51 publications

Structure and Immunogenicity of a Peptide Vaccine, Including the Complete HIV-1 gp41 2F5 Epitope

Structure and Immunogenicity of a Peptide Vaccine, Including the Complete HIV-1 gp41 2F5 Epitope

Developing strategies to enhance and focus humoral immune responses using filamentous phage as a model antigen

A peptide inhibitor of HIV‐1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120

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