Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible cross-reactivity with acid sphingomyelinase-like phosphodiesterase 3b precursor

Blood ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 1070-1077 ◽  
Author(s):  
Federico Perosa ◽  
Elvira Favoino ◽  
Maria Antonietta Caragnano ◽  
Franco Dammacco
Keyword(s):  
Cyclic Peptides ◽  
Cross Reactivity ◽  
Acid Sphingomyelinase ◽  
Biologically Active ◽  
Active Immunotherapy ◽  
Effector Functions ◽  
Fine Specificity ◽  
Phage Display Peptide Library ◽  
Phosphodiesterase 3B ◽  
Anti Cd20

Abstract Heterogeneity of the effector functions displayed by rituximab and other anti-CD20 monoclonal antibodies (mAbs) apparently recognizing the same CD20 epitope suggests that additional mechanisms, probably related to mAb fine specificity, are responsible for B-cell depletion. To improve our understanding of rituximab's function, its fine specificity was investigated by means of phage display peptide library (PDPL)-expressing 7-mer cyclic (c7c) or 7-/12-mer linear peptides. Rituximab-specific c7c PDPL-derived clone insert sequences expressed the motif A(S)NPS overlapping the human CD20 170ANPS173. P172 was the most critical for rituximab binding, since its replacement with S172 (of mouse CD20) abolished the reactivity. The WPXWLE motif expressed by the linear PDPL-derived clone insert sequences could only be aligned to the reverse-oriented 161WPXWLE156 of acid sphingomyelinase-like phosphodiesterase 3b precursor (ASMLPD), though linear peptides bearing WPXWLE competed with cyclic ones for rituximab-paratope binding. Anti-CD20 mAb 1F5 only displayed a reactivity profile similar to that of rituximab, which also reacted with ASMLPD-derived peptides. Peptides induced antibodies with specificity and effector functions similar to those of rituximab. Our results show a unique fine specificity of rituximab, define the molecular basis for the lack of rituximab reactivity with mouse CD20 (mCD20), and the potential of targeting CD20 in an active immunotherapy setting. A possible rituximab interaction with ASMLPD is suggested.

Hierarchy in the Avidity and Cross-reactivity of Anti-citrullinated Protein Antibodies in the Serum of Patients With Rheumatoid Arthritis

2020 ◽  
Author(s):  
Akihisa Haraguchi ◽  
Hisakata Yamada ◽  
Takahide Sakuragi ◽  
Tomomi Tsuru ◽  
Masakazu Kondo ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Response ◽  
Serum Antibody ◽  
Cross Reactivity ◽  
Sodium Thiocyanate ◽  
Fine Specificity ◽  
Thiocyanate Solution ◽  
Citrullinated Protein ◽  
Citrullinated Peptide ◽  
Substantial Extent

Abstract BackgroundFine specificity of anti-citrullinated protein antibodies (ACPAs), in which cross-reactivity exists, varies among patients with rheumatoid arthritis (RA), but it is unclear whether the mechanism of ACPA production is same or different among individuals. Since avidity of serum antibody reflects the direction of immune response, we compared the levels of avidity and cross-reactivity between various ACPAs in a cohort of RA patient.MethodsSera from 180 RA patients positive for anti-cyclic citrullinated peptide (CCP) 2 antibody were screened for positivity of antibodies against CCP1, and citrullnated fibrinogen (cFib), enolase (cEno), and vimentin (cVim) peptides. Avidity of the four ACPAs, and some autoantibodies and antibodies against foreign antigens was determined by an elution assay using sodium thiocyanate solution. Cross-reactivity between different ACPAs was estimated by measuring the inhibition of binding by competitor peptides. ResultsThe prevalence of anti-CCP1, anti-cFib, anti-cEno, and anti-cVim antibodies in the anti-CCP2-positive RA cohort were 37.7%, 38.3%, 15.6%, and 23.9%, respectively. The avidity of ACPAs, except for anti-cVim antibody, was significantly lower than that of antibodies against foreign antigens, while there was a large variety in the avidity of other autoantibodies. At individual levels, the avidity of anti-cVim was significantly higher than that of other ACPAs, and there was a significant correlation in the avidity of anti-CCP and anti-cFib antibodies. Substantial extent of cross-reactivity was seen between different ACPAs, which also showed a fixed hierarchy.ConclusionThe fixed hierarchy in the avidity and cross-reactivity between different ACPAs suggests that the mechanism underlying ACPA production is common to all RA patients. Presence of a dominant antigen that induces whole ACPA response is speculated.

Synthesis of biologically active cyclic peptides

Biopolymers ◽  
1981 ◽  
Vol 20 (9) ◽  
pp. 1785-1791 ◽  
Author(s):  
Nobuo Izumiya ◽  
Tetsuo Kato ◽  
Michinori Waki
Keyword(s):  
Cyclic Peptides ◽  
Biologically Active

scholarly journals Shaping the Innate Immune Response by Dietary Glucans: Any Role in the Control of Cancer?

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 155 ◽  
Author(s):  
Manuela Del Cornò ◽  
Sandra Gessani ◽  
Lucia Conti
Keyword(s):  
Biological Response ◽  
Cancer Control ◽  
Biologically Active ◽  
Innate And Adaptive Immunity ◽  
Effector Functions ◽  
Naturally Occurring ◽  
Health Promoting ◽  
Innate Immunity Cells ◽  
Ancient Times ◽  
Regulatory Effects

β-glucans represent a heterogeneous group of naturally occurring and biologically active polysaccharides found in many kinds of edible mushrooms, baker’s yeast, cereals and seaweeds, whose health-promoting effects have been known since ancient times. These compounds can be taken orally as food supplements or as part of daily diets, and are safe to use, nonimmunogenic and well tolerated. A main feature of β-glucans is their capacity to function as biological response modifiers, exerting regulatory effects on inflammation and shaping the effector functions of different innate and adaptive immunity cell populations. The potential to interfere with processes involved in the development or control of cancer makes β-glucans interesting candidates as adjuvants in antitumor therapies as well as in cancer prevention strategies. Here, the regulatory effects of dietary β-glucans on human innate immunity cells are reviewed and their potential role in cancer control is discussed.

scholarly journals Fine specificity of alloimmune cytotoxic T lymphocytes directed against H-2K. A study with Kb mutants.

1980 ◽  
Vol 151 (5) ◽  
pp. 993-1013 ◽  
Author(s):  
C J Melief ◽  
L P de Waal ◽  
M Y van der Meulen ◽  
R W Melvold ◽  
H I Kohn
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Mixed Lymphocyte Culture ◽  
Cross Reactivity ◽  
Lymphocyte Culture ◽  
Target Cells ◽  
Stimulator Cell ◽  
F1 Hybrid ◽  
Fine Specificity ◽  
Close Relationship

The fine specificity of alloimmune cytotoxic T lymphocytes (CTL) was investigated in CTL responses across the smallest known H-2 differences, those based on mutation at a single H-2 locus. CTL were generated in all possible mixed lymphocyte culture (MLC) combinations among seven H-2Kb mutants and the mouse strain of origin, C57BL/6 (B6-H-2b). CTL were also generated in all F1 hybrid responder/homozygous stimulator-cell combinations among four Kb mutants and B6-H-2b. CTL activity was measured in cell-mediated lympholysis (CML) against target cells from all Kb mutants and B6-H-2b. Cross-reactivity against targets other than the MLC stimulator was extensive and led to the distinction of 64 CML target determinants. Two Kb mutants (B6-H-2bm6 and B6.C-H-2bm9) showed identical typing for all 64 CML determinants. CML reactions after MLC between these two haplotypes were mutually negative. The mutants B6-H-2bm3 and B6.C-H-2bm11 showed identical typing for 47 of the 64 determinants. Their close relationship is in agreement with the finding that H-2bm3 anti-H-2bm11 CTL were the only ones that exclusively lysed target cells of stimulator-cell genotype. On the basis of CML typing, the sequence of relatedness of the mutants with H-2b is as follows: bm6/bm9-bm10-bm3-bm1-bm11, bm6/bm9 being the closest to, and bm11 the most distant from H-2b. The extensive cross-reactivity of alloimmune CTL appears to reflect immunogenetic complexity rather than lack of specificity. Comparison with other reports supports the notion that the system of Kb CML determinants, recognized by alloimmune CTL, is at least partially overlapping with the H-2Kb specificity repertoire involved in the associative T cell recognition of virus-infected cells.

scholarly journals Molecular construction of HIV-gp120 discontinuous epitope mimics by assembly of cyclic peptides on an orthogonal alkyne functionalized TAC-scaffold

2016 ◽  
Vol 14 (2) ◽  
pp. 701-710 ◽  
Author(s):  
P. R. Werkhoven ◽  
M. Elwakiel ◽  
T. J. Meuleman ◽  
H. C. Quarles van Ufford ◽  
J. A. W. Kruijtzer ◽  
...  
Keyword(s):  
Cyclic Peptides ◽  
Biologically Active ◽  
Discontinuous Epitope ◽  
Protein Mimics ◽  
Gp120 Protein ◽  
Hiv Gp120

An orthogonally alkyne functionalized TAC-scaffold was used for molecular construction of biologically active gp120 protein mimics containing different peptide loops.

N-glycan engineering of a plant-produced anti-CD20-hIL-2 immunocytokine significantly enhances its effector functions

2017 ◽  
Vol 115 (3) ◽  
pp. 565-576 ◽  
Author(s):  
Carla Marusic ◽  
Claudio Pioli ◽  
Szymon Stelter ◽  
Flavia Novelli ◽  
Chiara Lonoce ◽  
...  
Keyword(s):  
Effector Functions ◽  
Anti Cd20

scholarly journals A human antibody that broadly neutralizes betacoronaviruses protects against SARS-CoV-2 by blocking the fusion machinery

2021 ◽  
Author(s):  
Dora Pinto ◽  
Maximilian M. Sauer ◽  
Nadine Czudnochowski ◽  
Jun Siong Low ◽  
M. Alejandra Tortorici ◽  
...  
Keyword(s):  
Viral Entry ◽  
Cross Reactivity ◽  
Human Antibody ◽  
Cell Repertoire ◽  
Viral Neutralization ◽  
Effector Functions ◽  
Functional Studies ◽  
B Cell Repertoire ◽  
Protective Antibodies ◽  
Rapid Emergence

The repeated spillovers of β-coronaviruses in humans along with the rapid emergence of SARS-CoV-2 escape variants highlight the need to develop broad coronavirus therapeutics and vaccines. Five monoclonal antibodies (mAbs) were isolated from COVID-19 convalescent individuals and found to cross-react with multiple β-coronavirus spike (S) glycoproteins by targeting the stem helix. One of these mAbs, S2P6, cross-reacts with more than twenty human and animal β-coronavirus S glycoproteins and broadly neutralizes SARS-CoV-2 and pseudotyped viruses from the sarbecovirus, merbecovirus and embecovirus subgenera. Structural and functional studies delineate the molecular basis of S2P6 cross-reactivity and broad neutralization and indicate that this mAb blocks viral entry through inhibition of membrane fusion. S2P6 protects hamsters challenged with SARS-CoV-2 (including the B.1.351 variant of concern) through viral neutralization and Fc-mediated effector functions. Serological and B cell repertoire analyses indicate that antibodies targeting the stem helix are found in some convalescent donors and vaccinees but are predominantly of narrow specificity. Germline reversion of the identified cross-reactive mAbs revealed that their unmutated ancestors are specific for the endemic OC43 or HKU1 viruses and acquired enhanced affinity and breadth through somatic mutations. These data demonstrate that conserved epitopes in the coronavirus fusion machinery can be targeted by protective antibodies and provide a framework for structure-guided design of pan-β-coronavirus vaccines eliciting broad protection.

scholarly journals The Glutamate-Rich Protein (GLURP) of Plasmodium falciparum Is a Target for Antibody-Dependent Monocyte-Mediated Inhibition of Parasite Growth In Vitro

1998 ◽  
Vol 66 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Michael Theisen ◽  
Soe Soe ◽  
Claude Oeuvray ◽  
Alan W. Thomas ◽  
Jens Vuust ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Cross Reactivity ◽  
Parasite Growth ◽  
Biologically Active ◽  
Dependent Manner ◽  
Igg Antibodies ◽  
Inhibitory Effects ◽  
Direct Invasion

ABSTRACT Monocyte-dependent as well as direct inhibitory effects of antimalarial antibodies point toward antigens accessible at the time of merozoite release as targets for biologically active antibodies capable of mediating protection against Plasmodium falciparum. The glutamate-rich protein (GLURP), being an antigen associated with mature schizont-infected erythrocytes, was therefore the object of the present investigation, in which we analyzed whether anti-GLURP antibodies can either interfere directly with merozoite invasion or act indirectly by promoting a monocyte-dependent growth inhibition, antibody-dependent cellular inhibition. GLURP-specific human immunoglobulin G (IgG) antibodies, from pooled IgG of healthy Liberian adults who were clinically immune to malaria, were purified by affinity chromatography on columns containing R0 (N-terminal nonrepetitive region of GLURP) or R2 (C-terminal repetitive region of GLURP) recombinant protein or synthetic peptides as ligands. Analysis of the pattern of reactivity of highly purified anti-GLURP antibodies led to the definition of at least four B-cell epitopes. One epitope was specific for R0, two were specific for R2, and the fourth displayed cross-reactivity between R0 and R2. None of the purified IgG antibodies had direct invasion-inhibitory effects, even at high concentrations. In contrast, when allowed to cooperate with monocytes, all anti-GLURP IgG preparations mediated a strong monocyte-dependent parasite growth inhibition in a dose-dependent manner.

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