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PubMed1991

Enhanced in vivo targeting of an asymmetric bivalent hapten to double-antigen-positive mouse B cells with monoclonal antibody conjugate cocktails.

In order to target specifically double-Ag-positive cells in vivo, we synthesized chemically two mAb conjugates with specificities for both an allelic murine B cell-surface Ag and for a synthetic hapten. One conjugate was designed for its specificities for I-Ek and for N-epsilon-(2,4-DNP)-amino-caproate, and the other one for its reactivity to Lyb-8.2 and to indium-diethylenetriamine pentaacetate. A radiolabeled tracer, containing both the N-epsilon-(2,4-DNP)-amino-caproate and the indium-diethylenetriamine pentaacetate haptens, was obtained by reacting diethylenetriamine pentaacetic acid dianhydride with mono-[N-epsilon-(2,4-DNP)-amino-caproyl]-tyrosyl-lysine and labeling with indium-111. Mice from various strains (CBA/N: I-Ek+, Lyb-8.2+; AKR/N: I-Ek+, Lyb-8.2-; BALB/c: I-Ek-, Lyb-8.2+; and DBA/2: I-Ek-, Lyb-8.2-) were given simultaneous i.v. injections of microgram amounts of less than anti-[N-epsilon-(2,4-DNP)-amino-caproate], anti-I-Ek greater than and of [anti-(indium-diethylene-triaminepentaacetate), anti-Lyb-8.2] antibody conjugates and picomole amounts of the tracer. As expected, specific uptake of the tracer by the spleen was observed in strains where spleen cells expressed at least one Ag (CBA/N, AKR/N, and BALB/c). Furthermore, spleen cells from the double-Ag-positive mouse strain (CBA/N), when compared with spleen cells from single-positive mouse strains, exhibited a significantly higher uptake of the bivalent hapten. This specificity for double-Ag-positive cells, it is suggested, occurs through the formation of stable complexes between both cell-surface Ag, both conjugates, and the asymmetric bivalent hapten. The use of such asymmetric bivalent haptens, together with matched (anti-hapten, anti-cell) antibody conjugates, is proposed as a general method for increasing the in vivo specificity of immunoimaging and radioimmunotherapy.

Animals↗
PubMed1990

[The clinico-immunological evaluation of a bivalent vaccine against measles and rubella].

Prevention of measles and rubella can be obtained by a single administration of bivalent vaccine which can be added to the trivalent vaccine already practice in the USA since 1970 and in the Scandinavian Countries since 1982. We evaluated the immunological response and the clinical reactions to a bivalent vaccine against measles and rubella by the study of a control group including 29 children (17 females and 12 males) aged from a minimum of 15 months to a maximum of 9 years and 4 months. All the children who resulted not to be immune to the 2 viruses by serologic tests showed a rise in the antibody titer with 100% seroconversion, whereas in those proving to be already immune to one of the 2 viruses, a persistent antibody titer or an increase was revealed in all except one. Neither general nor local clinical reactions were observed except for two children who showed feverish measles-like reactions 8 days after the vaccine administration. These results suggest that this bivalent vaccine is highly effective, without negative effects. Furthermore associated with trivalent vaccines, it offers larger immunization opportunity mainly in children who have already been affected by mumps.

Antibodies, Viral↗
PubMed1989

Precocious desynapsis of XY-bivalent in mouse germinal cells: influence of mitomycin C on tumour-bearing and normal mice.

A comparative study on the cytotoxic potential of anticancer-antibiotic mitomycin C has been made on tumour-bearing and normal mice considering precocious desynapsis of sex bivalent as parameter. The study indicates a strikingly differential effect of the drug on the phenomenon in two different types of mice. The administration of mitomycin C at therapeutic dose although enhances the frequency of precocious desynapsis of XY-bivalent in non-tumour (normal) mice to a significant extent (compared to control), the same drug at the same dose fails to produce a similar effect on tumour-bearing specimens. Discussions have been made on: (i) the probable cause for this differential effect, (ii) the mechanism of mitomycin action on precocious desynapsis of sex bivalent and, (iii) the possible significance of the findings in relation to cancer chemotherapy.

Animals↗
PubMedDate not supplied

Experience with monovalent and bivalent influenza vaccines in Canada 1976. Clinical evaluation of vaccines from four sources.

Clinical trials in adults of monovalent (200 CCA Units per dose) and bivalent (400 CCA Units per dose) inactivated influenza whole virus A/Swine and A/Victoria vaccines from different sources resulted in variations in clinical reactivity which may not be significant because of lack of controls and observer bias. In adults with no pre-vaccine antibody (HI less than 1/10) the A/Swine Monovalent vaccine from one source evoked significantly lower response than did the A/Swine component of the Bivalent vaccine from another source. Serologic response to A/Victoria antigen was comparable for vaccines prepared with material from two sources. In medically high risk children two doses of Bivalent A/Swine A/Victoria influenza vaccine, with the dosage adjusted according to age, stimulated acceptable serologic response without an unacceptable frequency of local and general reactions. The response was higher in the youngest and older age groups included in the clinical trial than in the seven to twelve year old group implying a dose to age relationship.

Adolescent↗
PubMedDate not supplied

Field trials with a bivalent vaccine (HVT and SB-1) against Marek's disease.

White leghorn chickens on five farms were given a bivalent Marek's disease (MD) vaccine consisting of turkey herpesvirus (HVT) and SB-1 (a nononcogenic MD virus); other chickens received only HVT. The farms had histories of "vaccination failures," presumably owing to an exceptionally virulent challenge MD virus. The bivalent vaccine uniformly protected chickens better than HVT alone between 12 and 16-20 weeks of age, when serious MD losses occurred. During that period, total mortality in groups given both viruses ranged from 0.39 to 1.26% (mean 0.86%), whereas that in HVT-vaccinated groups not exposed to SB-1 varied from 1.92 to 7.44% (mean 3.43%). Chickens in pens or rows with close contact to those given bivalent vaccine also had low MD mortality rates (0.46-1.06%, mean 0.77%), probably from the spread of SB-1.

Animals↗
PubMed1995

Aliphatic and heterocyclic analogues of arecaidine propargyl ester. Structure-activity relationships of mono- and bivalent ligands at muscarinic M1 (M4), M2 and M3 receptor subtypes.

The pharmacological profiles of tertiary and quaternary monovalent (1b-6b) and bivalent ligands (7a-12b), closely related to arecaidine propargyl ester (CAS 35516-99-5, APE, 1a), were evaluated at muscarinic receptors in rat superior cervical ganglia (M1), rabbit was deferens (M1/M4-like), guinea-pig atria (M2) and guinea-pig ileum (M3). In the monovalent ligand series (1a-6b) APE (1a) displayed the highest potency at all three muscarinic receptors [M2 (-log EC50 = 8.12) > or = M3 (-log EC50 = 7.77) = M1/M4 (-log EC50/vas deferens = 7.72)], whereas in the bivalent ligand series (7a-12b) arecaidine 2-butyne-1,4-diyl bisester (bisABE, 7a) was the most potent agonist with functional selectivity for M1/M4 (-log EC50/vas deferens = 6.94) and M2 receptors (-log EC50 = 7.10) over M3 receptors (-log EC50 = 6.27). On ganglia bisABE elicited M2 receptor-mediated hyperpolarisations, which were followed by long-lasting pirenzepine-sensitive depolarisations. However, the potency at M1 receptors in ganglia of APE (-log EC50 = 6.96) and bisABE (-log EC50 = 5.69) was lower than that in rabbit vas deferens. All bivalent molecules exhibited decreased potencies when compared with their monovalent analogues. However, a change in potency profiles was often obtained. The quaternary isonicotinic acid 2-butyne-1,4-diyl bisester (10b) displayed some functional selectivity for M2 receptors (-log EC50 = 5.78) [6- to 9-fold over M1/M4 (-log EC50/vas deferens = 5.03) and M3 receptors (-log EC50 = 4.83)] without showing nicotinic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies.

We have previously described anti-epidermal growth factor (EGF) receptor monoclonal antibodies (MAbs) which can block binding of transforming growth factor alpha (TGF-alpha) and EGF to receptors and inhibit activation of receptor tyrosine kinase. Studies with these MAbs involving cell cultures and nude mouse xenografts demonstrated their capacity to inhibit the growth of a variety of tumor cell lines, which express EGF receptors and TGF-alpha and appear to depend upon receptor activation for cell proliferation. To explore the mechanism(s) by which anti-EGF receptor 225 MAb inhibits cell proliferation, we have compared the activity of native 225 MAb with the response to bivalent 225 F(ab')2 and monovalent 225 Fab' fragments. Both native 225 MAb and its fragments could inhibit the binding of 125I-EGF to EGF receptors. Scatchard analysis revealed that the Kd of 225 F(ab')2 is comparable to that of 225 MAb (1 nM), whereas the Kd of 225 Fab' is 5 nM. Both bivalent 225 MAb and 225 F(ab')2 and monovalent 225 Fab' were able to completely inhibit TGF-alpha-induced EGF receptor tyrosine kinase activation, as assayed by autophosphorylation of tyrosine residues of EGF receptors on MCF10A nonmalignant human mammary cells, MDA468 human breast adenocarcinoma cells, and A431 human vulvar squamous carcinoma cells. The bivalent forms of MAb could inhibit proliferation stimulated by endogenous (autocrine) TGF-alpha in cultures of these three cell lines. They also blocked growth stimulation by added exogenous TGF-alpha in cultures of MCF10A cells and the growth-inhibitory effect of exogenous TGF-alpha upon MDA468 and A431 cell cultures. Monovalent 225 Fab' had weaker inhibitory effects upon the proliferation of these cell lines. To determine whether the in vivo antiproliferative activity of anti-EGF receptor MAb can occur without the participation of the Fc portion of MAb, the capacities of 225 F(ab')2 and native 225 MAb to inhibit growth of s.c. A431 cell xenografts were compared. Equimolar amounts of either 225 MAb or 225 F(ab')2 were administered at intervals equivalent to the half-lives of the molecules, to attempt to maintain comparable plasma levels. Both 225 MAb and 225 F(ab')2 inhibited A431 cell xenograft growth in a dose-dependent manner, with a more sustained response in the case of the intact antibody.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Structure of a neutralizing antibody bound bivalently to human rhinovirus 2.

The structure of a complex between human rhinovirus serotype 2 (HRV2) and the weakly neutralizing monoclonal antibody 8F5 has been determined to 25 A resolution by cryo-electron microscopy and 3-D reconstruction techniques. THe antibody is seen to be bound bivalently across the icosahedral 2-fold axis, despite the very short distance of 60 A between the symmetry-related epitopes. The canyon around the 5-fold axis is not obstructed. Due to extreme flexibility of the hinge region the Fc domains occupy random orientations and are not visible in the reconstruction. The atomic coordinates of Fab-8F5 complexes with a synthetic peptide derived from the viral protein 2 (VP2) epitope were fitted to the structure obtained by cryo-electron microscope techniques. The X-ray structure of HRV2 is not unknown, so that of the closely related HRV1A was placed in the electron microscopic density map. The footprint of 8F5 on the viral surface is largely on VP2, but also covers the VP3 loop centred on residue 3060. C alpha atoms of VP1 and 8F5 come no closer than 10 A. Based on the fit of the X-ray coordinates to the electron microscope data, the synthetic 15mer peptide starts and ends in close proximity to the corresponding amino acids of VP2 on HRV1A. However, the respective loops diverge considerably in their overall spatial disposition. It appears from this study that bivalent binding of an antibody directed against a picornavirus exists for a smaller spanning distance than was previously thought possible. Also bivalent binding does not ensure strong neutralization.

Animals↗
PubMed2026

Structure-informed theoretical modeling defines principles governing avidity in bivalent protein interactions.

In signaling cascades, signaling proteins often encode multiple domains or motifs, which presents the possibility for avidity -- where multivalent binding drastically increases interaction strength and duration. However, predicting and validating multivalent interactions that interact with avidity is a challenge. Here, we integrate mechanistic modeling, structure-based analysis, and experimental approaches as a framework for defining the conditions under which avidity plays a role. We explore the tandem SH2 domain family of interactions with bisphosphorylated partners as a multivalent archetype, which encompasses key secondary messengers in tyrosine kinase signaling networks. Theoretical modeling suggests that maximum avidity occurs with closely spaced tyrosine phosphorylation sites combined with moderate monovalent affinities - exactly around the innate range of SH2 domain affinity - or with phosphorylation sites separated by sufficiently flexible linkers. Surprisingly, despite sequence diversity, structure-based analysis showed relatively conserved three-dimensional spacing between SH2 domains across all tandem SH2 families, which we corroborate experimentally, suggesting evolutionary optimization for avidity interactions. The combination of structure-based analysis of domain spacing with available monovalent experimental data appears, along with iterative experimental refinement of biophysical parameters, can identify high affinity interactions of tandem SH2 domain recruitment to the EGFR C-terminal tail. Using these principles, we extended bivalent predictions into the full phosphoproteome space and structural parameterization of other partners of SH2 domain binding, providing resources and methods for more rapid expansion of bivalent analysis. These approaches lay the groundwork for larger utility in multivalent prediction and testing to help better understand protein interactions that drive cell signaling.

BLI↗
PubMed1997

Therapy for colon carcinoma xenografts with bispecific antibody-targeted, iodine-131-labeled bivalent hapten.

BACKGROUND: One of the main limitations of radioimmunotherapy (RIT) is the secondary toxicity related to the poor therapeutic indices achieved with labeled whole immunoglobulin (Ig)G or F(ab')2 fragments. To overcome this problem, we have developed a two-step targeting method, which we refer to as the Affinity Enhancement System (AES), using a radiolabeled bivalent hapten and a bispecific antibody recognizing the hapten and a target cell antigen. This method has been applied successfully to immunoscintigraphy in carcinoembryonic antigen (CEA)-expressing carcinoma patients and increased tumor to normal tissue uptake ratios have been achieved. The aim of the current study was to evaluate the application of AES to RIT of CEA-expressing solid tumors in an animal model. METHODS: Nude mice grafted with LS174T human colorectal carcinoma were treated either with 111 megabecquerels (MBq) of iodine-131 labeled bivalent diethylenetriamine pentaacetic acid (DTPA) hapten 20 hours after pretargeting by anti-CEA x anti-DTPA-indium bispecific antibody or 12 MBq of iodine-131 labeled anti-CEA IgG. RESULTS: Treatment with the IgG induced only a growth delay of 53 +/- 5 days but all tumors progressed. Treatment with the AES was highly efficient because tumor growth inhibition was achieved over 150 days. Hematologic and overall toxicity of both treatments were equivalent. CONCLUSIONS: The long term tumor regression consecutive to AES RIT represents a very significant improvement over the use of directly labeled IgG. Toxicity consecutive to AES or IgG RIT were similar despite an administered activity nearly ten times higher with the AES. However, given the efficacy of the AES treatment, a lower dose may afford lower toxicity and significant antitumor effect.

Animals↗
PubMed2002

Dopamine/serotonin receptor ligands, part III [1]: synthesis and biological activities of 7, 7'-alkylene-bis-6, 7, 8, 9, 14, 15-hexahydro-5H-benz[d]indolo[2, 3-g]azecines -- application of the bivalent ligand approach to a novel type of dopamine receptor antagonist.

A series of 7, 7'-alkylene-bridged dimers(7a-e) of the benz [d]indolo[3, 2-f]azecine derivative LE300 was synthesized. Affinity and functional activity at dopamine D(1) and D(2) receptors were estimated by radioligand binding and a functional Ca(2+) assay. All the new bivalent ligands showed significant binding affinities to both D(1) and D(2) receptors with an optimal distance between the two monomeric recognition units of 6 methylene moieties. The D(1)/D(2)-selectivity pattern was dependent on the spacer length. No (7a, b) or only moderate (7c-e) functional activity was detected for all bivalent compounds by measuring the inhibition of agonist-induced increase in intracellular Ca(2+).

Algorithms↗
PubMed1988

The use of a bivalent counter anion to control the effective mobility of the hydrogen ion constituent in cationic isotachophoresis.

The use of a bivalent counter anion for cationic isotachophoresis was studied both theoretically and experimentally. A mathematical model was proposed and solved to give the effective mobility of the hydrogen ion constituent, uH,H, in the respective electrolyte systems. The theoretical values agreed well with the experimental data in a series of electrolyte systems. The dependence of uH,H on such parameters as pH of the leading electrolyte, ionic mobilities of leading and counter ions, and dissociation constants was calculated and discussed. A bivalent counter anion will prove useful for the separation of low mobility cations and weak bases, as shown for the separation of substituted anilines in a succinate electrolyte system.

Anions↗
PubMed2002

Complexes of bivalent metal cations in electrospray mass spectra of common organic compounds.

In the standard electrospray ionization mass spectra of many common, low molecular mass organic compounds dissolved in methanol, peaks corresponding to ions with formula [3M + Met](2+) (M = organic molecule, Met = bivalent metal cation) are observed, sometimes with significant abundances. The most common are ions containing Mg(2+), Ca(2+) and Fe(2+). Their presence can be easily rationalized on the basis of typical organic reaction work-up procedures. The formation of [3M + Met](2+) ions has been studied using N-FMOC-proline methyl ester as a model organic ligand and Mg(2+), Ca(2+), Sr(2+), Ba(2+), Fe(2+), Ni(2+), Mn(2+), Co(2+) and Zn(2+) chlorides or acetates as the sources of bivalent cation. It was found that all ions studied form [3M + Met](2+) complexes with N-FMOC-proline methyl ester, some of them at very low concentrations. Transition metal cations generally show higher complexation activity in comparison with alkaline earth metal cations. They are also more specific in the formation of [3M + Met](2+) complexes. In the case of alkaline earth metal cations [2M + Met](2+) and [4M + Met](2+) complex ions are also observed. It has been found that [3M + Met](2+) complex ions undergo specific fragmentation at relatively low energy, yielding fluorenylmethyl cation as a major product. [M + Na](+) ions are much more stable and their fragmentation is not as specific.

Journal Article↗
PubMed1994

Bivalent vaccines against bacterial enteropathogens: construction of live attenuated vaccine strains with two O-serotype specificities.

A considerable interest exists worldwide in the development of live attenuated oral vaccines against diarrhoeal diseases. In addition to vaccination against the corresponding pathogens, such vaccine strains can be used as carriers for the expression of protective antigens from other organisms. The antigenic repertoire of a given vaccine strain may thereby be extended, potentially leading to a bivalent vaccine. The lipopolysaccharide is known to be a major antigenic surface component of bacterial enteric pathogens. The feasibility of the development of combined vaccines based on live attenuated carriers expressing two O-serotype specificities is illustrated here by the development of candidate live oral vaccines against Shigella sonnei using Salmonella typhi and Vibrio cholerae as carriers. Various factors that may limit the potential of such hybrid strains as bivalent vaccines are discussed.

Animals↗
PubMed1997

Bivalent binding of a neutralising antibody to a calicivirus involves the torsional flexibility of the antibody hinge.

The structure of a complex between rabbit haemorrhagic disease virus (RHDV) virus-like particles (VLPs) and a neutralising monoclonal antibody mAb-E3 has been determined at low resolution by cryo-electron microscopy and three-dimensional (3-D) reconstruction techniques. The atomic co-ordinates of an Fab were fitted to the cryo-electron microscope density map to produce a binding model. The VLP has a T = 3 icosahedral lattice consisting of a hollow spherical shell with 90 protruding arches. Each dimeric arch presents two mAb binding sites; however, steric hindrance between the variable domains of the Fabs prevents the occupation of both sites simultaneously. Thus the maximum mAb occupation is 50%. Once a mAb is bound to one site it may bind to either of two neighbouring sites related by a local 3-fold axis. The mAbs are bound bivalently on epitopes not related by a 2-fold symmetry axis. This binding geometry implies a torsional flexibility of the mAb hinge region, involving a 60 degrees rotation of one Fab arm with respect to the other. Owing to extreme flexibility of the hinge region, the Fc domains occupy random orientations and are not visible in the reconstruction. The bivalent attachment of mAb-E3 to RHDV suggests that the neutralisation mechanism(s) involves inhibition of viral decapsidation and/or the inhibition of binding to the receptor.

Animals↗
PubMed1999

Development of bivalent (B/E) vaccines able to neutralize CCR5-dependent viruses from the United States and Thailand.

Recombinant envelope glycoproteins prepared from a subtype B (MN) strain and a subtype E (CM244) strain of HIV-1 were combined to create a bivalent vaccine (B/E) effective against viruses circulating in the United States and Asia. Combining the two antigens resulted in formulations that increased the breadth and potency of the inter-subtype neutralizing response. Antibodies to the bivalent vaccine formulation neutralized viruses possessing diverse phenotypes, including syncytia-inducing and non-syncytia-inducing primary isolates, viruses using either the CCR5 or the CXCR4 chemokine receptors, and viruses differing in their sensitivity to soluble CD4. These studies demonstrate for the first time that the magnitude and quality of the immune response to HIV-1 can be improved by combining recombinant envelope glycoproteins from different genetic subtypes.

AIDS Vaccines↗
PubMed1977

Pachytene mapping of the C9 and acrocentric bivalents in the human oocyte.

Provisional maps are presented for all acrocentric bivalents and bivalent 9, according to their chromomere patterns at pachytene in the human oocyte. Each G band is subdivided into several sub-bands whose numbers varies according to the degree of chromosomal compacting. Chromomere number and sequence are in basic agreement with those observed in late prophase mitotic chromosomes. Thus, metaphase G bands of mitotic chromosomes result from progressive compressing together of smaller chromomeres whose individuality disappears as chromosomal condensation increases with progression of prophase.

Azure Stains↗
PubMed1983

Nonhomologous synapsis of the sex chromosomes in the heteromorphic bivalents of two X-7 translocations in male mice: R5 and R6.

Electron microscopy of pachytene nuclei of mice heterozygous for either of two reciprocal X-7 translocations (R5 or R6) revealed a high frequency of heteromorphic bivalents involving the translocated chromosomes. In both translocations the break was in the proximal third of the 7 and the distal third of the X, but the R5 breaks were closer to the 7 centromere and X telomere than the R6 breaks. In both translocations the 7 frequently synapsed nonhomologously with the X7. In R5 the part of the X to which the 7 synapsed may include a region that synapses with the Y in normal mice. However, in R6 the 7 synapsed with a portion of the X that never synapses with the Y (Synapsis was clearly in the "differentiated" region). In both translocations the Y synapsed maximally with the X portion of the 7X in those nuclei in which there was nonhomologous synapsis of the 7 with the X7. The Y occasionally synapsed nonhomologously with the 7 portion of the 7X. The behavior of the bivalents suggests that the autosomal portions of the 7X and X7 may alter the behavior of the sex-chromosome portions. Both the nonhomologous synapsis of the Y with the 7X and the timing of events during pachytene have led us to question the "homology" between the X and Y in this species.

Animals↗