21 research outputs found
The use of plasma donor-derived, cell-free DNA to monitor acute rejection after kidney transplantation
The preclinical pharmacology of the high affinity anti-IL-6R Nanobody (R) ALX-0061 supports its clinical development in rheumatoid arthritis
Introduction: The pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of different diseases, including rheumatoid arthritis (RA). ALX-0061 is a bispecific Nanobody (R) with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum albumin. We describe here the relevant aspects of its in vitro and in vivo pharmacology. Methods: ALX-0061 is composed of an affinity-matured IL-6R-targeting domain fused to an albumin-binding domain representing a minimized two-domain structure. A panel of different in vitro assays was used to characterize the biological activities of ALX-0061. The pharmacological properties of ALX-0061 were examined in cynomolgus monkeys, using plasma levels of total soluble (s)IL-6R as pharmacodynamic marker. Therapeutic effect was evaluated in a human IL-6-induced acute phase response model in the same species, and in a collagen-induced arthritis (CIA) model in rhesus monkeys, using tocilizumab as positive control. Results: ALX-0061 was designed to confer the desired pharmacological properties. A 200-fold increase of target affinity was obtained through affinity maturation of the parental domain. The high affinity for sIL-6R (0.19 pM) translated to a concentration-dependent and complete neutralization of sIL-6R in vitro. In cynomolgus monkeys, ALX-0061 showed a dose-dependent and complete inhibition of hIL-6-induced inflammatory parameters, including plasma levels of C-reactive protein (CRP), fibrinogen and platelets. An apparent plasma half-life of 6.6 days was observed after a single intravenous administration of 10 mg/kg ALX-0061 in cynomolgus monkeys, similar to the estimated expected half-life of serum albumin. ALX-0061 and tocilizumab demonstrated a marked decrease in serum CRP levels in a non-human primate CIA model. Clinical effect was confirmed in animals with active drug exposure throughout the study duration. Conclusions: ALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six times smaller than monoclonal antibodies. High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA
The preclinical pharmacology of the high affinity anti-IL-6R NanobodyÂź ALX-0061 supports its clinical development in rheumatoid arthritis
Molecular and immunological characterization of soluble aggregated A/Victoria/3/75 (H3N2) influenza haemagglutinin expressed in insect cells.
Cross-neutralizing antibodies against primary isolates in African women infected with HIV-1
Not the final published versio
NanobodiesÂź: new ammunition to battle viruses
In 1989, a new type of antibody was identified, first in the sera of dromedaries and later also in all other species of the Camelidae family. These antibodies do not contain a light chain and also lack the first constant heavy domain. Today it is still unclear what the evolutionary advantage of such heavy chain-only antibodies could be. In sharp contrast, the broad applicability of the isolated variable antigen-binding domains (VHH) was rapidly recognized, especially for the development of therapeutic proteins, called NanobodiesÂŻ. Here we summarize first some of the unique characteristics and features of VHHs. These will next be described in the context of different experimental therapeutic applications of Nanobodies against different viruses: HIV, Hepatitis B virus, influenza virus, Respiratory Syncytial virus, Rabies virus, FMDV, Poliovirus, Rotavirus, and PERVs. Next, the diagnostic application of VHHs (Vaccinia virus, Marburg virus and plant Tulip virus X), as well as an industrial application (lytic lactococcal 936 phage) will be described. In addition, the described data show that monovalent Nanobodies can possess unique characteristics not observed with conventional antibodies. The straightforward formatting into bivalent, multivalent, and/or multispecific Nanobodies allowed tailoring molecules for potency and cross-reactivity against viral targets with high sequence diversity.Fil: Vanlandschoot, Peter. No especifĂca;Fil: Stortelers, Catelijne. No especifĂca;Fil: Beirnaert, Els. No especifĂca;Fil: Ibañez, Lorena ItatĂ. University of Ghent; BĂ©lgica. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Schepens, Bert. University of Ghent; BĂ©lgicaFil: Depla, Erik. No especifĂca;Fil: Saelens, Xavier. University of Ghent; BĂ©lgic
A FAIRLY CONSERVED EPITOPE ON THE HEMAGGLUTININ OF INFLUENZA-A (H3N2) VIRUS WITH VARIABLE ACCESSIBILITY TO NEUTRALIZING ANTIBODY.
AbstractA monoclonal antibody LMBH5 was derived from mice which had been immunized with A/Victoria/3/75 (H3Ng)-type recombinant, secreted hemagglutinin (HA), and were subsequently challenged with a potentially lethal dose of X31 [A/Aichi/2/68 (H3N2) Ă A/PR/8/34 (H1N1)] virus. LMBH5 reacted strongly with the native and low-pH-induced conformations of the HA of A/Aichi (X31 strain) and A/Victoria (X47 strain), but very weakly with the native structure of the HA of A/Philippines/2/82 (X79 strain) and not at all with the HA of A/Guizhou/54/89 H3 (NIB25 strain). However, the acid-induced conformations of the latter two viruses were recognized by LMBH5. The antibody prevented infection of MDCK cells with X31 and X47, whereas X79 virus was partially neutralized by LMH5. X31 monoclonal escape variants had single amino acid substitutions (Ser 227 â Pro) near the interface. The data obtained suggest that the neutralizing LMBH5 reacts with a fairly conserved epitope of influenza A (H3N2) virus, which as a result of antigenic drift becomes inaccessible in the native state of the HA
Evaluation of recombinant A/Victoria/3/75 (H3N2) influenza neuraminidase mutants as potential broad-spectrum subunit vaccines against influenza A.
The intraspleen huPBL NOD/SCID model to study the human HIV-specific antibody response selected in the course of natural infection
Sellami Bernadette. Compte rendu de la sortie de la section de botanique dans les Monts d'Or, le 17 mai 1998. In: Bulletin mensuel de la Société linnéenne de Lyon, 70ᔠannée, n°5, mai 2001. pp. 110-112