44 research outputs found
Biosimilar Monoclonal Antibodies in Latin America
In the last decade, the expiration of patents protecting therapeutic monoclonal antibodies opened an opportunity for the development and approval of biosimilar versions of these drugs. The complexity of these biologic molecules required the imposition of strict regulations to establish robust comparability with the antibody of reference in physicochemical, analytical, biological and, when deemed necessary, clinical data. Accordingly, this period coincides with the updating of the requirements and guidelines for the manufacture and approval of biologics in Latin American countries by their respective regulatory agencies. Although the term “biosimilar” does not appear in the official regulatory provisions in most of the countries, it is of general use in Latin America, and several biosimilars of therapeutic monoclonal antibodies were approved based on comparative quality, nonclinical and clinical data that demonstrate similarity to a licensed biological reference registered before in a Regulatory Health Authority of reference. Here, we provide an overview of how the complexities of therapeutic monoclonal antibodies shaped the regulatory landscape of similar biologics, the current status of biosimilar monoclonal antibodies in Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, México, Paraguay, Perú and Uruguay and their potential to reduce the cost of antibody therapies in this region
Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domain
Pathogenic clade B New World mammarenaviruses (NWM) can cause Argentine, Venezuelan, Brazilian, and Bolivian hemorrhagic fevers. Sequence variability among NWM glycoproteins (GP) poses a challenge to the development of broadly neutralizing therapeutics against the entire clade of viruses. However, blockade of their shared binding site on the apical domain of human transferrin receptor 1 (hTfR1/CD71) presents an opportunity for the development of effective and broadly neutralizing therapeutics. Here, we demonstrate that the murine monoclonal antibody OKT9, which targets the apical domain of hTfR1, can sterically block cellular entry by viral particles presenting clade B NWM glycoproteins (GP1-GP2). OKT9 blockade is also effective against viral particles pseudotyped with glycoproteins of a recently identified pathogenic Sabia-like virus. With nanomolar affinity for hTfR1, the OKT9 antigen binding fragment (OKT9-Fab) sterically blocks clade B NWM-GP1s and reduces infectivity of an attenuated strain of Junin virus. Binding of OKT9 to the hTfR1 ectodomain in its soluble, dimeric state produces stable assemblies that are observable by negative-stain electron microscopy. A model of the OKT9-sTfR1 complex, informed by the known crystallographic structure of sTfR1 and a newly determined structure of the OKT9 antigen binding fragment (Fab), suggests that OKT9 and the Machupo virus GP1 share a binding site on the hTfR1 apical domain. The structural basis for this interaction presents a framework for the design and development of high-affinity, broadly acting agents targeting clade B NWMs. IMPORTANCE Pathogenic clade B NWMs cause grave infectious diseases, the South American hemorrhagic fevers. Their etiological agents are Junin (JUNV), Guanarito (GTOV), Sabiá (SABV), Machupo (MACV), Chapare (CHAV), and a new Sabiá-like (SABV-L) virus recently identified in Brazil. These are priority A pathogens due to their high infectivity and mortality, their potential for person-to-person transmission, and the limited availability of effective therapeutics and vaccines to curb their effects. While low homology between surface glycoproteins of NWMs foils efforts to develop broadly neutralizing therapies targeting NWMs, this work provides structural evidence that OKT9, a monoclonal antibody targeting a single NWM glycoprotein binding site on hTfR1, can efficiently prevent their entry into cells.Fil: Ferrero, Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Flores, Maria D.. University of California at Los Angeles; Estados UnidosFil: Short, Connor. University of California at Los Angeles; Estados UnidosFil: Vázquez, Cecilia Alejandra. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Clark, Lars E.. Harvard Medical School; Estados UnidosFil: Ziegenbein, James. University of California at Los Angeles; Estados UnidosFil: Zink, Samantha. University of California at Los Angeles; Estados UnidosFil: Fuentes, Daniel. University of California at Los Angeles; Estados UnidosFil: Payés, Cristian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Batto, María V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Collazo, Michael. University of California at Los Angeles; Estados UnidosFil: García, Cybele C.. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Abraham, Jonathan. Harvard Medical School; Estados Unidos. Brigham and Women's Hospital; Estados UnidosFil: Cordo, Sandra Myriam. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Rodriguez, Jose A.. University of California at Los Angeles; Estados UnidosFil: Helguera, Gustavo Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin
First detection of a VHE gamma-ray spectral maximum from a Cosmic source: H.E.S.S. discovery of the Vela X nebula
The Vela supernova remnant (SNR) is a complex region containing a number of
sources of non-thermal radiation. The inner section of this SNR, within 2
degrees of the pulsar PSR B0833-45, has been observed by the H.E.S.S. gamma-ray
atmospheric Cherenkov detector in 2004 and 2005. A strong signal is seen from
an extended region to the south of the pulsar, within an integration region of
radius 0.8 deg. around the position (RA = 08h 35m 00s, dec = -45 deg. 36'
J2000.0). The excess coincides with a region of hard X-ray emission seen by the
ROSAT and ASCA satellites. The observed energy spectrum of the source between
550 GeV and 65 TeV is well fit by a power law function with photon index = 1.45
+/- 0.09(stat) +/- 0.2(sys) and an exponential cutoff at an energy of 13.8 +/-
2.3(stat) +/- 4.1(sys) TeV. The integral flux above 1 TeV is (1.28 +/- 0.17
(stat) +/- 0.38(sys)) x 10^{-11} cm^{-2} s^{-1}. This result is the first clear
measurement of a peak in the spectral energy distribution from a VHE gamma-ray
source, likely related to inverse Compton emission. A fit of an Inverse Compton
model to the H.E.S.S. spectral energy distribution gives a total energy in
non-thermal electrons of ~2 x 10^{45} erg between 5 TeV and 100 TeV, assuming a
distance of 290 parsec to the pulsar. The best fit electron power law index is
2.0, with a spectral break at 67 TeV.Comment: 5 pages, 4 figures, accepted for publication in Astronomy and
Astrophysics letter
3.9 day orbital modulation in the TeV gamma-ray flux and spectrum from the X-ray binary LS 5039
New observations of LS 5039, a High Mass X-ray Binary comprising a massive
star and compact object, were carried out with the High Energy Stereoscopic
System of Cherenkov Telescopes (H.E.S.S.) in 2005 at very high energy (VHE)
gamma-ray energies. These observations reveal that its flux and energy spectrum
are modulated with the 3.9 day orbital period of the binary system. This is the
first time in gamma-ray astronomy that orbital modulation has been observed,
and periodicity clearly established using ground-based gamma-ray detectors. The
VHE gamma-ray emission is largely confined to half of the orbit, peaking around
the inferior conjunction epoch of the compact object. For this epoch, there is
also a hardening of the energy spectrum in the energy range between 0.2 TeV and
a few TeV. The flux vs. orbital phase profile provides the first clear
indication of gamma-ray absorption via pair production within an astrophysical
source, a process which is expected to occur if the gamma-ray production site
is situated within ~1 AU of the compact object. Moreover the production region
size must be not significantly greater than the binary separation (~0.15 AU).
Notably, these constraints are also considerably smaller than the collimated
outflows or jets (extending out to ~1000 AU) observed in LS 5039. The spectral
hardening could arise from variations with phase in the maximum electron
energies, and/or the dominant VHE gamma-ray production mechanism.Comment: 8 pages, 8 figures, accepted for publication in Astronomy &
Astrophysic
Discovery of Very High Energy Gamma-Ray Emission from the BL Lac Object H2356-309 with the H.E.S.S. Cherenkov Telescopes
The extreme synchrotron BL Lac object H2356-309, located at a redshift of z =
0.165, was observed from June to December 2004 with a total exposure of approx.
40 h live-time with the H.E.S.S. (High Energy Stereoscopic System) array of
atmospheric-Cherenkov telescopes (ACTs). Analysis of this data set yields, for
the first time, a strong excess of 453 gamma-rays (10 standard deviations above
background) from H2356-309, corresponding to an observed integral flux above
200 GeV of I(>200GeV) = (4.1+-0.5) 10^12 cm^-2.s^-1 (statistical error only).
The differential energy spectrum of the source between 200 GeV and 1.3 TeV is
well-described by a power law with a normalisation (at 1 TeV) of N_0 = (3.00 +-
0.80_stat +- 0.31_sys) 10^-13 cm^-2.s^-1.TeV^-1 and a photon index of Gamma =
3.09 +- 0.24_stat +- 0.10_sys. H2356-309 is one of the most distant BL Lac
objects detected at very-high-energy gamma-rays so far. Results from
simultaneous observations from ROTSE-III (optical), RXTE (X-rays) and NRT
(radio) are also included and used together with the H.E.S.S. data to constrain
a single-zone homogeneous synchrotron self-Compton (SSC) model. This model
provides an adequate fit to the H.E.S.S. data when using a reasonable set of
model parameters.Comment: 7 pages, 4 figures, accepted for publication in Astronomy and
Astrophysics (05/07/2006
Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study
Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research
Fine-tuning the immune response against cancer with antibody-cytokine fusion proteins
Antibody-cytokine fusion proteins, also known as immunocytokines, comprise a novel class of biopharmaceuticals designed to localize immunomodulatory agents toward the tumor site and stimulate local immune cells to activate an anticancer response. The engineering of antibody-cytokine fusion proteins includes a broad variety of formats (e.g., full IgGs or antibody fragments), molecular targets (e.g., cell membrane antigens or extracellular matrix components), and different cytokine moieties, which need to be assembled to reach their correct targets and achieve an effective antitumor activity. Early preclinical studies hinted at the therapeutic potential of antibody-cytokine fusion proteins in several tumor models, but their application in clinical studies often resulted in complications associated with undesirable side effects or poor efficacy. These problems could be attributed to the pleiotropic activity of the cytokines and/or undesired off-target cell interactions that could not be compensated by the antibody affinity and specificity. A deeper understanding of the cytokine’s structure, interactions, and signaling is allowing the rational design of a new generation of immunocytokines with fine-tuned immune responses for safer and more effective cancer immunotherapy. The construction of new cytokine muteins fused to antibodies that are addressing many of the problems associated with the use of wild-type cytokines is transforming this field, and some of these novel immunocytokines are reaching clinical trials. This chapter presents the latest advances in the field of antibody-cytokine fusion proteins engineered with novel cytokine variants and their great potential for cancer therapy.Fil: Ferrero, Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gatto, Matías Iván. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Helguera, Gustavo Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin
Unveiling a new extragalactic structure hidden by the Milky Way
Context. The zone of avoidance (ZoA) does not allow for clear optical observations of extragalactic sources behind the Milky Way due to the meaningful extinction of the optical emission of these objects. Observations in near-infrared (NIR) wavelengths represent a potential source of astronomical discoveries that support the detection of new galaxies and potentially complete the picture of the large-scale structures in this as-yet poorly explored area of the sky.
Aims. Our aim is to decipher the nature of the overdensity located behind the Milky Way in tile b204 of the VISTA Variables in Vía Láctea (VVV) survey.
Methods. We studied an area of six arcmin around a galaxy concentration located at l = 354.82° and b = −9.81°. We selected five galaxies, taking into account the source distribution on the sky to optimise the requested time for the observations, and we obtained the spectra with Flamingos 2 long-slit spectrograph at Gemini South 8.1-meter telescope. To identify and characterise the absorption features, we fit the galaxies underlying spectrum using the STARLIGH
Unveiling a new extragalactic structure hidden by the Milky Way
Context. The zone of avoidance (ZoA) does not allow for clear optical observations of extragalactic sources behind the Milky Way due to the meaningful extinction of the optical emission of these objects. Observations in near-infrared (NIR) wavelengths represent a potential source of astronomical discoveries that support the detection of new galaxies and potentially complete the picture of the large-scale structures in this as-yet poorly explored area of the sky. Aims. Our aim is to decipher the nature of the overdensity located behind the Milky Way in tile b204 of the VISTA Variables in Vía Láctea (VVV) survey. Methods. We studied an area of six arcmin around a galaxy concentration located at l = 354.82° and b = −9.81°. We selected five galaxies, taking into account the source distribution on the sky to optimise the requested time for the observations, and we obtained the spectra with Flamingos 2 long-slit spectrograph at Gemini South 8.1-meter telescope. To identify and characterise the absorption features, we fit the galaxies underlying spectrum using the STARLIGHT code together with the IRTF stellar library. In addition, the spectroscopic findings are reinforced using complementary photometric techniques such as red-sequence and photometric redshift estimation. Results. The mean spectroscopic redshift estimated from the NIR spectra is z = 0.225 ± 0.014. This value presents a good agreement with that obtained from photometric analysis, photoz = 0.21 ± 0.08, and the probability distribution function of the galaxies in the studied region. Also, the red-sequence slope is consistent with the one expected for NIR observations of galaxy clusters. Conclusions. The redshifts obtained from both, photometric and spectroscopic techniques are in good agreement, allowing for the confirmation of the nature of this structure at z = 0.225 ± 0.014, thereby unveiling a new galaxy cluster, VVVGCl-B J181435-381432, behind the Milky Way bulge