A systematic review of commercial high concentration antibody drug products approved in the US: formulation composition, dosage form design and primary packaging considerations.

Three critical aspects that define high concentration antibody products (HCAPs) are as follows: 1) formulation composition, 2) dosage form, and 3) primary packaging configuration. HCAPs have become successful in the therapeutic sector due to their unique advantage of allowing subcutaneous self-administration. Technical challenges, such as physical and chemical instability, viscosity, delivery volume limitations, and product immunogenicity, can hinder successful development and commercialization of HCAPs.

A Large Retrospective Study of Epidemiological Characteristics of COVID-19 Patients in the North of Iran: Association between SARS-CoV-2 RT-PCR Ct Values with Demographic Data.

Objectives: To avoid worsening from mild, moderate, and severe diseases and to reduce mortality, it is necessary to identify the subpopulation that is more vulnerable to the development of COVID-19 unfavorable consequences. This study aims to investigate the demographic information, prevalence rates of common comorbidities among negative and positive real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) patients, and the association between SARS-CoV-2 cycle threshold (Ct) at hospital admission, demographic data, and outcomes of the patients in a large population in Northern Iran.

Methods: This large retrospective cross-sectional study was performed from 7 March to 20 December 2020.

Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor.

Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntington's disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice.

Structure of full-length human anti-PD1 therapeutic IgG4 antibody pembrolizumab.

Immunoglobulin G4 antibodies exhibit unusual properties with important biological consequences. We report the structure of the human full-length IgG4 S228P anti-PD1 antibody pembrolizumab, solved to 2.3-Å resolution.

A novel cytidine analog, RX-3117, shows potent efficacy in xenograft models, even in tumors that are resistant to gemcitabine.

RX-3117 (fluorocyclopentenylcytosine) is a cytidine analog and this class of drugs, including gemcitabine, has been widely used for the treatment of various types of cancers. However, there is no oral formulation of gemcitabine and drug resistance to gemcitabine is common. In this study, the efficacy of orally-administered RX-3117 was examined in 9 different human tumor xenograft models (colon, non-small cell lung, small cell lung, pancreatic, renal and cervical), grown subcutaneously in athymic nude mice.

Formulation design and high-throughput excipient selection based on structural integrity and conformational stability of dilute and highly concentrated IgG1 monoclonal antibody solutions.

A systematic approach is presented to characterize and stabilize the higher order structural integrity of an immunoglobulin G (IgG1) monoclonal antibody (mAb) formulated at both low concentrations and as a highly concentrated solution. The conformational and colloidal stabilities of a recombinant humanized IgG1κ mAb at both 1 and 100 mg/mL were investigated as a function of solution temperature (10°C-87.5°C) and pH (3-8).

Treatment of resistant human colon cancer xenografts by a fluoxetine-doxorubicin combination enhances therapeutic responses comparable to an aggressive bevacizumab regimen.

Pre-clinical studies of multidrug resistance (MDR) usually address severe resistance, yet moderate MDR is already clinically-impeding. The purpose of this study was to characterize moderate drug resistance in human colon cancer, and it's modulation by fluoxetine. In vitro fluoxetine enhanced doxorubicin's cytotoxicity (10-fold), increased doxorubicin's intracellular accumulation (32%) and decreased efflux of intracellular doxorubicin (70%).

Conformational lability of two molecular chaperones Hsc70 and gp96: effects of pH and temperature.

Hsc70 and gp96 are two heat shock proteins with molecular chaperone and immune-related activities. The dynamic conformational properties of heat shock proteins appear to play a critical role in their biological activities. In this study, we investigated the effects of pH and temperature on the conformational states of Hsc70 and gp96.

Effect of metal cations on the conformation and inactivation of recombinant human factor VIII.

Heavy metals have been implicated in the aggregation of proteins and the pathophysiology of several neurodegenerative diseases. Herein, we describe the interaction of recombinant human factor VIII (rhFVIII) with Al(+3), Tb(+3), Co(+2), and Fe(+3) using a combination of intrinsic fluorescence, circular dichroism, and high-resolution fourth-derivative absorbance analysis. rhFVIII in solution was titrated with the metal cations and the properties of the resulting complexes were examined.

Topology of factor VIII bound to phosphatidylserine-containing model membranes.

Factor VIII (FVIII), a plasma glycoprotein, is an essential cofactor in the blood coagulation cascade. It is a multidomain protein, known to bind to phosphatidylserine (PS)-containing membranes. Based on X-ray and electron crystallography data, binding of FVIII to PS-containing membranes has been proposed to occur only via the C2 domain.

N-hydroxy-3-phenyl-2-propenamides as novel inhibitors of human histone deacetylase with in vivo antitumor activity: discovery of (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (NVP-LAQ824).

A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines.

Conformational origin of the aggregation of recombinant human factor VIII.

Aggregation of proteins is a major problem in their use as drugs and is also involved in a variety of pathological diseases. In this study, biophysical techniques were employed to investigate aggregate formation in the pharmaceutically important protein, recombinant human factor VIII (rhFVIII). Recombinant human factor VIII incubated in solution at 37 degrees C formed soluble aggregates as detected by molecular sieve chromatography and dynamic light scattering.

A human vision based computational model for chromatic texture segregation.

We have developed a computational model for texture perception which has physiological relevance and correlates well with human performance. The model attempts to simulate the visual processing characteristics by incorporating mechanisms tuned to detect luminance-polarity, orientation, spatial frequency and color, which are characteristic features of any textural image. We obtained a very good correlation between the model's simulation results and data from psychophysical experiments with a systematically selected set of visual stimuli with texture patterns defined by spatial variations in color, luminance, and orientation.

Changes in tumor vascular permeability in response to experimental radioimmunotherapy: a comparative study of 11 xenografts.

Single and fractionated doses of radioimmunotherapy (RAIT) and standard chemotherapy (0.6 mg 5-FU/day and 0.36 leucovorin/day on days 1-5) result in decreases in vascular permeability (VP) in the GW-39 human colonic xenograft.

Characterization of aggregates of recombinant human factor VIII by size-exclusion chromatography and immunoassay.

The presence of aggregates of Factor VIII (FVIII) was assessed for a highly purified form (rFVIII) and for the formulated preparation containing human serum albumin (rFVIIIf). Size-exclusion chromatography (SEC) on Sepharose CL-6B and TSK 4000 matrices under native conditions revealed < 1% aggregates of FVIII in either rFVIII or rFVIIIf, as determined by FVIII immunoassay of chromatographic fractions. No degradation products were observed.

Quantitative and qualitative effects of experimental radioimmunotherapy on tumor vascular permeability.

Localization of radiolabeled antibodies in the perivascular space of tumors resulted in morphological changes in blood vessel structure and physiological changes in tumor vessel function. Vessel diameter decreased by day 14 and was associated with a significant decline in vascular volume (VV). Upon recovery of VV, the basement membrane surrounding the endothelium had thickened.

Comparison of equitoxic radioimmunotherapy and chemotherapy in the treatment of human colonic cancer xenografts.

The therapeutic efficacy of 5-fluorouracil (5-FUra; 0.6 mg/day x 5 days) + leucovorin (LV; 1.8 mg/day x 5 days) and of 131I-labeled MN-14 anticarcinoembryonic antigen IgG (275 microCi single dose) was evaluated in size-matched (0.

Physiological factors influencing radioantibody uptake: a study of four human colonic carcinomas.

We evaluated the accretion of 131I-labeled NP-4 anticarcinoembryonic antigen (CEA) into 4 size-matched human colonic carcinomas grown s.c. in nude mice.

Improved radioimmunotherapy of colorectal cancer xenografts using antibody mixtures against carcinoembryonic antigen and colon-specific antigen-p.

Radioimmunotherapy of GW-39 human colonic tumor xenografts grown in the hamster cheek pouch with 131I-labeled NP-4 anti-(carcinoembryonic antigen) (CEA) and 131I-labeled Mu-9 anti-(color-specific antigen-p) (CSAp) murine monoclonal antibodies, administered in combination, was more effective than using either antibody alone for tumor masses less than 0.5 cm3 in size. The antibody mixture had no therapeutic advantage for larger tumors.

Suppression of tumor vascular activity by radioantibody therapy: implications for multiple cycle treatments.

Autoradiographic analysis of the intratumor location of radioiodinated Mu-9 anti-CSAp antibody within 7 days of administration reveals a restricted distribution within 3-6 cell layers surrounding tumor vessels. Within 7-14 days after suboptimal radioantibody treatment (approximately 3000 rads), tumor vessel morphology and physiology are altered. Vessel number is reduced by 60-70%, vessel diameter is reduced, and remaining vessels are surrounded by fibrotic tissue.

The effect of antibody protein dose on the uniformity of tumor distribution of radioantibodies: an autoradiographic study.

The inaccessibility of radiolabeled antibody to poorly vascularized regions of solid tumors may reduce the therapeutic efficacy of these macromolecules. Theoretical mathematical models have predicted that increasing the protein dose administered would reduce the heterogeneity of radioantibody distribution. This investigation was undertaken to evaluate this hypothesis in experimental animal models.

Influence of animal host and tumor implantation site on radio-antibody uptake in the GW-39 human colonic cancer xenograft.

The magnitude and kinetics of tumor uptake of a monoclonal antibody (MAb) directed against carcinoembryonic antigen (CEA) in the GW-39 human colorectal cancer xenograft differ according to the animal used (nude mouse or hamster) and the site of implantation of the tumor within the animal (cheek pouch, leg muscle, subcutaneous or liver). Several physiological factors have been evaluated in an attempt to explain these differences in radio-antibody accumulation. The following observations have been made: (1) The animal host with the slower blood clearance of radio-antibody and the higher non-tumor tissue uptake has the higher tumor uptake; (2) the xenografts with a higher blood-flow rate, vascular volume and/or vascular permeability have a higher specific radio-antibody targeting; (3) the smaller, more viable tumors take up more radio-antibody per gram than the larger tumors; and (4) tumors with higher specific antigen content accrete more radio-antibody.

Comparison of therapeutic efficacy and host toxicity of two different 131I-labelled antibodies and their fragments in the GW-39 colonic cancer xenograft model.

The in vivo uptake, therapeutic potential, and host toxicity were evaluated for both the intact IgG and F(ab')2 fragment of 2 murine monoclonal antibodies (MAbs) directed against either carcino-embryonic antigen (CEA), called NP-4, or colon-specific antigen-p (CSAp), called Mu-9, in the GW-39 human colorectal carcinoma grown in the hamster cheek pouch. Mu-9 IgG and F(ab')2 were retained longer by the tumor than was the NP-4 IgG or F(ab')2, respectively. Localization of the two antibodies by micro-autoradiography revealed two distinct patterns.

A synergistic effect between anti-idiotype antibodies and anti-neoplastic drugs in the therapy of a murine B-cell tumor.

Antibodies directed against idiotypic determinants of the cell-surface IgM of a B lymphoma, 38c, were effective in delaying development of the tumor and in some instances in preventing its growth. The efficacity of the anti-idiotype antibodies was markedly increased when they were injected in combination with anti-neoplastic drugs. Since chemotherapy, as such, is limited by the general toxicity of the drugs it was of advantage to apply them in low doses.

The covalent linking of two nucleotide analogues to antibodies.

Two anticancer drugs, antagonists of nucleic acids, were covalently linked to antibodies specifically reactive with B leukemia cells and thus with a potential possibility of drug targeting to the tumor site. The drugs cytosine 1-beta-D-arabinoside and 5-fluorouridine, competitive inhibitors of enzymes involved in DNA synthesis, were linked to antibodies via a dextran bridge. Cytosine 1-beta-D-arabinoside was linked to periodate-oxidized dextran and fluorouridine to dextran hydrazide.