In Northern Italy, 60 volunteers who thought they'd never suffered COVID-19 gave blood. 40 of them tested positive for antibodies to the virus. : Coronavirus

In איך החדר? by סיוון מזרחי

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Binding is expressed as Geometric mean Alexa 647 fluorescence intensity (Fl). Figure 21 shows the potency of the combination of humanized lgGl-hDR5-01-K409R-E430G + lgGl-hDR5-05-F405L-E430G antibodies and of the combination of humanized lgGl-DR5- 01-E430G + lgGl-DR5-05-E430G antibodies as measured in a viability assay on BxPC-3 pancreatic cancer cells.

Killing efficacy was restored when repulsion was neutralized by combining two antibodies each having one of the complementary mutations K439E or S440K. These data indicate that hexamerization by Fc-Fc interactions is required for the induction of cell death by lgGl-hDR5-01-G56T-E430G and lgGl-hDR5-05-E430G.

Innate immune system

Cells that eventually become T cells travel from the bone marrow to the thymus by way of our bloodstream where they mature (hence the name “T cell”). The thymus is located just above the heart behind the sternum, or breastbone. If the immune system is http://cryptolisting.org/coin/club a police force, the bone marrow is the police academy because this is where the different types of immune system cells are created. All cells of the immune system are created in the bone marrow from a common type of starting cell, called a stem cell.

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Treatment with a single dose of 0.5 mg/kg or 2 mg/kg of the antibody combination lgGl-DR5-01-K409R-E430G + IgGl- DR5-05-F405L-E430G resulted in complete tumor regression until the study was stopped on day 126. Treatment with 0.5 mg/kg and 2 mg/kg IgGl-CONA also induced tumor regression, but the regression was incomplete with recurring tumor outgrowth in all mice or almost all (7/8) mice, respectively. At 0.1 mg/kg, neither IgGl-CONA nor the combination of IgGl- DR5-01-K409R-E430G + lgGl-DR5-05-F405L-E430G showed anti-tumor activity. Figure 26B shows that on day 16 after tumor inoculation, tumor inhibition by 2 mg/kg and 0.5 mg/kg lgGl-D 5-01-K409 -E430G + lgGl-DR5-05-F405L-E430G was significantly better compared to an equivalent dose IgGl-CONA (unpaired t-test).

The number of people with primary glaucoma in the world by the year 2000 is estimated at nearly 66.8 million, with 6.7 million suffering from bilateral blindness. In developed countries, fewer than 50% of those with glaucoma are aware of their disease.

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Table 15 displays the data obtained from the initial buffer screen, wherein glutamate, acetate, succinate, histidine, citrate and phosphate buffers were tested. Figure 51 shows that introduction of the hexamerization-enhancing mutation E430G resulted in dose-dependent killing by lgGl-DR5-CONA-E430G, whereas the parental wild type antibody lgGl-DR5-CONA was not able to kill attached COLO 205 colon cancer cells. The combination lgGl-hDR5-01-G56T-E430G + lgGl-hDR5-05-E430G induced potent killing in BxPC-3 and HCT15 cells, and cytotoxicity was not further enhanced in the presence of a secondary crosslinker (Figure 44). In contrast, the efficacy of lgGl-DR5-CONA and the wild type antibody combination lgGl-hDR5-01-G56T + lgGl-hDR5-05 was enhanced by the presence of a secondary crosslinker in both BxPC-3 and HCT15.

In one embodiment the Fc region comprises a hexamerization enhancing mutation such as E345K and a hexamerization inhibiting mutation such as S440K. The term "caspase activation", as used herein, refers to cleavage of inactive pro- forms of effector caspases by initiator caspases, leading to their conversion into effector caspases, which in turn cleave protein substrates within the cell to trigger apoptosis.

In one embodiment the antibody comprises a further mutation at an amino acid position corresponding to one of the following positions S440 or K439 in human IgGl, EU numbering. In one embodiment the Fc region comprises a further mutation in a position corresponding to S440 or K439, with the proviso that the further mutation is not in position S440 if the hexamerization enhancing mutation is in S440. However, antibodies comprising hexamerization enhancing mutation in E430, beat cop igg E345 or S440 and a further mutation in K439 such a K439E do form oligomers with antibodies comprising a hexamerization enhancing mutation in E430 or E345 and a further mutation in S440 such as S440K. However, antibodies comprising hexamerization enhancing mutation in E430 or E345 and a further mutation in S440 such a S440K do form oligomers with antibodies comprising a hexamerization enhancing mutation in E430 or E345 and a further mutation in K439 such as K439E.

These data indicate that BsAB lgGl-DR5-01-K409R-E430G x DR5-05-F405L-E430G induces both the early and late stages of cell death in COLO 205 colon cancer cells, and does so more effectively than the bispecific antibody without the E430G hexamerization enhancing mutation. These data indicate that the combination of lgGl-DR5-01-K409R-E430G + lgGl-DR5-05- F405L-E430G induces both the early and late stages of cell death in COLO 205 colon cancer cells, and does so more effectively than the combination of the antibodies without the E430G hexamerization enhancing mutation. Figure 13 shows that the combination of lgGl-hDR5-01-G56T-E430G and lgGl-hDR5-05- E430G variants that both harbor the same repulsion mutation (K439E or S440K) showed strongly diminished killing efficacy in BxPC-3 (A) and HCT-15 cells (B).

Hereby are embodiments provided that allow compositions wherein hexamerization exclusively occur between combinations of antibodies comprising a K439E mutation and antibodies comprising a S440K mutation. In one embodiment the antibody is an anti-DR5 antibody and said anti-DR5 antibody has enhanced agonistic activity. That the anti-DR5 antibody has activity is to be understood as the antibody is able to cluster DR5 or activate at least the same intracellular pathways as TRAIL bound to DR5. That is anti-DR5 antibody with enhanced agonistic activity is able to induce increased level of apoptosis or programmed cell death in a cell or tissue expressing DR5 compared to TRAIL or a wild-type IgGl antibody against DR5. In one embodiment the Fc region comprises a further hexamerization-inhibiting mutation such as K439E or S440K in human IgGl, EU numbering.

Proteomics and Immunoproteomics e.g. in ocular fluids and tissues

Figure 49 shows evaluation of the in vivo efficacy of the combination of lgGl-hDR5-01- G56T-E430G + lgGl-hDR G antibodies in combination with 15 mg/kg paclitaxel in a subcutaneous xenograft model with SK-MES-1 human lung cancer cells. (A) Tumor size (mean & SEM) in mice treated with the indicated compounds is shown in time. (C) The percentage of mice with tumor sizes smaller than 500 mm3 is shown in a Kaplan-Meier plot. Figure 43 shows the kinetics of Caspase-3/7 activation upon binding of the antibody combination lgGl-hDR5-01-G56T-E430G + lgGl-hDR5-05-E430G on BxPC-3 pancreatic cancer cells, compared to the parental WT combination without the E430G mutation and TRAIL.

In another embodiment of the present invention the composition comprises a first antibody comprising at least two mutations such as E345K and K439E and a second antibody comprising at least two mutations such as E345K and S440K. Hereby are embodiments provided that allow for hexamerization of antibodies with different specificities.

  • Additionally, alterations in serum antibody profiles of glaucoma patients, upregulation (e.g. anti-HSP60, anti-MBP) and downregulation (e.g. anti ), have been described, but it still remains elusive if the autoantibodies seen in glaucoma are an epiphenomenon or causative.
  • DLS data showed that histidine pH 5.5 and 6.0 formulations in the presence of charged excipients had the least change in polydispersity.
  • e) the (VH) CDR1, CDR2, CDR3 and (VL) CDR1, CDR2 and CDR3 as defined in any one of a) to d) above having one to five mutations or substitutions in total across said six CDR sequences.
  • The TonSet values of succinate and histidine buffers as well as acetate pH 5.5 indicated that these two buffers between pH 5.5 and 6.5 confer greater thermal stability.
  • Variants of the human-mouse chimeric antibodies lgGl-DR5-01-K409R (A), lgGl-DR5-05-F405L (B) and bispecific antibody lgGl-DR5-01-K409R x lgGl-DR5-05-F405L (BsAb lgGl-DR5-01-K409R x DR5-05-F405L) (C) were tested flowcytometric analysis on FACS for binding to COLO 205 cells.
  • Recent animal model studies have shown a possible role of the immune system in the pathophysiology of glaucoma.

These stem cells later develop into specific cell types, including red blood cells, platelets (important for blood clotting), and white blood cells (important for immune responses). The cell generation and differentiation process occurs every day for as long as we live. As a result, in the same way that the red blood cells in our blood are replenished after an injury or blood donation, our immune system cells are constantly replenished. Available published data on glaucoma prevalence were reviewed to determine the relation of open angle and angle closure glaucoma with age in people of European, African, and Asian origin. A comparison was made with estimated world population data for the year 2000.

Finally, succinate buffer at pH 5.5 and 6.0 exhibited higher TonSet values, 50°C and 54°C, respectively, but were observed to have high levels of polydispersity (13.8% and 14.7%, respectively). Due to the inconclusive results in the aforementioned buffer formulations, all four buffers (glutamate, acetate, succinate, and histidine) were used in biophysical screening with excipients for further examination.

These data indicate that killing of BxPC-3 and HCT15 cancer cells by the antibody combination lgGl-hDR5-01-G56T- E430G + lgGl-hDR5-05-E430G is independent of the presence of a secondary Fc crosslinker. Figure 33 shows that the antibodies lgGl-hDR5-01-G56T-E430G and lgGl-hDR5-05-E430G showed similar dose-dependent binding to HCT 116 cells as their corresponding antibodies without the E430G mutation. Introduction of the E430G mutation had no effect on the binding of the DR5 antibodies. The EC50 values were calculated from six repeat experiments as 74.4 (+/- 58.4) ng/mL for lgGl-hDR5-01-G56T-E430G and 101.2 (+/- 52.6) ng/mL for lgGl-hDR5-05-E430G.

Improved methods of screening and therapy for glaucoma are urgently needed. The antibody concentrations obtained by UV analysis were not significantly different between agitated, freeze-thaw and control samples with different concentrations of PS-80, and ranged between 17.80 and 21.32 mg/mL (data not shown). Results from the DLS data from the initial biophysical screening did correlate strongly with formulation ranking results obtained from DSC for some formulations. Phosphate and citrate buffers exhibited high degrees of %Pd (14.1% – 18.9%) as well as relatively lower Tonset values (48°C – 51°C).

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Such tumors and/or cancers may all be suitable targets for treatment with anti-DR5 antibodies, bispecific antibodies and compositions comprising such antibodies according to the present invention. In one embodiment of the invention the composition comprises a first antibody comprising a mutation corresponding to K439 such as K439E and a second antibody comprising a mutation corresponding to S440 such as S440K. In one embodiment o fthe invention the composition comprises a first antibody comprising a mutation corresponding to S440 such as S440K and a second antibody comprising a mutation corresponding to K439 such as K439E. Hereby embodiment are provided wherein the composition comprises a first antibody comprising at least two mutations such as E430G and K439E and a second antibody comprising at least two mutations such as E430G and S440K.

In one embodiment the Fc region comprises a hexamerization enhancing mutation such as E430G and a hexamerization inhibiting mutation such as K439E. In one embodiment the Fc region comprises a hexamerization enhancing mutation https://cryptolisting.org/ such as E345K and a hexamerization inhibiting mutation such as K439E. In another embodiment the Fc region comprises a hexamerization enhancing mutation such as E430G and a hexamerization inhibiting mutation such as S440K.

Initial biophysical screening was performed to select buffer/pH combinations to move forward into the excipient screening. DSC analysis provided the melting temperatures (Tml and Tm2) along with the TonSet- DLS analysis provided information on polydispersity and hydrodynamic radius of the protein. Higher TonSet values indicate greater thermal stability, thus the buffers of extreme low and high pH (glutamate, acetate, citrate, and phosphate), having the lowest TonSet values, are not optimal. The TonSet values of succinate and histidine buffers as well as acetate pH 5.5 indicated that these two buffers between pH 5.5 and 6.5 confer greater thermal stability.

Figure 38 shows the efficacy of non-crossblocking antibodies lgGl-DR5-CONA-E430G + lgGl-DR5-chTRA8-E430G to induce killing of BxPC-3 urbonline human pancreatic cancer cells. (A) Crossblock ELISA between lgGl-DR5-CONA-K409R (CONA) and lgGl-DR5-chTRA8-F405L (chTRA8).

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(B) Introduction of the E430G hexamerization-enhancing mutation resulted in enhanced induction of killing of BxPC-3 cells by the combination of lgGl-DR5-CONA-C49W- E430G + lgGl-DR5-chTRA8-E430G as determined in a 3-days viability assay. Figure 36 shows a 3-days viability assay to show the effect of introducing the E430G mutation in the non-crossblocking antibodies lgGl-hDR5-01-G56T and lgGl-hDR5-05 on COLO 205 colon cancer cells. Figure 35 shows binding of anti-DR5 antibodies to human and cynomolgus monkey DR5. Antibodies lgGl-hDR5-01-G56T-E430G and lgGl-hDR5-05-E430G were tested by flow cytometry for binding to (A) human DR5-transfected CHO cells and (B) cynomolgus DR5- transfected CHO cells. Figure 34 shows binding to DR5-positive HCT 116 human colon cancer cells by anti-DR5 antibodies lgGl-hDR5-01-G56T-E430G and lgGl-hDR5-05-E430G as measured by flow cytometry with directly labeled antibodies.

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Due to the evidence of aggregation and thermal instability, these two formulations were eliminated from further study. The other formulations (glutamate, acetate, succinate, histidine) did not have strong correlations between DSC and DLS data. For example, 25 mM histidine pH 6.0 and 6.5 had %Pd of 18.5% and 23.3%, respectively, however these same two buffers exhibited some of the highest TonSet values, 53°C and 55°C, respectively. Both glutamate and acetate pH 4.5 buffers had somewhat lower TonSet values, between 46°C and 50°C, but had the lowest %Pd values (between 3.5% – 7.6%).

His-tagged recombinant protein was purified by immobilized metal affinity chromatography. Protein batches were analyzed by a number of bioanalytical assays including SDS-PAGE, size exclusion chromatography and measurement of endotoxin levels. In some of the Examples, reference antibodies against DR5 were used that have been previously described. IgGl-CONA (based on US B2 and WO2010/138725) and IgGl- chTRA8 (based on EP B1 and US B2) were cloned in the relevant antibody expression vectors as supra. Tumors and/or cancers may express DR5 on some tumor and/or cancer cells and/or tissues showing DR5 expression, some tumor and/or cancers may show over- expression or aberrant expression of DR5, whereas other tumors and/or cancers show heterogeneous expression of DR5.