A5087915072- Cytokine Signaling Pathways and Interactions
- Protein Structure and Dynamics
- Monoclonal and Polyclonal Antibodies Research
- Spectroscopy and Quantum Chemical Studies
- Cancer Immunotherapy and Biomarkers
- Protein purification and stability
- Enzyme Structure and Function
- DNA and Nucleic Acid Chemistry
- Virus-based gene therapy research
- Viral Infectious Diseases and Gene Expression in Insects
- Molecular spectroscopy and chirality
- Immunotherapy and Immune Responses
- Advanced Chemical Physics Studies
- CAR-T cell therapy research
- Spectroscopy Techniques in Biomedical and Chemical Research
- Nanoplatforms for cancer theranostics
- interferon and immune responses
- HER2/EGFR in Cancer Research
- Transgenic Plants and Applications
- Proteins in Food Systems
- Mass Spectrometry Techniques and Applications
- Thin-Film Transistor Technologies
- Glycosylation and Glycoproteins Research
- ZnO doping and properties
- RNA and protein synthesis mechanisms
Xilio Therapeutics (United States)
2020-2023
The Sanskrit College and University
2023
Pfizer (United States)
2016-2021
Johns Hopkins University
2013-2018
Rice University
2018
Early stage developability assessments of monoclonal antibody (mAb) candidates can help reduce risks and costs associated with their product development. Forecasting viscosity highly concentrated mAb solutions is an important aspect such assessments. Reliable predictions concentration-dependent behaviors for in platform formulations screen or optimize drug flexible manufacturing delivery options. Here, we present a computational method to predict curves mAbs solely from sequence-structural...
The impact of drug loading and distribution on higher order structure physical stability an interchain cysteine-based antibody conjugate (ADC) has been studied. An IgG1 mAb was conjugated with a cytotoxic auristatin payload following the reduction disulfides. 2-D LC-MS analysis shows that there is preference for certain isomers within various to ratios (DARs). unconjugated monoclonal antibody, ADC, isolated species specific DAR, were compared using calorimetric, thermal, chemical...
Simulations and experiments show oligo-glycines, polypeptides lacking any side chains, can collapse in water. We assess the hydration thermodynamics of this by calculating free energy at each end points reaction coordinate, here taken as end-to-end distance (r) chain. To examine role various conformations for a given r, we study conditional distribution, P(Rg|r), radius gyration value r. The change versus Rg, -kBT ln is found to vary more gently compared corresponding variation excess...
For a model deca-alanine peptide the cavity (ideal hydrophobic) contribution to hydration favors helix state over extended states and paired bundle in assembly of two helices. The energetic contributions attractive protein-solvent interactions are separated into quasi-chemical components consisting short-range part arising from with solvent first shell remaining long-range that is well described by Gaussian. In helix-coil transition, outweigh hydrophobic favor coil states. Analysis enthalpic...
Developability considerations should be integrated with lead engineering of antibody drug candidates in interest their cost effective translations into medicines. To explore feasibility this imperative, we have performed rational mutagenesis studies on a monoclonal (MAB1) whose development was discontinued owing to manufacturability hurdles. Seven computationally designed variants MAB1 containing single point (V44K, E59S, E59T and E59Y) double (V44KE59S, V44KE59T V44KE59Y) mutations its...
We address the association of hydrophobic driving forces in protein folding with inverse temperature dependence hydration, wherein stabilizing hydration effects strengthen increasing a physiological range. All-atom calculations free energy aqueous deca-alanine conformers, holistically including backbone and side-chain interactions together, show that attractive peptide–solvent thermal expansion solvent dominate signatures have been interpreted traditionally as stabilization proteins...
The hydration thermodynamics of the amino acid X relative to reference G (glycine) or a small-molecule analog side chain is often used model contribution protein stability and solution thermodynamics. We consider reasons for successes limitations this approach by calculating comparing conditional excess free energy, enthalpy, entropy isoleucine in zwitterionic isoleucine, extended penta-peptides, helical deca-peptides. Butane gauche conformation serves as chain. Parsing hydrophobic...
Abstract IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells tumors. However, systemic administration been accompanied considerable toxicity, prompting interest researching alternatives to drive preferential bioactivity tumor. Here, we have generated XTX301, tumor-activated linked human Fc protein via protease cleavable linker pharmacologically inactivated an receptor subunit beta 2 masking...
The occupancy distribution of water molecules in the first hydration shell around a solute is intimately connected with solvent density fluctuations and fundamental interest understanding hydration. free energies to evacuate cavity defined by depend on system size, emphasizing that are themselves dependent size. This observation interpreted within quasichemical theory shows both hydrophilic hydrophobic contributions decreasing increasing net energy benefits somewhat from compensation...
We study the solvation free energy of two different conformations (helix and extended) peptides (deca-alanine deca-glycine) in solvents (water aqueous guanidinium chloride, GdmCl). The energies are obtained using quasichemical organization potential distribution theorem, an approach that naturally provides repulsive (solvophobic or cavity) attractive (solvophilic) contributions to solvation. solvophilic contribution is further parsed into a chemistry arising from solute interaction with...
<div>Abstract<p>IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells tumors. However, systemic administration IL12 been accompanied considerable toxicity, prompting interest researching alternatives to drive preferential bioactivity tumor. Here, we have generated XTX301, tumor-activated linked human Fc protein via protease cleavable linker pharmacologically inactivated an receptor...
<p>Supplemental Figure S1: A representative triplex fluorescent western blot image showing cleavage of XTX301 in primary human tumor specimens. Antibodies against IL-12 (Green), IL-12Rβ2 (Red) and IgG (Blue) were used, a merged is shown the figure. The 145 Kda band intact or non-cleavable construct, 85Kda cleaved XTX301/unmasked green arrow indicates free released upon XTX301. % mXT301 refers to percentage molecule compared total (intact cleaved) detected by using IL-12R2 signal.</p>
<div>Abstract<p>IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells tumors. However, systemic administration IL12 been accompanied considerable toxicity, prompting interest researching alternatives to drive preferential bioactivity tumor. Here, we have generated XTX301, tumor-activated linked human Fc protein via protease cleavable linker pharmacologically inactivated an receptor...
<p>Supplemental Figure S4: Gating strategy for multi-color flow cytometry analysis of tumor-infiltrating and splenic immune cell populations.</p>
<p>Supplemental Figure S2: XTX301 demonstrates enhanced activity upon proteolytic cleavage in primary cells. (a) Primary mouse splenocytes were pre-activated with PMA & Ionomycin and then incubated varying doses of rm IL-12 murine surrogate test articles for 24 hours, supernatants assessed by IFN- ELISA. (b) Human peripheral blood mononuclear cells (PBMCs) preactivated + 4 days (c) Cynomolgus monkey PBMCs rhIL-12 hours evaluated production ELISA.</p>
<p>Supplemental Figure S5: IFN- production in plasma: MC38 tumor-bearing mice were treated with the indicated doses of mXT301 or unmasked control. Plasma concentration was measured by MSD assay at time points. The data represent mean ± SEM, N = 3 to 5 per group, and level assessed a two-way ANOVA Bonferroni’s post-hoc pairwise comparison test compared vehicle (PBS) animals (*p < 0.05, **p 0.005, ****p 0.0001)</p>
<p>Supplemental Figure S3: Repeated mXTX301 dosing was well tolerated and resulted in dose dependent TGI mice bearing large (~360mm3) MC38 tumors (a) C57BL/6J were implanted subcutaneously with tumor cells received a single intravenous injection of mXTX301, unmasked control, or vehicle (PBS) at indicated levels (N=12 per group). Tumor measurements taken two/three times week. Animals euthanized due to health issues body weight loss. The data represent individual survival curves. CR:...
<p>Supplemental Figure S7: XTX301 caused transient and reversible changes to LFTs other safety parameters in NHP a repeat dose GLP toxicology study. Male female NHPs (N=3/sex; 2/sex for recovery animals) were administered by intravenous infusion once weekly total of four doses, followed four-week period. Changes (a) aspartate aminotransferase, (b) alanine (c) lymphocytes, (d) albumin, (e) IFN- fully the main study animals. All values are shown as mean ± SD. The reference ranges,...