The HapImmune TM platform exploits covalent inhibitors as haptens for creating major histocompatibility complex (MHC)-presented tumor-specific neoantigens by design, combining targeted therapies with immunotherapy for the treatment of drug-resistant cancers. A HapImmune antibody, R023, recognizes multiple sotorasib-conjugated KRAS(G12C) peptides presented by different human leukocyte antigens (HLAs). This high specificity to sotorasib, coupled with broad HLA-binding capability, enables such antibodies, when reformatted as T cell engagers, to potently and selectively kill sotorasib-resistant KRAS(G12C) cancer cells expressing different HLAs upon sotorasib treatment. The loosening of HLA restriction could increase the patient population that can benefit from this therapeutic approach. To understand the molecular basis for its unconventional binding capability, we used single-particle cryogenic electron microscopy to determine the structures of R023 bound to multiple sotorasib–peptide conjugates presented by different HLAs. R023 forms a pocket for sotorasib between the V H and V L domains, binds HLAs in an unconventional, angled way, with V L making most contacts with them, and makes few contacts with the peptide moieties. This binding mode enables the antibody to accommodate different hapten–peptide conjugates and to adjust its conformation to different HLAs presenting hapten–peptides. Deep mutational scanning validated the structures and revealed distinct levels of mutation tolerance by sotorasib- and HLA-binding residues. Together, our structural information and sequence landscape analysis reveal key features for achieving MHC-restricted recognition of multiple hapten–peptide antigens, which will inform the development of next-generation therapeutic antibodies.

2023-01-01·International journal of thermophysics

PvT Properties and Thermodynamic Property Correlations for the Low Global Warming Potential Hydrofluoroolefin Refrigerant R-1132a (1,1-Difluoroethene).

Article

作者: Miyane, Kozue ; Higashi, Yukihiro ; Perera, Uthpala ; Sakoda, Naoya ; Thu, Kyaw

R-1132a is increasingly being considered as a low global warming potential component in alternative mixtures to R-23 in specialized low temperature and ultra-low temperature refrigeration systems. Though the thermodynamic properties of R-1132a were investigated in several studies up to 2018, reinvestigations have been carried out in recent years. In order to contribute toward these renewed measurements, the critical parameters of R-1132a were experimentally re-determined. Thirty-two vapor pressures from 240 K to the critical temperature, fifteen saturated vapor and six saturated liquid densities above 254 K and the PvT properties in both the vapor phase (98 points) and liquid phase (34 points) from densities of 50 kg·m^-3 to 760 kg·m^-3 were also measured. Specific correlations for each of these properties were optimized and compared to previously available data from the literature. Additionally, the Peng-Robinson equation of state was used to represent the aforementioned properties and further utilized to determine the enthalpy and entropy of R-1132a.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10765-023-03184-4.

2013-10-01·Theriogenology2区 · 农林科学

Resynchronization of estrous cycle with eCG and temporary calf removal in lactating Bos indicus cows

2区 · 农林科学

Article

作者: P.A. Lunardelli ; L.S.R. Marinho ; J.T. Campos ; F. Morotti ; M.M. Seneda

The aim of this study was to compare four methods of estrus resynchronization performed 23 days after timed artificial insemination (TAI) plus estrus observation in Bos indicus cows. Eight hundred fourteen lactating Nelore cows were submitted to TAI and then randomly assigned to one of the five following treatments: R23 (resynchronization without eCG), R23/200 (resynchronization with 200 IU of eCG), R23/300 (resynchronization with 300 IU of eCG), R23/TCR (resynchronization with temporary calf removal [TCR]), and a control group, with estrus observation followed by AI (with no resynchronization). Treatment consisted of a progesterone device plus administration of estradiol benzoate on Day 0; on Day 8, the device was removed and cloprostenol was applied, together with estradiol cypionate. Also on Day 8, either eCG was administered or TCR was performed in the resynchronized groups, except for R23. The females were inseminated 48 hours after device removal or TCR (33 days after the first TAI). The control group was kept under estrus observation from 18 to 23 days after the first TAI and was inseminated 12 hours after detection of estrus. The first pregnancy evaluation was performed using ultrasound examination 31 days after the first TAI. After 30 days of the resynchronization, a second pregnancy evaluation was performed and the animals in the R23/300 and R23/TCR groups achieved the highest conception rates, 76.6% and 74.0%, respectively (P < 0.05). There were no differences between the conception rates of the animals in the R23/200 (63.3%), R23 (61.3%), and control (54.3%) groups (P > 0.05). These results suggest that estrus resynchronization at 23 days after TAI can effectively improve the conception rate of lactating Bos indicus cows in a short time period. Furthermore, resynchronization with 300 IU of eCG or with TCR provided the best results.

100 项与 R023 相关的药物交易

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