The present and future of bispecific antibodies for cancer therapy.

Co-signaling receptors for the T cell receptor are important therapeutic targets, with blockade of co-inhibitory receptors such as PD-1 now central in immuno-oncology. Advancing additional therapeutic immune modulation approaches requires understanding ligand regulation of other co-signaling receptors. One poorly understood potential therapeutic target is TIM-3 (T cell immunoglobulin and mucin domain containing-3). Which of TIM-3's several proposed regulatory ligands is/are relevant for signaling is unclear, and different studies have reported TIM-3 as a co-inhibitory or co-stimulatory receptor in T cells. Here, we show that TIM-3 promotes NF-kB signaling and IL-2 secretion following T cell receptor stimulation in Jurkat cells, and that this activity is regulated by binding to phosphatidylserine (PS). TIM-3 signaling is stimulated by PS exposed constitutively in cultured Jurkat cells, and can be blocked by mutating the PS-binding site or by occluding this site with an antibody. We also find that TIM-3 signaling alters CD28 phosphorylation. Our findings clarify the importance of PS as a functional TIM-3 ligand, and may inform the future exploitation of TIM-3 as a therapeutic target.

Phosphatidylserine binding directly regulates TIM-3 function.

Glioblastoma multiforme (GBM) is the most malignant intracranial tumor in adults, characterized by extensive infiltrative growth, high vascularization, and resistance to multiple therapeutic approaches. Among the many factors affecting the therapeutic effect, the immunosuppressive GBM microenvironment that is created by cells and associated molecules via complex mechanisms plays a particularly important role in facilitating evasion of the tumor from the immune response. Accumulating evidence is also revealing a close association of the gut microbiota with the challenges in the treatment of GBM. The gut microbiota establishes a connection with the central nervous system through bidirectional signals of the gut–brain axis, thus affecting the occurrence and development of GBM. In this review, we discuss the key immunosuppressive components in the tumor microenvironment, along with the regulatory mechanism of the gut microbiota involved in immunity and metabolism in the GBM microenvironment. Lastly, we concentrate on the immunotherapeutic strategies currently under investigation, which hold promise to overcome the hurdles of the immunosuppressive tumor microenvironment and improve the therapeutic outcome for patients with GBM.

/pdf/the-immunosuppressive-microenvironment-and-immunotherapy-in-tirpk555.pdf

The immunosuppressive microenvironment and immunotherapy in human glioblastoma

Background Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and exert an important role in tumor progression. Due to the heterogeneity and plasticity of TAMs, modulating the polarization states of TAMs is considered as a potential therapeutic strategy for tumors. Long noncoding RNAs (lncRNAs) have been implicated in various physiological and pathological processes, yet the underlying mechanism on how lncRNAs manipulate the polarization states of TAMs is still unclear and remains to be further investigated. Methods Microarray analyses were employed to characterize the lncRNA profile involved in THP-1-induced M0, M1 and M2-like macrophage. Among those differentially expressed lncRNAs, NR_109 was further studied, for its function in M2-like macrophage polarization and the effects of the condition medium or macrophages mediated by NR_109 on tumor proliferation, metastasis and TME remodeling both in vitro and in vivo. Moreover, we revealed how NR_109 interacted with far upstream element-binding protein 1 (FUBP1) to regulate the protein stability through hindering ubiquitination modification by competitively binding with JVT-1. Finally, we examined sections of tumor patients to probe the correlation among the expression of NR_109 and related proteins, showing the clinical significance of NR_109. Results We found that lncRNA NR_109 was highly expressed in M2-like macrophages. Knockdown NR_109 impeded IL-4 induced M2-like macrophage polarization and significantly reduced the activity of M2-like macrophages to support the proliferation and metastasis of tumor cells in vitro and in vivo. Mechanistically, NR_109 competed with JVT-1 to bind FUBP1 at its C-terminus domain, impeded the ubiquitin-mediated degradation of FUBP1, activated c-Myc transcription and thus promoted M2-like macrophages polarization. Meanwhile, as a transcription factor, c-Myc could bind to the promoter of NR_109 and enhance the transcription of NR_109. Clinically, high NR_109 expression was found in CD163+ TAMs from tumor tissues and was positively correlated with poor clinical stages of patients with gastric cancer and breast cancer. Conclusions Our work revealed for the first time that NR_109 exerted a crucial role in regulating the phenotype-remodeling and function of M2-like macrophages via a NR_109/FUBP1/c-Myc positive feedback loop. Thus, NR_109 has great translational potentials in the diagnosis, prognosis and immunotherapy of cancer.

/pdf/the-nr-109-fubp1-c-myc-axis-regulates-tam-polarization-and-2m8zzql1.pdf

The NR_109/FUBP1/c-Myc axis regulates TAM polarization and remodels the tumor microenvironment to promote cancer development

High antibody affinity against the ancestral SARS-CoV-2 strain seems to be necessary (but not always sufficient) for the control of emerging immune-escape variants. Therefore, aiming at strong B cell somatic hypermutation - not only at high antibody titers - is a priority when utilizing vaccines that are not targeted at individual variants. Here, we developed a next-generation sequencing based SARS-CoV-2 B cell tracking protocol to rapidly determine the level of immunoglobulin somatic hypermutation at distinct points during the immunization period. The percentage of somatically hypermutated B cells in the SARS-CoV-2 specific repertoire was low after the primary vaccination series, evolved further over months and increased steeply after boosting. The third vaccination mobilized not only naïve, but also antigen-experienced B cell clones into further rapid somatic hypermutation trajectories indicating increased affinity. Together, the strongly mutated post-booster repertoires and antibodies deriving from this may explain why the booster, but not the primary vaccination series, offers some protection against immune-escape variants such as Omicron B.1.1.529. Brief summary Priming SARS-CoV-2 vaccinations generate antibodies from low-level matured B cells while the third vaccination strongly boosts somatic hypermutation potentially explaining different protection from immune-escape variants.

/pdf/rapid-hypermutation-b-cell-trajectory-recruits-previously-qb5b2sj5.pdf

Rapid Hypermutation B Cell Trajectory Recruits Previously Primed B Cells Upon Third SARS-Cov-2 mRNA Vaccination

The present invention relates to novel antibodies and antibody fragments that specifically bind to PD-L1 and compositions containing the same. Furthermore, the invention relates to nucleic acids encoding the antibodies or antibody fragments thereof, and host cells comprising the same, and related uses. Furthermore, the invention relates to the therapeutic and diagnostic use of these antibodies and antibody fragments. In particular, the invention relates to the combination therapy of these antibodies and antibody fragments with other therapies.

Anti PD-L1 antibodies and uses thereof

IBI112, a selective anti-IL23p19 monoclonal antibody, displays high efficacy in IL-23-induced psoriasiform dermatitis

The present invention provides antibodies and antibody fragments that specifically bind to IL-23p19 and compositions containing the antibodies or antibody fragments. In addition, the present invention also provides nucleic acids encoding the antibodies or antibody fragments thereof, and host cells comprising the antibodies or antibody fragments thereof, and related uses. In addition, the present invention also provides the therapeutic and diagnostic uses of these antibodies and antibody fragments.

Anti-il-23p19 antibody and uses thereof

The invention relates to a novel antibody capable of specifically binding PD-L1, an antibody fragment and a composition containing the antibody or the antibody fragment. In addition, the invention relates to nucleic acid for coding the antibody or the antibody fragment, a host cell containing the nucleic acid, and relevant purpose. In addition, the invention relates to the treatment and diagnosispurpose of the antibody and the antibody fragment. Specifically, the invention relates to united treatment of the antibody, the antibody fragment and other treatment methods.

PD-L1 resisting antibody and purpose thereof

The invention relates to a novel antibody and an antibody fragment that specifically bind to PD-L1 and a composition comprising the antibody or the antibody fragment. In addition, the invention relates to a nucleic acid encoding the antibody or the antibody fragment thereof, a host cell comprising the nucleic acid, and a related use. Furthermore, the invention relates to a therapeutic and diagnostic use of these antibodies and antibody fragments. Particularly, the invention relates to a combined treatment of these antibodies and antibody fragments with other therapies.

Anti-pd-l1 antibody and uses thereof

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