Stratification of asthmatics based on relevant biomarkers enables it to predict the responsiveness against immune-targeted therapies in patients with asthma. Individualised therapy in patients with eosinophilic asthma has yielded improved clinical outcomes, and similar approaches in those with neutrophilic asthma have yet to be developed. We determined whether the colony stimulating factors (CSFs) in the airway reflect the inflammatory phenotypes of asthma and contribute to disease progression of neutrophilic asthma. We analysed three different mouse models of asthma and assessed the cytokine profiles in sputum from human patients with asthma stratified according to inflammatory phenotype; in addition, we evaluated the therapeutic efficacy of various cytokine blockades in a mouse model of neutrophilic asthma. Among the CSFs, airway granulocyte-CSF (G-CSF) contributes to airway neutrophilia by promoting neutrophil development in the bone marrow (BM), and thereby distinguishes neutrophilic inflammation from eosinophilic inflammation in mouse models of asthma. G-CSF is produced by concurrent stimulation of the lung epithelium with IL-17A and TNF-α; therefore, dual blockade of upstream stimuli using monoclonal antibodies or genetic deficiency of the cytokines in IL-17A × TNF-α double knockout (DKO) mice reduced the serum level of G-CSF, leading to alleviation of neutrophilic inflammation in the airway. In humans, the sputum level of G-CSF can be used to stratify patients with asthma with neutrophil-dominated inflammation. Our results indicated that myelopoiesis-promoting G-CSF and cytokines as the upstream inducing factors are potential diagnostic and therapeutic targets in patients with neutrophilic asthma.

Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3×m4-1BB elicited a 4-1BB–dependent antitumor response in hB7-H3–overexpressing tumor models without systemic toxicity. BsAb primarily targets CD8 T cells in the tumor and increases their proliferation and cytokine production. Among the CD8 T cell population in the tumor, 4-1BB is solely expressed on PD-1⁺Tim-3⁺ “terminally differentiated” subset, and bsAb potentiates these cells for eliminating the tumor. Furthermore, the combination of bsAb and PD-1 blockade synergistically inhibits tumor growth accompanied by further increasing terminally differentiated CD8 T cells. B7-H3×h4-1BB also shows antitumor activity in h4-1BB–expressing mice. Our data suggest that B7-H3×4-1BB is an effective and safe therapeutic agent against B7-H3–positive cancers as monotherapy and combination therapy with PD-1 blockade.

Lee and colleagues investigated the role of the intestinal microbiota in steady-state hematopoieisis, demonstrating that microbiota-derived DNA circulates to the bone marrow, where uptake by mononuclear cells leads to inflammatory cytokine production favoring myeloid-cell maturation of hematopoietic progenitors.

Ji-Hae Kim, Kun-Joo Lee & Seung-Woo Lee. BMB Reports 2021;54:21-30. https://doi.org/10.5483/BMBRep.2021.54.1.257

Following the clinical success of cancer immunotherapies such as immune checkpoint inhibitors blocking B7/CTLA-4 or PD-1/PD-L1 signaling and ongoing numerous combination therapies in the clinic,3 bispecific antibodies (BsAbs) are now emerging as a growing class of immunotherapies with the potential to improve clinical efficacy and safety further. Here, we describe four classes of BsAbs: (a) immune effector cell redirectors; (b) tumor-targeted immunomodulators; (c) dual immunomodulators; and (d) dual tumor-targeting BsAbs. This review describes each of these classes of BsAbs and presents examples of BsAbs in development. We reviewed the biological rationales and characteristics of BsAbs and summarized the current status and limitations of clinical development of BsAbs and strategies to overcome limitations. The field of BsAb-based cancer immunotherapy is growing, and more data from clinical trials are accumulating. Thus, BsAbs could be the next generation of new treatment options for cancer patients.

Moon D, et al. Immune Netw. 2022 Feb;22(1):e4. https://doi.org/10.4110/in.2022.22.e4