IL-2Rα-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating CD25+CD8+ T cells.

To avoid regulatory T cell promotion and vascular toxicity, the interleukin-2 receptor-ß/interleukin-2 receptor-γ (IL-2Rßγ)-biased approach is used by most IL-2 analogs in immuno-oncology. However, recent clinical disappointments in these IL-2 agonists have questioned this strategy. Here we show that both wild-type (IL-2wt) and IL-2Rßγ-attenuated (IL-2α-bias) agonists that preserve IL-2Rα (CD25) activities can effectively expand tumor-specific CD8+ T cells (TSTs) and exhibit better antitumor efficacy and safety than the 'non-α' counterpart (IL-2nα). Mechanistically, TSTs coexpress elevated CD25 and PD-1 and are more susceptible to stimulation by IL-2Rα-proficient agonists. Moreover, the antitumor efficacy of anti-PD-1 depends on activation of PD-1+CD25+ TSTs through autocrine IL-2-CD25 signaling. In individuals with cancer, a low IL-2 signature correlates with non-responsiveness to anti-PD-1 treatment. In mouse models, IL-2α-bias, but not IL-2nα, restores the IL-2 signature and synergizes with anti-PD-1 to eradicate large established tumors. These findings underscore the indispensable function of CD25 in IL-2-based immunotherapy and provide rationales for evaluating IL-2Rα-biased agonists in individuals with cancer.

Pharmacology, pharmacokinetics, and toxicity characterization of a novel anti-CD73 therapeutic antibody IBI325 for cancer immunotherapy.

It is an intriguing approach to target the ecto-5'-nucleotidase CD73 to confer synergetic beneficial survival in cancer patients, along with clinically established immunotherapy targets. In this study, a fully human, subnanomolar affinity CD73 antibody IBI325 was developed using the yeast display platform. Compared with Oleclumab, IBI325 was equivalent in hCD73 affinity and more potent in cell-bound and soluble CD73 enzymatic inhibition, and no hook effects were observed. Correspondingly, adenosine monophosphate-mediated immune suppression was reversed by IBI325, and significant T cell proliferation and release of cytokines were observed. Also, IBI325 enhanced the T cell recall response by inducing interferon-γ secretion. The antitumor efficacy of IBI325 was investigated in a hPBMC-reconstituted NOG mouse model, and a hCD73 knock-in mouse model. Consequently, IBI325 induced a significant tumor regression by inducing intratumoral immune cell expansion, and a combo therapy of IBI325 and aPD-1 was superior in efficacy than aCD73 or aPD-1 monotherapy. Additionally, the binding epitopes of CD73 to IBI325 were distinct from previously reported aCD73 therapeutics. IBI325 displayed acceptable pharmacokinetics and sufficient tolerable safety profiles to support clinical development. In conclusion, the pharmacology, pharmacokinetics, and toxicity profiles of IBI325 with complete CD73 inhibition were characterized, and encouraging preclinical outcomes were reported.

Characterization of anti-CD79b/CD3 bispecific antibody, a potential therapy for B cell malignancies.

High rates of relapse and poor prognosis confer an urgent need for novel therapeutic agents for B cell non-Hodgkin lymphomas (B-NHLs). Herein, we describe a human IgG-like anti-CD79b/CD3 bispecific antibody (IBI38D9-L) that selectively depletes antigen-positive malignant B cells as an alternative treatment option for relapsed or refractory NHL patients. The antitumor activity and mechanism of action of IBI38D9-L were investigated in vitro using B-NHL cell lines and human primary effector cells and in vivo using xenograft models reconstituted with human PBMCs (peripheral blood mononuclear cells). Pharmacokinetic (PK) properties and preclinical toxicology were evaluated in cynomolgus monkeys and HSC-NPG mice. IBI38D9-L exerted potent B cell killing as well as T cell activation and proliferation in a tumor cell-dependent manner in vitro and was active against B-NHL cell lines with various CD79b expression levels. Subcutaneous xenograft tumors in NOG mice engrafted with human PBMCs were eradicated by IBI38D9-L treatment. Moreover, IBI38D9-L-treated mice showed a strong infiltration of activated T cells. In HSC-NPG mice, IBI38D9-L resulted in potent B cell depletion in peripheral blood and induced only slight body weight loss and cytokine release syndrome without significant toxicological findings. In cynomolgus monkeys, IBI38D9-L was well tolerated with good pharmacokinetic profiles. Collectively, these preclinical efficacy and safety data provide strong scientific rationales for using anti-CD79b/CD3 bispecific antibody as a promising therapeutic agent for B cell malignancies.

Optimal target saturation of ligand-blocking anti-GITR antibody IBI37G5 dictates FcγR-independent GITR agonism and antitumor activity.

Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a co-stimulatory receptor and an important target for cancer immunotherapy. We herein present a potent FcγR-independent GITR agonist IBI37G5 that can effectively activate effector T cells and synergize with anti-programmed death 1 (PD1) antibody to eradicate established tumors. IBI37G5 depends on both antibody bivalency and GITR homo-dimerization for efficient receptor cross-linking. Functional analyses reveal bell-shaped dose responses due to the unique 2:2 antibody-receptor stoichiometry required for GITR activation. Antibody self-competition is observed after concentration exceeded that of 100% receptor occupancy (RO), which leads to antibody monovalent binding and loss of activity. Retrospective pharmacokinetics/pharmacodynamics analysis demonstrates that the maximal efficacy is achieved at medium doses with drug exposure near saturating GITR occupancy during the dosing cycle. Finally, we propose an alternative dose-finding strategy that does not rely on the traditional maximal tolerated dose (MTD)-based paradigm but instead on utilizing the RO-function relations as biomarker to guide the clinical translation of GITR and similar co-stimulatory agonists.

Production of D-tagatose, a functional sweetener, utilizing alginate immobilized Lactobacillus fermentum CGMCC2921 cells.

D-tagatose is a ketohexose that can be used as a novel functional sweetener in foods, beverages, and dietary supplements. This study was aimed at developing a high-yielding D-tagatose production process using alginate immobilized Lactobacillus fermentum CGMCC2921 cells. For the isomerization from D-galactose into D-tagatose, the immobilized cells showed optimum temperature and pH at 65 °C and 6.5, respectively. The alginate beads exhibited a good stability after glutaraldehyde treatment and retained 90% of the enzyme activity after eight cycles (192 h at 65 °C) of batch conversion. The addition of borate with a molar ratio of 1.0 to D-galactose led to a significant enhancement in the D-tagatose yield. Using commercial ß-galactosidase and immobilized L. fermentum cells, D-tagatose was successfully obtained from lactose after a two-step biotransformation. The relatively high conversion rate and productivity from D-galactose to D-tagatose of 60% and 11.1 g l⁻¹ h⁻¹ were achieved in a packed-bed bioreactor. Moreover, lactobacilli have been approved as generally recognized as safe organisms, which makes this L. fermentum strain an attracting substitute for recombinant Escherichia coli cells among D-tagatose production progresses.