The invention is directed to treatment of cancer, infections and various inflammatory and autoimmune conditions by affecting regulatory T cell stability and function via a Neuropilin-1:Semaphorin axis.

The present disclosure relates to a method of screening an anti-NRP1 antibody or an antigen-binding fragment thereof by use of patient-derived tumor spheroids overexpressing NRP1 and an animal model comprising the same, and more particularly to a method of screening an antibody or an antigen-binding fragment thereof through in vitro and in vivo panning by use of a patient-derived tumor spheroid containing NRP1 and an animal model transplanted with the same, respectively.

The compositions and methods described herein are based, in part, on the discovery that regulatory B cells (Bregs) differentially express a specific set of coinhibitory molecules, including TIGIT, LAG-3, PD-1, CTLA4, and TIM-3. The data described herein indicate that TIGIT is required for both Breg-mediated tolerance maintenance at the steady state, and inflammation restraint during autoimmune and inflammatory diseases. Accordingly, provided herein are compositions and methods targeting coinhibitory molecules, such as TIGIT, LAG-3, PD-1, CTLA4, and TIM-3, in B cells, as novel therapeutic strategies for modulating immune suppression and treating diseases mediated or impacted by immune suppression mechanisms, such as autoimmune diseases and cancers.

Disclosed herein are non-human animals (e.g., rodents, e.g., mice or rats) genetically engineered to express a humanized or human T cell receptor (TCR) comprising a variable domain encoded by (a) at least one human TCR variable region ? gene segment and a (human) TCR ? constant region gene sequence and/or (b) or at least one human TCR variable region ? gene segment and a (human) TCR ? constant region gene sequence. Also provided are embryos, tissues, and cells expressing the same. Methods for making a genetically engineered animal that expresses the humanized or human ? and/or ? TCR are also provided. Methods for using the genetically engineered animals that mount a substantially humanized T cell immune response for developing human therapeutics are also provided.

The disclosure provides methods for rapid screening of the efficacy of immunoregulatory drugs, especially for cancer drug screening and treatment. The methods comprise an animal model wherein polymeric capsule tubes contain cells comprising tumor cells and immune cells in a single cell suspension. The capsule device is implanted into a mouse that is treated with an anti-cancer drug, especially an immunomodulatory anti-cancer drug. The methods provide a rapid and effective way for determining a specific individual's clinical response to an immunomodulatory drug with extremely high speed and subsequent efficacious treatment in the clinical setting.

The present disclosure provides a model and method for rapid screening the efficacy of immunoregulatory drugs. The method comprises constructing an animal model containing PVDF capsule tubes, and further comprises analyzing the pharmacodynamic data for the animal model in vivo, phenotype identification by paired flow cytometry and multi-omics data. The PVDF capsule tubes have cells comprising tumor cells and immune cells in a single cell suspension; wherein the tumor cells and immune cells are derived from fresh tumor tissues or body fluids of clinical patients. The animal model constructed according to the present disclosure can be used for immune system targeting and drug efficacy regulation screening, and drug screening for multiple patients at the same time. It provides a rapid and effective method and model for clinical precision medicine and new drug development.

Compositions and methods are provided for modifying a genomic locus of interest in a eukaryotic cell, a mammalian cell, a human cell or a non-human mammalian cell using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Further methods combine the use of the LTVEC with a CRISPR/Cas system. Compositions and methods for generating a genetically modified non-human animal comprising one or more targeted genetic modifications in their germline are also provided.

In one aspect, the invention provides methods of inhibiting the effects of MASP-2-dependent complement activation in a human subject suffering from graft-versus-host disease and/or diffuse alveolar hemorrhage and/or veno-occlusive disease associated with a hematopoietic stem cell transplant. The methods comprise the step of administering, to a subject in need thereof, an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

Compositions and methods for attenuating or preventing lymphoproliferation in a subject are provided. The subject may have, be suspected of having, or at risk of having a lymphoproliferative disease. The methods herein include administering to the subject a composition effective for decreasing WD repeat domain protein 37 (Wdr37) expression and/or activity.

The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) CD3e (T-cell surface glycoprotein CD3 epsilon chain), and methods of use thereof.