The invention relates generally to polypeptides that include at least a first cleavable moiety (CM1) that is a substrate for at least one matrix metalloprotease (MMP) and at least a second cleavable moiety (CM2) that is a substrate for at least one serine protease (SP), to activatable antibodies and other larger molecules that include these polypeptides that include at least a CM1 that is a substrate for at least one MMP protease and at least a CM2 that is a substrate for at least one SP protease, and to methods of making and using these polypeptides that include at least a CM1 that is a substrate for at least one MMP protease and at least a CM2 that is a substrate for at least one SP protease in a variety of therapeutic, diagnostic and prophylactic indications.

The present disclosure provides polypeptides derived from SARS-CoV-2 which have therapeutic use. One such polypeptide is a polypeptide, referred to as “Npep2,” is derived from the SARS-CoV-2 protein N and has at least 50 consecutive amino acids of the amino acid sequence having at least 90% identity with the amino acid sequence that ranges from the residue at position 276 to the residue at position 411 of SEQ ID NO:2. Further described are conjugates wherein a heterologous polypeptide is conjugated or fused to Npep2. The present disclosure further provides vaccines employing the polypeptides, polynucleotides encoding the polypeptides, and methods of vaccinating subjects against SARS-CoV-2 by administering a therapeutically effective amount of one or more of the polypeptides.

The present invention relates to, inter alia, compositions and methods, including chimeric proteins that find use in the treatment of disease, such as immunotherapies for cancer and autoimmunity. In part, the invention provides, in various embodiments, fusions of extracellular domains of transmembrane proteins that can have stimulatory or inhibitory effects.

Disclosed herein are compositions and methods for increasing the stability of recombinant nanobodies. Also disclosed herein are recombinant nanobodies comprising an IL-2 polypeptide that bind serum albumin and uses thereof for treating cancers.

The present invention relates to new CD22 Chimeric Antigen Receptors (CD22 CAR), an engineered immune cell endowed with said new CD22 CAR and comprising at least inactivated TRAC gene for use in therapy. The engineered immune cells endowed with such CARs are particularly suited for treating relapsed refractory CD22 expressing cancers.

The present disclosure provides pharmaceutical compositions comprising fibronectin based scaffold domain proteins that bind, for example, proprotein convertase subtilisin kexin-9 (PCSK9).

The present disclosure provides T-cell modulatory multimeric polypeptides (T-Cell-MMP) and their epitope conjugates comprising at least one immunomodulatory polypeptide (“MOD”) that may be selected to exhibit reduced binding affinity to a cognate co-immunomodulatory polypeptide (“Co-MOD”). The epitope may be, for example, a cancer-associated epitope, an infectious disease-associated epitope, or a self-epitope. The T-Cell-MMP-epitope conjugates are useful for modulating the activity of a T-cell by delivering immunomodulatory peptides, such as IL-2 or IL-2 variants that exhibit reduced binding affinity for the IL-2R, to T-cells in an epitope selective/specific manner, and accordingly, for treating individuals with a cancer, infectious disease or autoimmune disorder.

Described herein are compositions and techniques related to generation and therapeutic application of artificial synapses. Artificial synapses are engineered extracellular vesicles, including exosomes, which incorporate sticky binders on their surface to anchor signaling domains against biological targets, such as receptors. These engineered additives can be organized in genetic vector constructs, expressed in mammalian cells, wherein the sticky binders attach to extracellular vesicles such as exosomes, thereby presenting their joined signaling domains which are rapidly taken up by recipient cells. Artificial synapses adopt the hallmark biophysical and biochemical features of extracellular vesicles, allowing for rapid deployment and scale-up. Importantly, this strategy can allow for kinetically favorable signal generation and signal propagation. This includes, for example, increasing density of agonist presentation to support receptor clustering—an onerous barrier for traditional receptor targeting strategies.

Disclosed herein include methods, compositions, and kits suitable for use in vaccination. There are provided, in some embodiments, nucleic acid compositions (e.g., mRNA vaccine, DNA vaccine) comprising a polynucleotide encoding a fusion protein. The fusion protein can comprise an antigenic polypeptide (AP) and an endosomal sorting complex required for transport (ESCRT)-recruiting domain (ERD). A plurality of fusion proteins can be capable of self-assembling into an enveloped nanoparticle (ENP) secreted from a cell in which the fusion proteins are expressed. There are provided, in some embodiments, populations of ENPs.

RNA Control Devices and/or destabilizing elements (DE) can regulate the expression of Chimeric Antigen Receptors (CARs) in eukaryotic cells. More specifically, DEs, RNA Control Devices, and/or side-CARs can be used with small molecule ligands to regulate the expression of Chimeric Antigen Receptors. These DE-CARs, Smart CARs (Smart=small molecule actuatable RNA trigger), Smart-DE-CARs, and/or Side-CARs can be used in the treatment of disease.