Abstract: The present disclosure provides fusion proteins with a multifunctional biologic design for programmed target engagement. In certain embodiments, the fusion proteins described herein provide for concurrent T cell and target antigen engagement and immune checkpoint targeting.

Abstract: Systems and methods for polymer sequence prediction are provided. Atomic coordinates for at least the main chain atoms of a polypeptide comprising a plurality of residues is obtained and used to encode the residues into residue feature sets. Each residue feature set comprises, for the respective residue and for each neighboring residue within a nearest neighbor cutoff, an indication of secondary structure, a relative solvent accessible surface area of backbone atoms, and cosine and sine values of backbone dihedrals; a C? to C? distance of each neighboring residue; and an orientation and position of each neighboring residue backbone relative to the backbone residue segment of the respective residue. A residue in the plurality of residues is identified, and the corresponding residue feature set is inputted into a neural network comprising at least 500 parameters, thus obtaining a plurality of probabilities, including a probability for each naturally occurring amino acid.

Abstract: Disclosed systems and methods obtain a graph of a polymer comprising nodes and edges, the nodes representing polymer atoms, the edges encoding distances and relative orientations between corresponding pairs of nodes and whether pairs of nodes are covalently bound. Each subgraph in a plurality of first partial-context subgraphs of the graph is sequentially inputted into a first model to calculate first side chain dihedral angles for polymer residues. This updates the graph through first side chain dihedral angles. Each second subgraph in a plurality of second partial-context subgraphs of the updated graph is inputted into a second model, thereby obtaining calculated second side chain dihedral angles for polymer residues that serve to update the graph through second side chain dihedral angles. The graph is again updated with updated side chain dihedral angle values obtained by sequentially inputting full-context subgraphs, each such subgraph representing a different residue, into a full-context model.

Abstract: Disclosed herein are isolated multi-specific heteromultimer constructs that bind to CD3 expressed on T-cells and to an antigen expressed on B-cells. The multi-specific heteromultimer constructs are capable of bridging T- and B-cells and mediating killing of B-cells. The multi-specific heteromultimer constructs are based on a heterodimeric Fc scaffold or on a segmented albumin scaffold. Also disclosed herein are multi-specific heteromultimer constructs that bind to HER2 and HER3.

Abstract: The present disclosure describes multivalent (e.g., decavalent or dodecavalent) polypeptide constructs capable of binding to one or more viral spike protein(s) and capable of intercepting the interaction of a spike protein of a viral particle with a surface-bound ACE2 protein of a cell, pharmaceutical compositions comprising such constructs, and methods of producing and using the constructs for the treatment of, e.g., viral infections in a subject in need thereof.

Abstract: Heterodimeric IgA Fc (IgA HetFc) constructs comprising one or more amino acid mutations in the CH3 domain that allow for formation of a heterodimeric Fc having high purity and thermostability. The IgA HetFc constructs may comprise one or more target binding domains. Higher order IgA HetFc multimers comprising multiple IgA HetFc constructs may be prepared in which two of the IgA HetFc constructs are joined by a J chain.

Abstract: Provided herein are biparatopic antigen-binding constructs that specifically bind HER2. The biparatopic antigen-binding constructs comprise one antigen-binding moiety that binds to ECD2 of HER2, a second antigen-binding moiety that binds to ECD4 of HER2, and an Fc. At least one of the antigen-binding moieties is an scFv. The biparatopic antigen-binding constructs can be used in the treatment of cancer.

Abstract: Described herein are methods and compositions for selective activation of cells using variant cytokine receptor and cytokine pairs, wherein the cytokine receptors comprise an extracellular domain (ECD) of granulocyte-colony stimulating factor receptor (G-CSFR). In certain embodiments, the methods and compositions described herein are useful for exclusive activation of cells for adoptive cell transfer therapy. Thus, included herein are methods of producing cells expressing variant receptors that are selectively activated by a cytokine that does not bind its native receptor. Also disclosed herein are methods of treating a subject in need thereof, comprising administering to the subject cells expressing an variant receptor comprising an extracellular domain of G-CSFR and co-administering a variant cytokine that activates the variant receptor.

Abstract: Heterodimeric IgA Fc (IgA HetFc) constructs comprising one or more amino acid mutations in the CH3 domain that allow for formation of a heterodimeric Fc having high purity and thermostability. The IgA HetFc constructs may comprise one or more target binding domains. Higher order IgA HetFc multimers comprising multiple IgA HetFc constructs may be prepared in which two of the IgA HetFc constructs are joined by a J chain.

Abstract: The present disclosure provides fusion proteins with a multifunctional biologic design for programmed target engagement. In certain embodiments, the fusion proteins described herein provide for concurrent target antigen engagement and immune checkpoint or costimulatory receptor targeting. In certain aspects, the fusion protein is masked from presenting any on-target off-tissue action (i.e., toxicity) associated with target engagements. In certain embodiments, the fusion proteins provide a masked antigen binding domain as well as a masked immunomodulatory target binding domain, such that the programmed activation of one binding functionality results in the activation of the other binding functionality as well, thereby yielding a bispecific molecule. Thus, the disclosure also provides for methods of masking and conditional activation of antigen binding domains in specific target tissue setting and targeting and activation of immunomodulatory targets without severe adverse toxicity effects.

Abstract: Provided herein are biparatopic antigen-binding constructs that specifically bind HER2. The biparatopic antigen-binding constructs comprise one antigen-binding moiety that binds to ECD2 of HER2, a second antigen-binding moiety that binds to ECD4 of HER2, and an Fc. At least one of the antigen-binding moieties is an scFv. The biparatopic antigen-binding constructs can be used in the treatment of cancer.

Abstract: The present invention provides heterodimer pairs that can comprise a first heterodimer and a second heterodimer wherein each heterodimer comprises an immunoglobulin heavy chain or fragment thereof and an immunoglobulin light chain or fragment thereof. At least one of the heterodimers can comprise one or more amino acid modifications in the CH1 and/or CL domains, one or more amino acid modifications in the VH and/or VL domains, or a combination thereof. The modified amino acid(s) can be part of the interface between the light chain and heavy chain and are typically modified to create preferential pairing between each heavy chain and a desired light chain such that when the two heavy chains and two light chains of the heterodimer pair are co-expressed in a cell, the heavy chain of the first heterodimer preferentially pairs with one of the light chains rather than the other. Likewise, the heavy chain of the second heterodimer typically preferentially pairs with the second light chain rather than first.

Abstract: Provided herein are biparatopic antigen-binding constructs that specifically bind HER2. The biparatopic antigen-binding constructs comprise one antigen-binding moiety that binds to ECD2 of HER2, a second antigen-binding moiety that binds to ECD4 of HER2, and an Fc. At least one of the antigen-binding moieties is an scFv. The biparatopic antigen-binding constructs can be used in the treatment of cancer.

Abstract: The present invention provides heterodimer pairs that can comprise a first heterodimer and a second heterodimer wherein each heterodimer comprises an immunoglobulin heavy chain or fragment thereof and an immunoglobulin light chain or fragment thereof. At least one of the heterodimers can comprise one or more amino acid modifications in the CH1 and/or CL domains, one or more amino acid modifications in the VH and/or VL domains, or a combination thereof. The modified amino acid(s) can be part of the interface between the light chain and heavy chain and are typically modified to create preferential pairing between each heavy chain and a desired light chain such that when the two heavy chains and two light chains of the heterodimer pair are co-expressed in a cell, the heavy chain of the first heterodimer preferentially pairs with one of the light chains rather than the other. Likewise, the heavy chain of the second heterodimer typically preferentially pairs with the second light chain rather than first.

Abstract: Provided herein are multifunctional heteromultimer proteins. In specific embodiments is a heteromultimer comprising: at least two polypeptide constructs, each polypeptide construct comprising at least one cargo polypeptide attached to a transporter polypeptide, said transporter polypeptides derived from a monomeric native protein such that said monomeric constructs associate to form the heteromultimer and said transporter polypeptides associate to form a quasi-native structure of the monomeric native protein or analog thereof. These therapeutically novel molecules encompass heteromultimers comprising constructs that function as scaffolds for the conjugation or fusion of therapeutic molecular entities (cargo polypeptides) resulting in the creation of bispecific or multivalent molecular species. Provided herein is a method for creation of bispecific or multivalent molecular species.

Abstract: Provided herein are biparatopic antigen-binding constructs that specifically bind HER2. The biparatopic antigen-binding constructs comprise one antigen-binding moiety that binds to ECD2 of HER2, a second antigen-binding moiety that binds to ECD4 of HER2, and an Fc. At least one of the antigen-binding moieties is an scFv. The biparatopic antigen-binding constructs can be used in the treatment of cancer.

Abstract: Disclosed herein are isolated multi-specific heteromultimer constructs that bind to CD3 expressed on T-cells and to an antigen expressed on B-cells. The multi-specific heteromultimer constructs are capable of bridging T- and B-cells and mediating killing of B-cells. The multi-specific heteromultimer constructs are based on a heterodimeric Fc scaffold or on a segmented albumin scaffold. Also disclosed herein are multi-specific heteromultimer constructs that bind to HER2 and HER3.

Abstract: The provided scaffolds have heavy chains that are asymmetric in the various domains (e.g. CH2 and CH3) to accomplish selectivity between the various Fc receptors involved in modulating effector function, beyond those achievable with a natural homodimeric (symmetric) Fc molecule, and increased stability and purity of the resulting variant Fc heterodimers. These novel molecules comprise complexes of heterogeneous components designed to alter the natural way antibodies behave and that find use in therapeutics.

Abstract: Systems, methods and non-transitory computer readable media identify favored polymer conformations. One or more residues are identified and may be replaced in the polymer, or the original primary sequence of the polymer may be retained. The conformations of residues in a subset of residues in a region of the identified one or more residues are altered. This conformational adjustment is repeated for other subsets of residues in the region of the identified one or more residues, and for other conformations, thereby deriving a plurality of polymer structures. A set of clusters is generated for each residue of the polymer using the conformationally adjusted structures, thereby creating sets of clusters. Structures in the plurality of structures are grouped into subgroups when the structures fall into the same clusters across a threshold number of the sets of clusters.

Abstract: Provided herein are biparatopic antigen-binding constructs that specifically bind HER2. The biparatopic antigen-binding constructs comprise one antigen-binding moiety that binds to ECD2 of HER2, a second antigen-binding moiety that binds to ECD4 of HER2, and an Fc. At least one of the antigen-binding moieties is an scFv. The biparatopic antigen-binding constructs can be used in the treatment of cancer.