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: 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 high affinity antigen binding constructs, e.g., antibodies, directed to the ECD2 domain of HER2. The antigen-binding constructs comprise at least one antigen-binding polypeptide construct that binds to ECD2 of HER2 (HER2 ECD2) with increased affinity compared to a wild-type 2C4 antibody. Such antigen-binding polypeptide constructs comprise one or more amino acid modifications in the framework region and/or CDRs compared to the amino acid sequence of a wild-type 2C4 antibody that increase affinity of the antigen-binding polypeptide construct for ECD2 by 2-fold or greater. The antigen-binding constructs can inhibit the growth of HER2-expressing breast cancer cells and gastric cancer cells. Antigen-binding constructs in biparatopic format are internalized in HER2-expressing cells.

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 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: Stabilized TCR constructs comprising a TCR alpha chain polypeptide having a variable alpha (V?) domain and a constant alpha (C?) domain and a TCR beta chain polypeptide having a variable beta (V?) domain and a constant beta (C?) domain. The TCR constructs are stabilized by the introduction into the C? domain and/or the C? domain of stabilizing mutations such as non-naturally occurring disulfide bonds between the C? domain and the C? domain (an interchain disulfide bond), non-naturally occurring intrachain disulfide bonds, point mutations, loop truncation mutations, and combinations thereof. TCR fusion proteins comprising one or more of the TCR constructs and a scaffold and/or other biologically active moiety are also described.

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 Fc variants comprising one or more asymmetric amino acid mutations in the CH2 domain and having increased selectivity of binding to Fc?RIIb as compared to a parental Fc region, polypeptides comprising the heterodimeric Fc variants and polynucleotides encoding the heterodimeric Fc variants. The one or more asymmetric mutations comprise replacement of a loop in the CH2 domain, a mutation at position 236 in the CH2 domain, or a combination of replacement of a loop in the CH2 domain and a mutation at position 236 in the CH2 domain.

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: Stabilized TCR constructs comprising a TCR alpha chain polypeptide having a variable alpha (V?) domain and a constant alpha (C?) domain and a TCR beta chain polypeptide having a variable beta (V?) domain and a constant beta (C?) domain. The TCR constructs are stabilized by the introduction into the C? domain and/or the C? domain of stabilizing mutations such as non-naturally occurring disulfide bonds between the C? domain and the C? domain (an interchain disulfide bond), non-naturally occurring intrachain disulfide bonds, point mutations, loop truncation mutations, and combinations thereof. TCR fusion proteins comprising one or more of the TCR constructs and a scaffold and/or other biologically active moiety are also described.

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: Fc variants are described comprising one or more amino acid mutations that increase the stability of the Fc variant as compared to a parental Fc that does not include the one or more amino acid mutations, as well as polypeptides comprising an Fc variant and polynucleotides encoding an Fc variant.

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: 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: 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 high affinity antigen binding constructs, e.g., antibodies, directed to the ECD2 domain of HER2. The antigen-binding constructs comprise at least one antigen-binding polypeptide construct that binds to ECD2 of HER2 (HER2 ECD2) with increased affinity compared to a wild-type 2C4 antibody. Such antigen-binding polypeptide constructs comprise one or more amino acid modifications in the framework region and/or CDRs compared to the amino acid sequence of a wild-type 2C4 antibody that increase affinity of the antigen-binding polypeptide construct for ECD2 by 2-fold or greater. The antigen-binding constructs can inhibit the growth of HER2-expressing breast cancer cells and gastric cancer cells. Antigen-binding constructs in biparatopic format are internalized in HER2-expressing cells.

Abstract: Provided herein are anti-PD-1/LAG3 bispecific antibodies and antigen-binding fragments. Also provided here are methods and uses of these antibodies and antigen-binding fragments in the treatment of cancer or infectious disease.

Abstract: Provided herein are anti-PD-1/LAG3 bispecific antibodies and antigen-binding fragments. Also provided here are methods and uses of these antibodies and antigen-binding fragments in the treatment of cancer or infectious disease.