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.

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 heteromultimer constructs with reduced or silenced effector function. In an embodiment is provided a heteromultimer construct comprising an IgG Fc construct having a first and a second Fc polypeptide, each Fc polypeptide comprising a modified lower hinge region wherein: the modified lower hinge region of said first Fc polypeptide comprises at least one amino acid modification, the modified lower hinge region of said second Fc polypeptide comprises at least one amino acid modification which is different from at least one amino acid modification of said first Fc polypeptide, and the IgG Fc construct displays reduced binding to all Fc? receptors and to C1q protein as compared to a corresponding parent IgG Fc construct. Also provided are methods of producing such heteromultimer constructs, and methods of reducing ADCC for an antibody construct by reducing effector function.

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: 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 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: 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 tumor-associated antigen (TAA) presentation inducer constructs comprising at least one innate stimulatory receptor (ISR)-binding construct that binds to an ISR expressed on an antigen-presenting cell (APC), and at least one TAA-binding construct that binds directly to a first TAA that is physically associated with tumor cell-derived material (TCDM) comprising one or more other TAAs. The ISR-binding construct and TAA-binding construct are linked to each other, and the TAA presentation inducer construct induces a polyclonal T cell response to the first TAA and to the one or more other TAAs. Also provided are methods of using the TAA presentation inducer constructs, for example, in the treatment of cancer.

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.