Zymeworks Inc.

Zymeworks Bc Inc.

National Research Council of Canada

Gordon Yiu Kon Ng

Surjit Bhimarao Dixit

Mario Sanches

Grant Raymond Wickman

Nina E Weisser

Eric Escobar-Cabrera

Thomas Spreter Von Kreudenstein

Igor Edmondo Paolo D'Angelo

Peter Wing Yiu Chan

Leonard G Presta

Maureen D O'Connor-McCourt

Jason Baardsnes

Adam Louis Corper

Anders Ohrn

Yang-Chieh Chou

Antonios Samiotakis

Maureen O'CONNOR-Mccourt

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.

Bispecific antigen binding constructs targeting HER2

Described herein methods of using antigen-binding constructs to treat HER2+ tumors in a subject such as breast, lung, or head and neck tumors. In some aspects, the tumor volume in the subject after receiving at least seven doses of the antigen binding construct is less than the tumor volume of a control subject receiving an equivalent amount of trastuzumab. In some aspects, the survival of the subject receiving the antigen binding construct is increased as compared to a control subject receiving an equivalent amount of a non-specific control antibody or as compared to a control subject not receiving treatment.

Methods of using bispecific antigen-binding constructs targeting HER2

Bispecific antigen-binding constructs targeting HER2

Bispecific antigen-binding constructs targeting Her2

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.

Multivalent heteromultimer scaffold design and constructs

Bispecific antigen-binding constructs e.g., antibodies conjugated to drugs (ADCs), which bind CD3 and other cell-surface target antigen such as tumor antigens e.g., CD19, CDH3, HER2, HER3 and EGFR antigens and methods of use are disclosed.

Drug-conjugated bi-specific antigen-binding constructs

The present invention provides a process and methods for producing asymmetric antibodies in a mammalian expression system. The asymmetric antibodies are transiently or stably expressed and in cells that stably express the asymmetric antibody, following a rapid 2-step process of stable pool to clone, a highly pure asymmetric antibody expressing clone can be identified at a success frequency that permits for screening of tens of clones rather than thousands. The asymmetric antibodies are produced at a high titre and with a high level of purity with no contaminating homodimer antibodies following protein A purification with a step yield of near 100%. Typical downstream purification processes employ standard hydrophobic interaction chromatography (HIC) and/or cation exchange (CEX) resins and the antibody is stable within a wide dynamic range of buffer pH (4-8) and within the requirements for manufacturing antibodies for pre-clinical and clinical applications.

Process and methods for efficient manufacturing of highly pure asymmetric antibodies in mammalian cells

Provided herein are monovalent antigen-binding constructs targeting EGFR and/or HER2. The monovalent antigen-binding constructs can include at least one antigen-binding polypeptide comprising a heavy chain variable domain, wherein the antigen-bind polypeptide specifically binds EGFR and/or HER2; and a heterodimeric Fc domain, the Fc domain comprising at least two CH3 domains, wherein the Fc domain is coupled, with or without a linker, to the antigen-binding polypeptide. Also provided are methods of making the constructs and methods of using the constructs.

Monovalent antigen binding constructs targeting EGFR and/or HER2 and uses thereof

Described herein are isolated bi-specific antigen binding constructs, e.g., antibodies. The bi-specific antigen binding constructs include two antigen binding polypeptide constructs, e.g., a Fab and an scFv. The first antigen-binding polypeptide construct monovalently and specifically binds to extracellular domain 4 (ECD4) of HER2 (human epidermal growth factor receptor 2); the second antigen-binding polypeptide construct monovalently and specifically binds to an extracellular domain (ECD) of HER3 (human epidermal growth factor receptor 3). One antigen binding polypeptide construct is a Fab format and the other antigen binding polypeptide construct is an scFv format. The bi-specific antigen binding constructs includes an Fc having two Fc polypeptides each having a CH3 domain for dimerization. Each Fc polypeptide is linked to the C-terminus of one of the antigen binding polypeptide constructs with or without a linker.

Bispecific HER2 and HER3 antigen binding constructs

Provided is a method of quantitatively determining the ability of individual IgG heavy chains to selectively pair with a particular IgG light chain when the heavy chains and two unique light chains are co-expressed. The method provides results with reasonable throughput and is robust and accurate. The co-expressed heavy and light chains do not need to be isolated and purified which enables more efficient screening.

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Vancouver, Canada

Gordon Yiu Kon Ng