The United States of America, As Represented by the Secretary, Department of Health and Human Services

Zhejiang Shimai Pharmaceutical Co., Ltd.

Fudan University

Weizao Chen

Dimiter Stanchev Dimitrov

Zuoxiang Xiao

Terry J Fry

Christopher D Chien

Yanping Wang

Yang Feng

Tianlei Ying

Haiying Qin

Tao Fu

Prabakaran Ponraj

Christopher Chien

The present invention provides recombinant bispecific antibodies designed to bind to a surface antigen on target cells and to an activating component on immune cells such as T cells. The bispecific antibodies comprise two polypeptide chains that contain Fv and Fab as antigen¬binding fragments and a modified Fc region to facilitate heterodimer formation. In one embodiment, the bispecific antibodies further comprise protease cleavage sites and/or motifs that would cause steric occlusion of the antigen binding sites so that the antibodies would be activated only in a specific environment, e.g. in the vicinity of a tumor. In another embodiment, the bispecific antibodies comprise modified sequences that confer reduced binding affinity to CDS and/or cross-reactive binding to CDS on cells from different species.

Protease cleavable bispecific antibodies and uses thereof

The present invention provides recombinant bispecific antibodies designed to bind to a surface antigen on target cells and to an activating component on immune cells such as T cells. The bispecific antibodies comprise two polypeptide chains that contain Fv and Fab as antigen-binding fragments and a modified Fc region to facilitate heterodimer formation. In one embodiment, the bispecific antibodies further comprise protease cleavage sites and/or motifs that would cause steric occlusion of the antigen binding sites so that the antibodies would be activated only in a specific environment, e.g. in the vicinity of a tumor. In another embodiment, the bispecific antibodies comprise modified sequences that confer reduced binding affinity to CDS and/or cross-reactive binding to CDS on cells from different species.

Human monoclonal antibodies that specifically bind Fms-like tyrosine kinase 3 (FLT3) are described. Chimeric antigen receptors (CARs) and other antibody conjugates that include the FLT3-specific monoclonal antibodies are also described. Methods for the diagnosis and treatment of FLT3-associated cancer, such as acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML), are further described.

Human monoclonal antibodies specific for FLT3 and uses thereof

The present disclosure provides isolated monoclonal antibodies that specifically bind to LAG3 with high affinity, particularly human monoclonal antibodies. Preferably, the antibodies bind human LAG3. In certain embodiments, the antibodies bind both human and monkey LAG3 but do not bind mouse LAG3. The invention provides anti-LAG3 antibodies that can inhibit the binding of LAG3 to MHC Class II molecules and that can stimulate antigen-specific T cell responses. Nucleic acid molecules encoding the antibodies of the invention, expression vectors, host cells and methods for expressing the antibodies of the invention are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. This disclosure also provides methods for stimulating an immune response, as well as methods for treating cancer using an anti-LAG3 antibody of the invention.

Human monoclonal antibodies against LAG3 and uses thereof

The invention provides a polypeptide comprising a single domain CD4, as well as a fusion protein comprising the single domain CD4 and one or more fusion partners. A nucleic acid encoding the polypeptide or fusion protein, as well as compositions or cells comprising the polypeptide, fusion protein, or nucleic acid also are provided.

Stabilized single human CD4 domains and fusion proteins

The invention provides a construct comprising two or more fusion proteins of Formulas (I)-(IV): A-(optional linker)-C-(optional linker)-B (Formula I), B-(optional linker)-D-(optional linker)-E-(optional linker)-B (Formula II), A-(optional linker)-C (Formula III), and B-(optional linker)-D-(optional linker)-E (Formula IV), wherein A denotes an antibody or antibody fragment, B denotes a single domain CD4, C denotes an immunoglobulin light chain constant region D denotes an immunoglobulin heavy chain constant region, and E denotes an Fc region or a portion thereof that is optionally defucosylated.

Bispecific multivalent fusion proteins

The invention provides single domain antibodies and derivatives thereof that bind antigens of interest, which are stable, soluble, and do not tend to aggregate. The invention also provides methods for constructing a dAb library and methods for screening dAb libraries to identify the dAb of the invention. The invention also provide methods of treating or preventing conditions by antigen neutralization by administering the dAbs of the invention.

Anti-HIV domain antibodies and method of making and using same

Antibodies and antibody fragments that bind to insulin-like growth factor (IGF) 1 receptor (IGF-1R) or IGF-2, as well as methods of using the antibodies for inhibiting the IGF-mediated signaling pathway, inhibiting IGF-1R signaling, and treating cancer, are described. A method of detecting the presence of IGF-1R or IGF-2 in a sample using the disclosed antibodies and antibody fragments is also described.

Human domain antibodies against components of the human insulin-like growth factor (IGF) system

Monoclonal antibodies (mAbs), antigen binding fragments and engineered antibody domains (eAds) that specifically bind IGF-II are disclosed herein. In some embodiments, these mAbs and eAds are included in a bispecific mAb. In some embodiments, the bispecific antibody specifically binds two different epitopes of IGF-II. Methods of using these mAbs, antigen binding fragments, and eAds, bispecific antibodies, and nucleic acids encoding these mAbs, antigen binding fragments, and eAds, bispecific antibodies are also disclosed.

Monospecific and bispecific human monoclonal antibodies targeting insulin-like growth factor II (IGF-II)

The invention provides antibodies or antibody fragments that bind to insulin-like growth factor (IGF) 1 receptor (IGF-1R) or IGF-2, as well as method of using the antibodies for inhibiting the IGF-mediated signaling pathway, inhibiting IGF-1R signaling, and treating cancer. The invention also provides a method of detecting the presence of IGF-1R or IGF-2 in a sample using the inventive antibodies and antibody fragments.

The invention provides engineered antibody domains (eAds), a polypeptide comprising a single domain CD4, as well as a fusion protein comprising the same. Nucleic acids encoding eAd and/or polypeptide or the fusion protein thereof, as well as compositions or cells comprising the eAd, polypeptide, fusion protein, or nucleic acid also are provided.

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Frederick, MD, United States of America

Weizao Chen