The invention provides methods for identifying protein modulators (e.g., antibody agonists) of eukaryotic cells. The methods typically involve expressing a combinatorial agent library (e.g., via lentiviral vectors) inside a eukaryotic cell type (e.g., a mammalian cell) and then directly selecting for agents (e.g., antibodies) that are agonist of a target molecule (e.g., a signaling receptor) that modulates a phenotype of or elicits a cellular response in the cell. Some related methods involve co-culturing a cell expressing a combinatorial agent library and a second cell, and then selecting agents that modulate a phenotype of or elicit a cellular response in the second cell. Preferably, the agents are antibodies and are introduced into and expressed in the starting cells under conditions each individual cell expresses no more than 3 different members of the antibody library. In addition, the invention provides methods for identifying protein agonists that capable of reprograming or trans-differentiating a target cell. Also provided in the invention are specific agonist antibodies of signaling receptors or biomolecules that modulate a phenotype or effectuate a cellular response in a eukaryotic cell (e.g., agonist antibodies of EpoR, TpoR or G-CSFR). Further provided in the invention are methods for selecting from combinatorial antibody libraries bispecific antibodies that can regulate cell phenotypes.

The present invention provides, in part, an antibody display system that simultaneously uses a secretion and a display mode. A bait complexed with a monovalent antibody fragment can be expressed on the surface of the host cell wherein the fragment may be assayed for antigen binding while full antibody is simultaneously secreted from the host cell. Methods of using the system for identifying antibodies that bind specifically to an antigen of interest are also provided. Polypeptides, polynucleotides and host cells useful for making the antibody display system are also provided along with methods of use thereof.

This invention provides, and in certain specific but non-limiting aspects relates to: assays that can be used to predict whether a given ISV will be subject to protein interference as described herein and/or give rise to an (aspecific) signal in such an assay (such as for example in an ADA immunoassay). Such predictive assays could for example be used to test whether a given ISV could have a tendency to give rise to such protein interference and/or such a signal; to select ISV's that are not or less prone to such protein interference or to giving such a signal; as an assay or test that can be used to test whether certain modification(s) to an ISV will (fully or partially) reduce its tendency to give rise to such interference or such a signal; and/or as an assay or test that can be used to guide modification or improvement of an ISV so as to reduce its tendency to give rise to such protein interference or signal; —methods for modifying and/or improving ISV's to as to remove or reduce their tendency to give rise to such protein interference or such a signal; —modifications that can be introduced into an ISV that remove or reduce its tendency to give rise to such protein interference or such a signal; ISV's that have been specifically selected (for example, using the assay(s) described herein) to have no or low(er)/reduced tendency to give rise to such protein interference or such a signal; modified and/or improved ISV's that have no or a low(er)/reduced tendency to give rise to such protein interference or such a signal.

The disclosure provides antibodies that are useful for, among other things, inhibiting terminal complement (e.g., the assembly and/or activity of the C5b-9 TCC) and C5a anaphylatoxin-mediated inflammation and, thus, treating complement-associated disorders. The antibodies have a number of improved properties relative to eculizumab, including, e.g., increased serum half-life in a human.

The present invention relates to antibody molecules and peptide delivery systems for use in the treatment and management of Alzheimer's disease and related disorders. In particular, the antibody molecules preferentially bind oligomeric forms of beta-amyloid peptide, in single domain format, and the peptide delivery systems facilitate specific transport of such antibody molecules, as well as other cargo molecules, across the blood-brain barrier. The invention also relates to constructs of the antibody molecules and the delivery peptides, as well as pharmaceutical compositions comprising effective amounts of the antibody molecules, delivery peptides, and/or their constructs, including humanized versions of the antibody molecules and constructs. The invention further relates to methods of making these products and pharmaceutical compositions thereof; and methods of using the pharmaceutical compositions in treating or preventing Alzheimer's and related disorders, such as those involving accumulation of beta-amyloid peptide or other peptides that aggregate in the brain; as well as to methods and kits for diagnosing these disorders.

There is provided inter alia a polypeptide comprising an immunoglobulin chain variable domain comprising three complementarity determining regions (CDR1-CDR3) and four framework regions, wherein: (a) at least one lysine residue in CDR1, CDR2 and/or CDR3 has been substituted with at least one histidine residue, and/or (b) at least one arginine residue in CDR1, CDR2 and/or CDR3 has been substituted with at least one histidine residue; wherein the polypeptide has increased intestinal stability relative to a corresponding polypeptide not having said histidine substitutions.

This disclosure provides dimeric, pentameric, and hexameric Tumor Necrosis Factor (TNF) superfamily receptor protein binding molecules and methods of using such binding molecules to direct apoptosis-mediated killing of TNF receptor-expressing cells.

An antibody that specifically binds to a glucocorticoid-induced tumor necrosis factor receptor (GITR), an antibody fragment and a polymer thereof, and a conjugate and a fusion comprising the antibody or the antibody fragment are provided in the present invention. A nucleic acid encoding the antibody, the antibody fragment, the polymer, the conjugate and the fusion, a vector, and a host cell expressing the nucleic acid are also provided in the present invention. In addition, a composition comprising the antibody and the antibody fragment thereof, the polymer, the conjugate or the fusion, and use thereof in therapy and diagnosis are also provided in the present invention.

VH domain, in which: (i) the amino acid residue at position 112 is one of K or Q; and/or (ii) the amino acid residue at position 89 is T; and/or (iii) the amino acid residue at position 89 is L and the amino acid residue at position 110 is one of K or Q; and (iv) in each of cases (i) to (iii), the amino acid at position 11 is preferably V; and in which said VH domain contains a C-terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I).

Antigen binding molecules (ABMs) comprising Fab domains in non-native configurations, ABM conjugates comprising the ABMs and cytotoxic or cytostatic agents, pharmaceutical compositions containing the ABMs and ABM conjugates, methods of using the ABMs, ABM conjugates and pharmaceutical compositions for treating cancer, nucleic acids encoding the ABMs, cells engineered to express the ABMs, and methods of producing ABMs.