Disclosed herein are methods for humanizing antibodies based on selecting variable region framework sequences from human antibody genes by comparing canonical CDR structure types for CDR sequences of the variable region of a non-human antibody to canonical CDR structure types for corresponding CDRs from a library of human antibody sequences, preferably germline antibody gene segments. Human antibody variable regions having similar canonical CDR structure types to the non-human CDRs form a subset of member human antibody sequences from which to select human framework sequences. The subset members may be further ranked by amino acid similarity between the human and the non-human CDR sequences. Top ranking human sequences are selected to provide the framework sequences for constructing a chimeric antibody that functionally replaces human CDR sequences with the non-human CDR counterparts using the selected subset member human frameworks, thereby providing a humanized antibody of high affinity and low immunogenicity without need for comparing framework sequences between the non-human and human antibodies. Chimeric antibodies made according to the method are also disclosed.
Disclosed herein are methods for humanizing antibodies based on selecting variable region framework sequences from human antibody genes by comparing canonical CDR structure types for CDR sequences of the variable region of a non-human antibody to canonical CDR structure types for corresponding CDRs from a library of human antibody sequences, preferably germline antibody gene segments. Human antibody variable regions having similar canonical CDR structure types to the non-human CDRs form a subset of member human antibody sequences from which to select human framework sequences. The subset members may be further ranked by amino acid similarity between the human and the non-human CDR sequences. Top ranking human sequences are selected to provide the framework sequences for constructing a chimeric antibody that functionally replaces human CDR sequences with the non-human CDR counterparts using the selected subset member human frameworks, thereby providing a humanized antibody of high affinity and low immunogenicity without need for comparing framework sequences between the non-human and human antibodies. Chimeric antibodies made according to the method are also disclosed.
The present invention encompasses monoclonal antibodies that bind to lipoteichoic acid (LTA) of Gram positive bacteria. The antibodies also bind to whole bacteria and enhance phagocytosis and killing of the bacteriain vitro. The invention also provides antibodies having human sequences (chimeric, humanized and human antibodies). The invention also sets forth the variable regions of three antibodies within the invention and presents the striking homology between them.
The present invention encompasses monoclonal antibodies that bind to lipoteichoic acid (LTA) of Gram positive bacteria. The antibodies also bind to whole bacteria and enhance phagocytosis and killing of the bacteriain vitro. The invention also provides antibodies having human sequences (chimeric, humanized and human antibodies). The invention also sets forth the variable regions of three antibodies within the invention and presents the striking homology between them.
The invention discloses a method for humanizing an antibody. In the invention, through comparing a standard CDR (Complementarity-Determining Region) structure type of a CDR sequence in a variable region of an inhuman antibody with a standard CDR structure type of a corresponding CDR in a human antibody sequence library, a frame sequence of the variable region is selected from human antibody genes, preferably the gene segments of an embryonic system antibody. The variable region of the human antibody which has the standard CDR structure type similar to an inhuman CDR forms a subgroup of a member antibody sequence and a human frame sequence can be selected from the subgroup. The subgroup members can be further rated through the amino acid similarity between the human and inhuman CDR sequences. The ahead human sequence in the rating is selected to provide the frame sequence and construct a chimeric antibody by utilizing the selected the subgroup member human frame. The chimeric antibody replaces the human CDR sequence by the counterpart functionality of the inhuman CDR, therefore, the humanized antibody which has high affinity and low immunogenicity is provided without comparing the frame sequences between the inhuman antibody and the human antibody. The invention also discloses the chimeric antibody prepared according to the method of the invention.
The present invention concerns a process by which a misfold in an Fc fusion molecule can be prevented or corrected. In one embodiment, the process comprises (a) preparing a pharmacologically active compound comprising an Fc domain; (b) treating the fusion molecule with a copper (II) halide; and (c) isolating the treated fusion molecule. The pharmacologically active compound can be an antibody or a fusion molecule comprising a pharmacologically active domain and an Fc domain. The preferred copper (II) halide is CuCl2. The preferred concentration thereof is at least about 10 mM for fusion molecules prepared in E. coli; at least about 30 mM for fusion molecules prepared in CHO cells. The process can be employed with any number of pharmacologically active domains. Preferred pharmacologically active domains include OPG proteins, leptin proteins, soluble portions of TNF receptors (e.g., wherein the fusion molecule is etanercept), IL-1ra proteins, and TPO-mimetic peptides. The Fc domain preferably has a human sequence, with an Fc sequence derived from IgG1 most preferred. An exemplary Fc sequence is shown in FIG. 5 hereinafter.
The invention discloses a partition method on human motion 3D data. First, use manifold analysis method ISOMAP to map the original human sequence motion data to the low dimensional manifold space; secondly, utilize a heuristic method to detect rough partition points of different types of movement in the motion data sequence, then long sequence of human motion data are partitioned to several segments; last, for every two segments concatenated in time in the low dimensional manifold space use K-average clustering algorithm to compute the accurate partition point.
The present invention relates to peptidomimetic macrocycles comprising at least one macrocycle-forming linker and an amino acid sequence chosen from the group consisting of : i) an amino acid sequence with at least about 50%, 60%, 70%, 80%, 90%, or 95% sequence identity to a human sequence IRAK2 54-71 (SEQ ID No.1) and 100% identity with the amino acids in the positions 5-6, 9-11, 14-15 or ii) an amino acid sequence with at least about 50%, 60%, 70, 80%, 90%, or 95% sequence identity to a human sequence IRAKM 66-83 (SEQ ID No.2) and 100% identity with the amino acids in the positions 5-6, 9-11, 13-14, wherein the peptidomimetic macrocycle comprises an a-helix and at least two natural or two non-natural amino acids crosslinked by a macrocycle-forming linker. It also concerns method of preparation of said peptidomimetic macrocycles and uses thereof, pharmaceutical composition and uses thereof, in particular as inhibitors of inflammatory pathways.
Provided herein, inter alia, are non-human animals comprising nucleic acid sequences encoding a C3 protein that comprises a human sequence as well as transgenic non-human animals comprising a C3 gene that is human in whole or in part as well as methods for using the same to screen for candidate therapeutic molecules to treat complement-related nephropathies. Also provided herein are methods for improving kidney function in an individual diagnosed with or thought to have a complement-related nephropathy.