Engineered scaffold proteins

Abstract

The present disclosure provides scaffold proteins that serve as framework regions for different sets of complementarity determining regions (CDRs) from source antibodies, where the source antibodies bind to different epitopes. The scaffold proteins find use in generating antigen binding polypeptides in single chain fragment variable (scFv) antibody format from a variety of antibodies of interest. These antigen binding polypeptides can have one or more advantageous properties as compared to a source antibody, such as, increased affinity, increased stability, increased expression in a cell, increased yield, etc. The sequence of a scaffold protein has a sequence identity of less than 68% to the sequence of the framework regions of the source antibody.

Description

Atty Dkt. No.: MOBI-015WOENGINEERED SCAFFOLD PROTEINS CROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Patent Application No. 63 / 736,342 filed on December 19, 2024, which application is herein incorporated by reference in its entirety.INCORPORATION-BY-REFERENCE OF ELECTRONICALLY SUBMITTED MATERIAL

[0002] A Sequence Listing is provided herewith as a Sequence Listing XML, " MOBI-015WO_SEQ._LIST" created on December 18, 2025, and having a size of 330,080 bytes. The contents of the Sequence Listing XML are incorporated by reference herein in their entirety.INTRODUCTION

[0003] Antibodies are specialized proteins produced by the immune system that recognize and bind to specific antigens, such as pathogens or foreign substances, with high specificity and affinity. Their ability to target precise molecular structures makes them invaluable not only in natural immune defense but also as powerful tools in biotechnology, diagnostics, and therapeutic applications.Producing antibodies is a slow, labor-intensive and capital-intensive process.SUMMARY

[0004] The present disclosure provides scaffold proteins that serve as framework regions for different sets of complementarity determining regions (CDRs) from source antibodies, where the source antibodies bind to different epitopes. The scaffold proteins find use in generating antigen-binding polypeptides, having a structure similar to that of single chain fragment variable (scFv) antibodies, from a variety of antibodies of interest. The sequence of a scaffold protein has a sequence identity of less than 68% to the sequence of the framework regions of the source antibodies in a scFv format.

[0005] A scaffold protein of the present disclosure can comprise CDRs in the order from N-terminus to C-terminus: light chain CDR (LCDR) 1, LCDR2, and LCDR3 followed by heavy chain CDR (HCDR)l, HCDR2, and HCDR3. A scaffold protein of the present disclosure can comprise CDRS in the order from N-terminus to C-terminus: HCDR1, HCDR2, and HCDR3 followed by LCDR1, LCDR2, and LCDR3.

[0006] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70% identical (e.g., at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at leastAtty Dkt. No.: MOBI-015WO97%, at least 98%, at least 99%, or 100% identical) to any one of SEQ ID NOs:l-5. The scaffold protein can comprise three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, and three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3, wherein CDRL1 is inserted between positions 20 and 27 (e.g., 23 and 24), CDRL2 is inserted between positions 35 and 42 (e.g., 38 and 39), CDRL3 is inserted between positions 67 and 74 (e.g., 70 and 71), CDRH1 is inserted between positions 134 and 141 (e.g., 137 and 138), CDRH2 is inserted between positions 148 and 155 (e.g., 151 and 152), CDRH3 is inserted between positions 180 and 187 (e.g., 183 and 184), wherein positions are numbered relative to SEQ ID NO:1 and wherein when the CDRL1-CDRL3 and CDRH1-CDRH3 are present in the scaffold, the CDRL1-CDRL3 and CDRH1-CDRH3 sequences are disregarded when calculating sequence identity of the scaffold protein. A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70% identical (e.g., at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO:6 or 7.

[0007] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70% identical (e.g., at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to any one of SEQ ID NOs:8-12. The scaffold protein can comprise three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3 and three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, wherein CDRH1 is inserted between positions 1 and 34 (e.g., 30 and 31), CDRH2 is inserted between positions 41 and 48 (e.g., 44 and 45), CDRH3 is inserted between positions 73 and 80 (e.g., 76 and 77) and CDRL1 is inserted between positions 133 and 140 (e.g., 136 and 137), CDRL2 is inserted between positions 148 and 155 (e.g., 151 and 152), CDRL3 is inserted between positions 180 and 187(e.g., 183 and 184), wherein positions are numbered relative to SEQ ID NO:8, and wherein when the CDRL1-CDRL3 and CDRH1-CDRH3 are present in the scaffold, the CDRL1-CDRL3 and CDRH1-CDRH3 are disregarded when calculating sequence identity of the scaffold protein.

[0008] Methods of using the scaffold proteins of the present disclosure for generating polypeptides that bind to antigens are also provided.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIGS. 1A to IB: Scaffold sequences of the disclosure. FIG. 1A: VL-VH type scaffold protein sequences (from top to bottom— SEQ ID NOs:l-4, 7, and 5-6) for generating a polypeptideAtty Dkt. No.: MOBI-015WOhaving a structure similar to VL-VH scFv. FIG. IB: VH-VL type scaffold protein sequences (from top to bottom— SEQ ID NOs:8-12) for generating a polypeptide having a structure similar to VH-VL scFv.

[0010] FIGS. 2A to 2B: Alignment of scaffold protein sequences and position of CDRs. FIG. 2A:Alignment of VL-VH type scaffold protein sequences (from top to bottom— SEQ ID NOs:l-4, 7, and 5-6).FIG. 2B: Alignment of VH-VL type scaffold protein sequences (from top to bottom— SEQ ID NOs:8-12).

[0011] FIGS. 3A to 3B: Alignment of VL-VH type scaffold proteins sequences that include the set of CDRs from an anti-IL6 antibody. FIG. 3A: Alignment of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 (from left to right— SEQ ID NQs:245-250) of an anti-l L6 antibody with VL-VH type scaffold protein sequences (from top to bottom— SEQ ID NOs:169-179) containing the LCDRsl-3 and HCDRsl-3. FIG. 3B:Alignment of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 (from left to right-SEQ ID NQs:248-250 and 245-247) from an anti-l L6 antibody with VH-VL type scaffold proteins sequences (from top to bottom— SEQ ID NQs:180-189).

[0012] FIGS. 4A to 4G: Alignment of a VL-VH type scaffold protein consensus sequence with VL-VH type scaffold protein sequences containing different CDR sets. FIG. 4A: Alignment of VLVH0230-binder-consensus (VLVH0230-B) scaffold protein consensus sequence to VLVH0230-B scaffold sequences optimized for binding to C-reactive protein (CRP), D-Dimer, Hemoglobin, procalcitonin (PCT), or soluble fms-like tyrosine kinase-1 (sFLT-1) (from top to bottom— SEQ ID NOs:2 and 97-101). FIG.4B: Alignment of VLVH0230-soluble-consensus (VLVH-S) scaffold protein consensus sequence with VLVH0230-S scaffold protein sequences optimized for binding to CRP, D-Dimer, Hemoglobin, PCT, thyroid stimulating hormone (TSH), sFLT-1, fluorescein isothiocyanate (FITC), or CRP (from top to bottom— SEQ ID NOs:l and 102-110). FIG. 4C: Alignment of VLVH0230-top5expression-consensus (VLVH0230-T5) scaffold protein consensus sequence with VLVH0230-T5 scaffold protein sequences optimized for binding to listed target (from top to bottom— SEQ ID NOs:3 and 114-117). FIG. 4D: Alignment of VLVH4717 scaffold protein consensus sequence with VLVH4717 scaffold protein sequences optimized for binding to the listed target (from top to bottom— SEQ ID NOs:5 and 118-122). FIG. 4E: Alignment of VLVH4721-genl (VLVH4721-1) scaffold protein consensus sequence with VLVH4721-1 scaffold protein sequences optimized for binding to the listed target (from top to bottom— SEQ ID NOs:4 and 123-128). FIG.4F: Alignment of VLVH4721-gen2 (VLVH4721-2) scaffold protein consensus sequence with VLVH4721-2 scaffold protein sequences optimized for binding to the listed target (from top to bottom— SEQ ID NOs:7 and 129-130). FIG. 4G: Alignment of VLVH6727 scaffold protein consensus sequence with VLVH6727 scaffold protein sequences optimized for binding to the listed target (from top to bottom— SEQ ID NOs:6Atty Dkt. No.: MOBI-015WOand 132-135). Percent sequence identities were calculated solely for the scaffold sequences and without including the CDR sequences.

[0013] FIGS. 5A to 5E: Alignment of VHVL type scaffold sequences including different CDR sets.FIG. 5A: Alignment of VHVL4736-soluble-consensus (VHVL4736-S) scaffold protein consensus sequence with VHVL4736-S scaffold protein sequences optimized for binding to the listed target (from top to bottom— SEQ ID NOs:8 and 137-141). FIG. 5B: Alignment of VHVL4739-soluble-consensus (VHVL4739-S) scaffold protein consensus sequence with VHVL4739-S scaffold protein sequences optimized for binding to the listed target (from top to bottom— SEQ ID NOs:9 and 144-146,148-150). FIG. 5C: Alignment of VHVL4742-soluble-consensus (VHVL4742-S) scaffold protein consensus sequence with VHVL4742-S scaffold protein sequences optimized for binding to the listed target (from top to bottom— SEQ ID NQs:10 and 152-153,155-157). FIG. 5D: Alignment of VHVL6375 scaffold protein consensus sequence with VHVL6375 scaffold protein sequences optimized for binding to the listed target (from top to bottom— SEQ ID NOs:ll and 164-168). FIG. 5E: Alignment of VHVL6486 scaffold protein consensus sequence with VHVL6486 scaffold protein sequences optimized for binding to the listed target (from top to bottom— SEQ ID NOs:12 and 159-161). Percent sequence identities were calculated solely for the scaffold sequences without consideration of the CDR sequences.

[0014] FIGS. 6A to 6B: Percent identity matrices for VLVH type scaffold sequences created via Clustal (v2.1). FIG. 6A: Percent identity matrix for VLVH6727 (SEQ ID NO:6), VLVH4721-2 (SEQ ID NO:7), VLVH4717 (SEQ ID NO:5), VLVH0230-S (SEQ ID NO:1), VLVH0230-B (SEQ ID NO:2), VLVH0230-T5 (SEQ ID NO:3), and VLVH4721-1 (SEQ ID NO:4) scaffold sequences. FIG. 6B: Percent identity matrix for VLVH4717 (SEQ ID NO:5), VLVH0230-S (SEQ ID NO:1), VLVH0230-B (SEQ ID NO:2), VLVH0230-T5 (SEQ ID NO:3), and VLVH4721-1 (SEQ ID NO:4) scaffold sequences.

[0015] FIG. 7: Alignment of VLVH4717 (SEQ ID NO ), VLVH0230-S (SEQ ID NO:1), VLVH0230-B (SEQ ID NO:2), VLVH0230-T5 (SEQ ID NOS), and VLVH4721-1 (SEQ ID NO:4) scaffold sequences.DETAILED DESCRIPTION

[0016] The present disclosure provides scaffold proteins that serve as framework regions for different sets of complementarity determining regions (CDRs) from source antibodies, where the source antibodies bind to different epitopes. The scaffold proteins find use in generating single chain fragment variable (scFv) antibodies-like polypeptides from a variety of antibodies of interest. The sequence of a scaffold protein has a sequence identity of less than 68% to the sequence of the framework regions of the source antibodies.Atty Dkt. No.: MOBI-015WO

[0017] Before the present invention is described in greater detail, it is to be understood that this invention is not limited to the particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0018] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0019] Certain ranges are presented herein with numerical values being preceded by the term "about." The term "about" is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number.

[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are now described.

[0021] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.Atty Dkt. No.: MOBI-015WO

[0022] It is noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.

[0023] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0024] While the apparatus and method has or will be described for the sake of grammatical fluidity with functional explanations, it is to be expressly understood that the claims, unless expressly formulated under 35 U. S. C. §112, are not to be construed as necessarily limited in any way by the construction of "means" or "steps" limitations, but are to be accorded the full scope of the meaning and equivalents of the definition provided by the claims under the judicial doctrine of equivalents, and in the case where the claims are expressly formulated under 35 U. S. C. §112 are to be accorded full statutory equivalents under 35 U. S. C. §112.DEFINITIONS

[0025] " Derived from" in the context of an amino acid sequence or polynucleotide sequence is meant to indicate that the polypeptide or nucleic acid has a sequence that is based on that of a reference polypeptide or nucleic acid, and is not meant to be limiting as to the source or method in which the protein or nucleic acid is made.

[0026] The terms "polypeptide", and "protein" are used interchangeably herein to designate a linear series of amino acid residues connected one to the other by peptide bonds between the alphaamino and carboxy groups of adjacent residues. The amino acid residues are usually in the natural " L" isomeric form. However, residues in the " D" isomeric form can be substituted for any L-amino acid residue, as long as the desired functional property is retained by the polypeptide. In addition, the amino acids, in addition to the 20 "standard" amino acids, include modified and unusual amino acids, which include, but are not limited to those listed in 37 CFR (§1.822(b)(4)). The term "peptide" also refers to a linear series of amino acid residues connected one to the other by peptide bonds between the alphaamino and carboxy groups of adjacent residues but is generally shorter than a protein or a polypeptide,Atty Dkt. No.: MOBI-015WOe.g., less than 50 amino acids long, e.g., 2-50 amino acids in length. The terms protein, polypeptide, and peptide may be used interchangeably.

[0027] As used herein, the term "binding" refers to the non-covalent interactions of the type which occur between two molecules. The strength or affinity of binding interactions can be expressed in terms of the dissociation constant (KD) of the interaction, wherein a smaller KDrepresents a greater affinity. Binding properties of selected polypeptides can be quantified using methods well known in the art.

[0028] " Isolated" refers to an entity of interest that is in an environment different from that in which the entity may naturally occur or is initially produced in. An "isolated" compound (e.g., an "isolated" polypeptide) is separated from all or some of the components that accompany it and may be substantially enriched, e.g., may be purified so that the compound is at least about 70% pure, at least about 80% pure, at least about 90% pure, at least about 95% pure, at least about 98% pure, at least about 99%, or greater than 99% pure, or free of impurities, contaminants, and / or components other than the compound. " Isolated" also refers to the state of a compound separated from all or some of the components that accompany it during manufacture (e.g., chemical synthesis, recombinant expression, culture medium, and the like).

[0029] As used herein, the amino acid residues are abbreviated as follows: alanine (Ala; A), asparagine (Asn; N), aspartic acid (Asp; D), arginine (Arg; R), cysteine (Cys; C), glutamic acid (Glu; E), glutamine (Gin; Q), glycine (Gly; G), histidine (His; H), isoleucine (lie; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Vai; V).

[0030] In all embodiments of polypeptides disclosed herein, any N-terminal methionine residues are optional (i.e., the N-terminal methionine residue may be present or absent). In some embodiments, one or more of the amino acids may have a modification, such as, a post-translational modification, e.g., acetylation or glycosylation.

[0031] The term "conservative substitution" is used in reference to proteins to reflect amino acid substitutions that do not substantially alter the activity (specificity or binding affinity) of the molecule. Typically, conservative amino acid substitutions involve substituting one amino acid for another amino acid with similar chemical properties (e.g., charge or hydrophobicity). The following six groups each contain amino acids that are typical conservative substitutions for one another: 1) Alanine (A), Serine (S), Threonine (T); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and 6) Phenylalanine (F),Atty Dkt. No.: MOBI-015WOTyrosine (Y), Tryptophan (W). The polypeptides encompassed by the present disclosure include those that have one or more conservative substitutions relative to the amino acid sequences provided here.

[0032] Percent identity between a pair of sequences may be calculated by multiplying the number of matches in the pair by 100 and dividing by the length of the aligned region, including gaps. Identity scoring only counts perfect matches and does not consider the degree of similarity of amino acids to one another. Only internal gaps are included in the length, not gaps at the sequence ends. Percent Identity = (Matches x 100) / Length of aligned region (with gaps).

[0033] Numeric ranges are inclusive of the numbers defining the range.SCAFFOLD PROTEINS

[0034] The present disclosure provides scaffold proteins that serve as framework regions for different sets of complementarity determining regions (CDRs) from source antibodies, where the source antibodies bind to different epitopes. The scaffold proteins find use in generating single chain fragment variable (scFv) antibodies-like polypeptides from a variety of antibodies of interest. An antigen binding polypeptide generated using a scaffold protein of the present disclosure and a set of CDRsl-6 from a source antibody retains binding to the antigen bound by the source antibody. The antigen binding polypeptide generated using a scaffold protein of the present disclosure and a set of CDRsl-6 from a source antibody retains binding to the antigen bound by the source antibody and have one or more advantageous properties as compared to a source antibody, such as, increased affinity (e.g., 2X-50X higher affinity, e.g., 5X-50X, 5X-40X, or 10X-30X higher affinity), increased stability, increased expression in a cell, increased yield, decreased size (e.g., an average size of 25-35kDa, such as, 30 kDa), etc. The sequence of an antigen binding polypeptide generated from a scaffold protein of the present disclosure and the CDRs of a source antibody has a sequence identity of less than 68% to the sequence of the source antibody.

[0035] A scaffold protein of the present disclosure can comprise CDRs from N-terminus to C-terminus in the order light chain CDR (LCDR) 1, LCDR2, and LCDR3 followed by heavy chain CDR (HCDR)l, HCDR2, and HCDR3. Such a scaffold is referred to as VLVH type scaffold. A scaffold protein of the present disclosure can comprise CDRS from N-terminus to C-terminus in the order HCDR1, HCDR2, and HCDR3 followed by LCDR1, LCDR2, and LCDR3. Such a scaffold is referred to as VHVLtype scaffold.

[0036] A scaffold protein of the present disclosure includes regions in which the CDRs can be inserted. The position for insertion of a CDR in a scaffold protein can be determined based on the framework regions of the antibody from which the CDR is derived. The position for insertion of a CDR inAtty Dkt. No.: MOBI-015WOa scaffold protein may be shifted by one or more amino acids (e.g., upstream or downstream) relative to the position with respect to the framework regions without affecting the binding affinity of the CDR to an antigen. For example, the scaffold protein may be represented as a single contiguous amino acid sequence with CDRs inserted in specific regions (e.g., between specific residues) of the sequence such that the contiguous framework sequence is divided into multiple framework regions each separated by a CDR, wherein guidance for dividing the scaffold region is obtained from the framework regions of the antibody from which the CDRs are derived. As such, the position at which each CDR is inserted may shift by one amino acid or more such as, e.g., two amino acids, or three amino acids, or four amino acids, either upstream or downstream without compromising the binding affinity of the CDRs to its antigen.

[0037] The scaffold proteins of the present disclosure can be designed to improve folding and stability, for example, the scaffold proteins of the present disclosure may not include any cysteine residues.VLVH Type Scaffold Proteins

[0038] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70% identical (e.g., at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to one of:DIVMTVDAKEVTVELGETATITVWYRQYPGEPPELLIYGVPSRFSGSGSGTDFTLTISNVEPEDEATYYAFSEGTKLLIVPT PETEELLEEARERRRKRLAERRANSPVKLTQSPDITVKEGETATLTVKASGFTFTWVKQAPGGPLEWIGRFTISRDTSKNT AYLTITNLTKEDTATYYAARWGEGTKLTVE (VLVH0230-S; SEQ ID NO:1), DIVMTVDAKEVTVKLGETATITVWYRQYPGEPPELLIYGVPSRISGSGSGTDFTLTISNVEPEDEATYYAFSEGTKLLIVPTP ETEKKLEEARERRRKRLAERRANSPVKLTQSPDITVKEGETATLTVAASGFTFTWVKQAPGGPLEWIGRFTISADTSKNT AYLTITNLTKEDTATYYAARWGEGTKLTVE (VLVH0230-B; SEQ. ID NO:2), DIQMTDDKAEVTVELGETATITVWYRQFPGEPPELLIYGVPDRISGSGSGTDFTLTIKNVEPEDEATYYAFSSGTKLLLVPT PETEEELEEARRRRERRLAERRKNSPVKLTQSPDLTVKEGETATLTVAASGFSFTWVRQAPGGPLEWIGRFSISRDTSKN TLYLTISNLTPEDTATYYAARWGEGTKLTVE (VLVH0230-T5; SEQ ID NO:3), DIVMTVDKSEVTVELGETATITVWYRQYPGEPPELLIYGVPSRFSGSGSGTDFTLTISNVEPEDEATYYAFSSGTKLLIVPTP ETEEELEEARERRARRLAERRKNSPVKLTQSPDLTVKEGETATLTAAASGFAFSWVRQAPGGPLQWIGRFSISRDTSKNT FYLTISNLTKEDTATYYAARWGEGTKLTVE (VLVH4721-1; SEQ ID NO:4), or DIVMTVDKAEVTVELGETATITVWYRQYPGEPPELLIYGVPSRISGSGSGTDFTLTISNVEPEDEATYYAFSQGTKLLLVPT PETEEELEEARRERAERLAERRKNSPVKLTQSPDLTVKEGETATLTATVTGYSITWVRQAPGGPLEWMGRFEISRDTSKN TLYLTIKNLTKEDTATYYAARWGEGTKLTVE (VLVH4717; SEQ ID NO:5), wherein " VLVH0230-S" is interchangeably used herein with " VLVH0230-soluble-consensus," " VLVH0230-soluble," and " VLVH0230-Atty Dkt. No.: MOBI-015WOsol" to refer to the amino acid sequence of SEQ ID NO:1, " VLVH0230-B" is interchangeably used herein with " LVH0230-binder-consensus," " VLVH0230-binder," and " VLVH0230-bin" to refer to the amino acid sequence of SEQ ID NO:2, " VLVH0230-T5" is interchangeably used herein with " VLVH0230-top5expression," " VLVH0230-top5expression-consensus," " VLVH0230-top5," and " VLVH0230-tp5" to refer to the amino acid sequence of SEQ ID NO:3, and " VLVH4721-1" is interchangeably used herein with " VLVH4721-genl" to refer to the amino acid sequence of SEQ ID NO:4.

[0039] The amino acid sequence of the VLVH type scaffold protein (e.g., SEQ ID NOs:l-5 above) can comprise three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, and three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3, wherein CDRL1 is inserted between positions 20 and 27, CDRL2 is inserted between positions 35 and 42, CDRL3 is inserted between positions 67 and 74, CDRH1 is inserted between positions 134 and 141, CDRH2 is inserted between positions 148 and 155, CDRH3 is inserted between positions 180 and 187, wherein positions are numbered relative to SEQ ID NO:1. When the CDRL1-CDRL3 and CDRH1-CDRH3 are present, CDRL1-CDRL3 and CDRH1-CDRH3 sequences are disregarded when calculating sequence identity of the sequence of the scaffold protein to any one of SEQ ID NOs:l-5.

[0040] CDRL1 may be inserted between positions 22 and 25, CDRL2 may be inserted between positions 37 and 40, CDRL3 may be inserted between positions 69 and 72, CDRH1 may be inserted between positions 136 and 139, CDRH2 may be inserted between positions 150 and 153, CDRH3 may be inserted between positions 182 and 185 of the amino acid sequence of the scaffold protein, wherein positions are numbered relative to SEQ ID NO:1.

[0041] CDRL1 may be inserted between positions 23 and 24, CDRL2 may be inserted between positions 38 and 39, CDRL3 may be inserted between positions 70 and 71, CDRH1 may be inserted between positions 137 and 138, CDRH2 may be inserted between positions 151 and 152, CDRH3 may be inserted between positions 183 and 184 of the amino acid sequence of the scaffold protein, wherein positions are numbered relative to SEQ ID NO:1.

[0042] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:1, wherein the amino acid sequence is:X1X2X3X4X5VDAKEVTVELGETATITVWYRQYPGEPPELX6IX7GVPSRFSGSGSGTDFTLTISNVEPEDEATYYAFSEGTKLL IVPTPETEXsLLEEAREXgRRKXioLAERRANSPVKLTQSPDITVKEGETATLTVXuXuXisGX^isXieXiyWVKQAPGGPLE WXi8Xi9RFTISRDTSKNTAYLTITNLTKEDTATYYAX2oX2iWGEGTKLTVE (SEQ ID NO:86), wherein XI may be D or E or Q or V, X2 may be I or V, X3 may be E or H or L or Q or R or V, X4 may be L or M, X5 may be S or T,Atty Dkt. No.: MOBI-015WOX6 may be L or W, X7 may be F or K or Y, X8 may be E or K, X9 may be E or R, X10 may be E or R, Xll may be A or K or T or V, X12 may be A or P or T or V, X13 may be S or T, X14 may be F or Y, X15 may be A or D or N or S or T, X16 may be F or I, X17 may be G or K or N or S or T, X18 may be I or M or V, X19 may be A or G or S, X20 may be A or P or T, and X21 may be G or R orT. CDRL1-CDRL3 and CDRH1-CDRH3 may be inserted in the same position as discussed above numbered relative to SEQ ID NO:1. CDRL1-CDRL3 and CDRH1-CDRH3 may be inserted in the same position as discussed above numbered relative to SEQ ID NO:1.

[0043] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:2, wherein the amino acid sequence is:DX1X2X3TX4DAKEVrVKLGETATITVWYRQYPGEPPELX5lYGVPSRXsSGSGSGTDFTLTISNVEPEDEATYYAFSEGTKLLI VPTPETEKKLEEAREX7RRKX8LAERRANSP KLTQSPDITVKEGETATX9TVXioXiiXi2GXi3Xi4Xi5Xi6WVKQAPGGPLE WX17X18X19FTISADTSKNTAYLTIX20NLTKEDTATYYAX21X22WGEGTKLTVE (SEQ ID NO:85), wherein XI may be I or V, X2 may be E or Q or V, X3 may be L or M, X4 may be M or V, X5 may be L or W, X6 may be F or I, X7 may be E or R, X8 may be E or R, X9 may be I or L, X10 may be A or K or T, Xll may be A or V, X12 may be S or T, X13 may be F or Y, X14 may be A or N or S or T, X15 may be F or I, X16 may be K or S or T, X17 may be I or M or V, X18 may be G or S, X19 may be K or R, X20 may be K or T, X21 may be A or T, and X22 may be R or T. CDRL1-CDRL3 and CDRH1-CDRH3 may be inserted in the same positions as discussed above numbered relative to SEQ ID NO:1.

[0044] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:3, wherein the amino acid sequence is:DX1X2MTDDKAEVTVELGETATITVWYRQFPGEPPELLIYGVPDRISGSGSGTDFTLTIKNVEPEDEATYYAFSSGTKLLLV PTPETEEELEEARRX3RERX4LAERRKNSPVKLTQSPDLTVKEGETATLTX5XsX7X8GX9XioX11Xi2WVRQAPGGPLEWX13 X14RFSISRDTSKNTLYLTISNLTPEDTATYYAX15X16WGEGTKLTVE (SEQ ID NO:87), wherein XI may be I or V, X2 may be Q or V, X3 may be E or R, X4 may be E or R, X5 may be A or V, X6 may be A or K or T, X7 may be A or V, X8 may be S or T, X9 may be F or Y, X10 may be A or N or S or T, Xll may be F or I, X12 may be K or S or T, X13 may be I or M or V, X14 may be G or S, X15 may be A or T, and X16 may be R or T. CDRL1-CDRL3 and CDRH1-CDRH3 may be inserted in the same positions as discussed above numbered relative to SEQ ID NO:1.

[0045] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at leastAtty Dkt. No.: MOBI-015WO98%, at least 99%, or 100% identical to SEQ ID NO:4, wherein the amino acid sequence is:XIX2X3X4TVDKSEVTVELGETATITVWYRQYPGEPPELLIX5GVPSRFSGSGSGTDFTLTISNVEPEDEATYYAFSSGTKLLIV PTPETEEELEEAREX6RARX7LAERRKNSPVKLTQSPDLTVKEGETATLTAX8X9X1OGX11X12X13X14WVRQAPGGPLQWX1 5X16RFSISRDTSKNTFYLTISNLTKEDTATYYAX17X18WGEGTKLTVE (SEQ ID NO:89), wherein XI may be D or E, X2 may be I or V, X3 may be Q or V, X4 may be L or M, X5 may be K or Y, X6 may be E or R, X7 may be E or R, X8 may be A or K or T, X9 may be A or V, X10 may be S or T, Xll may be F or Y, X12 may be A or D or N or S or T, X13 may be F or I, X14 may be K or S or T, X15 may be I or M or V, X16 may be A or G or S, X17 may be A or T, and X18 may be R or T. CDRL1-CDRL3 and CDRH1-CDRH3 may be inserted in the same positions as discussed above numbered relative to SEQ ID NO:1.

[0046] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:5, wherein the amino acid sequence is:DX1X2X3TVDKAEVTVELGETATITVWYRQYPGEPPELLIX4GVPSRISGSGSGTDFTLTISNVEPEDEATYYAFSQGTKLLLV PTPETEEELEEARRERAERLAERRKNSPVKLTQSPDLTVKEGETATLTAXsXeXyGXsXgXioXnWVRQAPGGPLEWXizXu RFEISRDTSKNTLYLTIKNLTKEDTATYYAX14X15WGEGTKLTVE (SEQ ID NO:88), wherein XI may be I or V, X2 may be Q or V, X3 may be L or M, X4 may be K or Y, X5 may be A or K or T, X6 may be A or V, X7 may be S or T, X8 may be F or Y, X9 may be A or D or N or S or T, X10 may be F or I, Xll may be K or S or T, X12 may be I or M or V, X13 may be G or S, X14 may be A or T, and X15 may be R or T. CDRL1-CDRL3 and CDRH1-CDRH3 may be inserted in the same positions as discussed above numbered relative to SEQ ID NO:1.

[0047] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70% identical (e.g., at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to the amino acid sequence:DIELTVDKKEIWEEGEPVTIKVWFQQYEGEPPRTLIYGVPERISGSGSGQDYTLTITKVEPEDEATYYAFSEGIKLRIKRTPE VEEKLAKAREERRRRLAEERRNAPVRLTQSPDITVKEGETATLTVTPSGFNIKWVKQAPGKGLEWIGKFELTADASSNTA YLTIKNLTKEDTATYYAPRWGEGTKLTVE (VLVH6727; SEQ ID NO:6), wherein the amino acid sequence can comprise three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, and three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3, wherein CDRL1 is inserted between positions 20 and 27, CDRL2 is inserted between positions 35 and 42, CDRL3 is inserted between positions 67 and 74, CDRH1 is inserted between positions 134 and 141, CDRH2 is inserted between positions 148 and 155, CDRH3 is inserted between positions 180 and 187, wherein positions are numbered relative to SEQ ID NO:6 and wherein the CDRL1-CDRL3 and CDRH1-CDRH3 areAtty Dkt. No.: MOBI-015WOdisregarded when calculating sequence identity of the scaffold protein. CDRL1 may be inserted between positions 23 and 24, CDRL2 may be inserted between positions 38 and 39, CDRL3 may be inserted between positions 70 and 71, CDRH1 may be inserted between positions 137 and 138, CDRH2 may be inserted between positions 151 and 152, CDRH3 may be inserted between positions 183 and 184.

[0048] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:6 and comprises the amino acid sequence:XIX2X3X4X5 DKKEIV EEGEP TIKVWFQQYEGEPPRTLIXSGVPERISGSGSGCIDYTLTITK EPEDEATYYAFSEGIKLRI KRTPE EEKLAKAREERRRRU\EERRNAP RLTQSPDITVKEGETATLTVX7X8X9GXIOXIIXI2XI3W KQAPGKGLEWXI4 X15KFELTADASSNTAYLTIKNLTKEDTATYYAX16X17WGEGTKLTVE (SEQ ID NO:91), wherein XI may be D or Q or V, X2 may be I or V, X3 may be E or H or R or V, X4 may be L or M, X5 may be S or T, X6 may be F or Y, X7 may be A or K or T or V, X8 may be A or P or T or V, X9 may be S or T, X10 may be F or Y, Xll may be A or N or S or T, X12 may be F or I, X13 may be G or K or S or T, X14 may be I or M or V, X15 may be A or G, X16 may be A or P orT, X17 may be G or R. CDRL1-CDRL3 and CDRH1-CDRH3 may be inserted in the same positions as discussed above numbered relative to SEQ ID NO:6.

[0049] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70% identical (e.g., at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to the amino acid sequence:QIMLSVDKPEVVVEEGETAEVKVWYRQFPGKPPEALVYGVPDRISGSGSGTEFTLTIKNVEPEDVATYYAFSSGTKLLLKK TPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKEGETATLTLTVSGFSLTWVKQAPGGPLQWLGRFTISRDTSKS QFYLTITNLKKEDTATYYAARWGQGTKLTVE (VLVH4721-gen2 [VLVH4721-2]; SEQ ID NO:7), wherein the amino acid sequence can comprise three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, and three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3, wherein CDRL1 is inserted between positions 20 and 27, CDRL2 is inserted between positions 35 and 42, CDRL3 is inserted between positions 67 and 74, CDRH1 is inserted between positions 134 and 141, CDRH2 is inserted between positions 148 and 155, CDRH3 is inserted between positions 180 and 187, wherein positions are numbered relative to SEQ ID NO:7 and wherein the CDRL1-CDRL3 and CDRH1-CDRH3 are disregarded when calculating sequence identity of the scaffold protein. CDRL1 may be inserted between positions 23 and 24, CDRL2 may be inserted between positions 38 and 39, CDRL3 may be inserted between positions 70 and 71, CDRH1 may be inserted between positions 137 and 138, CDRH2 may be inserted between positions 151 and 152, CDRH3 may be inserted between positions 183 and 184.Atty Dkt. No.: MOBI-015WO

[0050] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:7 and comprises the amino acid sequence:X1X2X3X4X5VDKPEVVVEEGETAEVKVWYRQFPGKPPEALX6X7GVPDRISGSGSGTEFTLTIKNVEPEDVATYYAFSSGTK LLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKEGETATLTLX8X9X1oGX1iXi2X13Xi4WVKQAPGGPLQW X15X16RFTISRDTSKSQFYLTITNLKKEDTATYYAX17X18WGQGTKLTVE (SEQ ID NO:90), wherein XI may be D or Q or V, X2 may be I or V, X3 may be E or H or M or R, X4 may be L or M, X5 may be S or T, X6 may be I or V, X7 may be F or Y, X8 may be T or V, X9 may be P or T or V, X10 may be S or T, Xll may be F or Y, X12 may be N or S or T, X13 may be F or I or L, X14 may be G or K or T, X15 may be I or L or M or V, X16 may be A or G, X17 may be A or P or T, and X18 may be G or R, and wherein CDRL1-CDRL3 and CDRH1-CDRH3 may be inserted in the same positions as discussed above numbered relative to SEQ ID NO:7.

[0051] The VLVH type scaffold proteins of the present disclosure may include one of the following sets of CDRs (each set including CDRL1-CDRL3 and CDRH1-CDRH3) for binding to, e.g., C-reactive protein (CRP), D-Dimer, Hemoglobin, procalcitonin (PCT), thyroid stimulating hormone (TSH), soluble fms-like tyrosine kinase-1 (sFLT-1), fluorescein isothiocyanate (FITC), Interleukin 6 (IL-6), or Histidine Tag (HisTag), as found in Table 1 below:Table 1: CDR Sets for VLVH Type Scaffold SequencesCDRL1 SASSSVSYMY (SEQ ID NO:13)CDRL2 RTSNLAS (SEQ ID NO: 14)CDRL3 QQYHSYPPT (SEQ ID NO:15)Set 1: CRP-2702CDRH1 HYSLY (SEQ ID NO:16)CDRH2 EINPRNDGTKFNEKFKS (SEQ ID NO:17)CDRH3 SGTTYDLALDY (SEQ ID NO:18)CDRL1 KASQNVGTPVA (SEQ ID NO:19)CDRL2 STSTRYP (SEQ ID NO:20)CDRL3 QQYSLYPLT (SEQ ID NO:21)Set 2: DDimer-3302CDRH1 SDYAWN (SEQ ID NO:22)CDRH2 YITYSGTTSYNPSLTS (SEQ ID NO:23)CDRH3 EWFPYYFDY (SEQ ID NO:24)CDRL1 RASEGIYHWLA (SEQ ID NO:25)CDRL2 KASSLAS (SEQ ID NO:26)CDRL3 QQYSNYPLT (SEQ ID NO:27)Set 3: Hemoglobin-3885CDRH1 NYAMS (SEQ ID NO:28)CDRH2 AISGSGGSTYYADSVKG (SEQ ID NO:29)CDRH3 YYGDGMDV (SEQ ID NO:30)Atty Dkt. No.: MOBI-015WOCDRL1 RSSQSLVHINGNTYVH (SEQ ID NO:31)CDRL2 KVSNRFS (SEQ. ID NO:32)CDRL3 SQSTHVPLT (SEQ. ID NO:33)Set 4: PCT-3322CDRH1 DTFIH (SEQ ID NO:34)CDRH2 RIDPANGNIIYDPRFQG (SEQ ID NO:35)CDRH3 VGDASLYFDY (SEQ ID NO:36)CDRL1 RASQSVSSSSYSYM H (SEQ ID NO:37)CDRL2 FASNLES (SEQ ID NO:38)CDRL3 QHTWEIPRT (SEQ ID NO:39)Set 5: TSH-2508CDRH1 LYWMS (SEQ ID NO:40)CDRH2 EIDPESNTINYTPSLKD (SEQ ID NO:41)CDRH3 SSMDY (SEQ ID NO:42)CDRL1 KASQSVGTAVA (SEQ ID NO:43)CDRL2 SASNRYT (SEQ ID NO:44)CDRL3 QQYFTYPYT (SEQ ID NO:45)Set 6: sFLTl-4129CDRH1 SYWMN (SEQ ID NO:46)CDRH2 QIYPGDGDTNYNGKFRG (SEQ ID NO:47)CDRH3 DDGYEGFDY (SEQ ID NO:48)CDRL1 RASQSVSSSYLA (SEQ ID NO:49)CDRL2 GASSRAT (SEQ ID NQ:50)CDRL3 QQYGSSPLT (SEQ ID NO:51)Set 7: sFLTl-4131CDRH1 SYGMH (SEQ ID NO:52)CDRH2 VIWYDGSNKYYADSVRG (SEQ ID NO:53)CDRH3 DHYGSGVHHYFYYGLDV (SEQ ID NO:54)CDRL1 RSSQSLVHSNGNTYLR (SEQ ID NO:55)CDRL2 KVSNRVS (SEQ ID NO:56)CDRL3 SQSTHVPWT (SEQ ID NO:57)Set 8: FITC-6486CDRH1 HYWMN (SEQ ID NO:58)CDRH2 QFRNKPYNYETYYSDSVKG (SEQ ID NO:59)CDRH3 ASYGMEY (SEQ ID NQ:60)CDRL1 KASQDINSYLS (SEQ ID NO:61)CDRL2 RADRLVD (SEQ ID NO:62)CDRL3 LQYDEFPLT (SEQ ID NO:63)Set 9: CRP-5809CDRH1 DTYIH (SEQ ID NO:64)CDRH2 RIDPANGHTRYAPKFQG (SEQ ID NO:65)CDRH3 IVWYSGGYAMDY (SEQ ID NO:66)CDRL1 GLSSGSVTASNYPG (SEQ ID NO:245)CDRL2 STNDRHS (SEQ ID NO:246)Set 10: IL-6-2418CDRL3 ALDIGDITE (SEQ ID NO:247)CDRH1 SYRMY (SEQ ID NO:248)Atty Dkt. No.: MOBI-015WOCDRH2 AISAGGGSTYYGDSVKG (SEQ ID NO:249)CDRH3 RAGWGMGDY (SEQ ID NO:250)CDRL1 KSSQSLFNSGHQKNYLA (SEQ ID NO:256)CDRL2 GASTRES (SEQ ID NO:257)CDRL3 QNDHRYPLT (SEQ ID NO:258)Set 11: HisTag-6446CDRH1 DYNMD (SEQ ID NO:259)CDRH2 DINPNNGGPIYNQNFRG (SEQ ID N0:260)CDRH3 DWSTAMDY (SEQ ID NO:261)VHVL Type Scaffold Proteins

[0052] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70% identical (e.g., at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to one of:EVQLQQSPDQTVEEGSTATLTATASGFNITWVKEDLDGSLEWIGRFTITSDTSSNTAYLTITNLTKADTATYYAARWGQ GTKLTVGELSEEEKEELIKERKERREEYYKENPDWKMTVEKETVTVKLGETATIKVWYKQKPGQPPQLUYGVPSRISGS GSGTDFTLTITNVQPEDEATYYAFSDPVKLIIE (VHVL4736; SEQ ID NO:8), QVQLQQSPDQTVEVGETVTLSAKASGFNIEWVRQPPGGPLQWIGRFTITADTSSNRVSLTITNVRIEDTATYYATRWG QGTKLTVKADPEEREKALKEYLERLKTEKRPGQVRLTPEKKTVKVKLGETATLKFWYKQAPGEPPQLLIYGVPSRISGSGS GTDFTLTITNVQPEDEATYYAFSEGTKLVIE (VHVL4739; SEQ ID NO:9), EVQLQAPPDQTVAVGETVTLTWTASGFNIKWVRQAPGGPLEWIGRFTITSDTSSNTASLTITNVQVGDTATYYAARW GEGTKLTVPASEEELKEAREERKEEREELIKRGEIIGLTPEKATVTVALGGTATLTVWYKQAPGQPPELLIYGVPSRFSGSG SGTDFTLTITDVQEEDEATYYAFSEGTKVVIL (VHVL4742; SEQ ID NO:10), DVHLQQSPDQTVEEGSTVTLTATVTGYSITWIREYLDGSLEWMGRFSITRDTSKNQFYLTITNLTKLDTATYYAARWGQ GTKLTVGELSEEEKEELIKERKERRKQYYKEHPNVIHMSVDQKVVKVKLGETAVIRVWYKQKPGQPPQLLIYGVPERISGS GSGTDFTLTITNVQEEDAATYYAFSEPVKLVIE (VHVL6375; SEQ ID NO:11), or DGVKLDESPDQEVEVGETVTLTAVTSGFTFGWVRQPPGGPLEWVARFSISRDDSKSSVSLTITNVRIEDHATYYFTGLGK GTKLTVKADPEELEEALRKYHEELKTREVPGQVRMTADKTTVTVKEGETATLKFWYKQAPGEPPRVLIYGVPSRISGSGS GTDFTLTITDVQPEDEATYYAFSEGTKLVIE (VHVL6486; SEQ ID NO:12), wherein " VHVL4736" is interchangeably used herein with " VHVL4736-soluble-consensus," " VHVL4736-soluble," and " VHVL4736-sol" to refer to the amino acid sequence of SEQ ID NO:8, " VHVL4739" is interchangeably used herein with " VHVL4739-soluble-consensus," " VHVL4739-soluble," and " VHVL4739-sol" to refer to the amino acid sequence of SEQ ID NO:9, and " VHVL4742" is interchangeably used herein with " VHVL4742-soluble-Atty Dkt. No.: MOBI-015WOconsensus," " VHVL4742-soluble," and " VHVL4742-sol" to refer to the amino acid sequence of SEQ ID NO:10.

[0053] The amino acid sequence of the VHVL type scaffold protein (e.g., SEQ ID NOs:8-12 above) can comprise three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3 and three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, wherein CDRH1 is inserted between positions 'Ll and 34, CDRH2 is inserted between positions 41 and 48, CDRH3 is inserted between positions 73 and 80, CDRL1 is inserted between positions 133 and 140, CDRL2 is inserted between positions 148 and 155, CDRL3 is inserted between positions 180 and 187, wherein positions are numbered relative to SEQ ID NO:8 and wherein the CDRL1-CDRL3 and CDRH1-CDRH3 are disregarded when calculating sequence identity of the scaffold protein. CDRH1 may be inserted between positions 29 and 32, CDRH2 may be inserted between positions 43 and 46, CDRH3 may be inserted between positions 75 and 78, CDRL1 may be inserted between positions 135 and 138, CDRL2 may be inserted between positions 150 and 153, CDRL3 may be inserted between positions 182 and 185. CDRH1 may be inserted between positions 30 and 31, CDRH2 may be inserted between positions 44 and 45, CDRH3 may be inserted between positions 76 and 77, CDRL1 may be inserted between positions 136 and 137, CDRL2 may be inserted between positions 151 and 152, CDRL3 may be inserted between positions 183 and 184.

[0054] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:8, wherein the amino acid sequence is:XiX2X3X4X5QSPDQTVEEGSTATLTAX6X7X8GX9X1oXi1X12WVKEDLDGSLEWXi3X14RFTITSDTSSNTAYLTITNLTKXi5D TATYYAX16X17WGQGTKLTVGELSEEEKEELIKERKERREEYYKENPDVVKMTVEKETVTVKLGETATIKVWYKQKPGQP PQLLIXisGVPSRISGSGSGTDFTLTITNVQPEDEATYYAFSDPVKLIlE (SEQ ID NO:92), wherein XI may be D or E or G or K or P or Q, X2 may be A or V, X3 may be A or H or K or Q or R or V, X4 may be L or V, X5 may be D or Q or T, X6 may be A or K or T or V, X7 may be A or P or T or V, X8 may be S or T, X9 may be F or Y, X10 may be A or N or S or T, Xll may be F or I, X12 may be G or K or S or T, X13 may be I or M or V, X14 may be A or G, X15 may be A or S, X16 may be A or P or T, X17 may be G or R, X18 may be F or K or Y. CDRL1-CDRL3 and CDRH1-CDRH3 may be inserted in the same positions as discussed above numbered relative to SEQ ID NO:8.

[0055] A scaffold protein of the present disclosure can comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:9, wherein the amino acid sequence is:Atty Dkt. No.: MOBI-015WOXIX2X3X4X5QSPDQTVEEGSTATLTAXSX7X8GX9XIOXIIXI2W KEDLDGSLEWXI3XI4RFTITSDTSSNTAYLTITNLTKXI5D TATYYAXisXiyWGQGTKLTVGELSEEEKEEUKERKERREEYYKENPDVVKMTVEKETVTVKLGETATlKVWYKQKPGQP PQLLIXigGVPSRISGSGSGTDFTLTITNVQPEDEATYYAFSDPVKLIlE (SEQ ID NO:93), wherein XI may be D or G or P or Q, X2 may be A or V, X3 may be A or H or K or Q or R, X4 may be L or V, X5 may be D or I or Q or T, X6 may be A or K or T or V, X7 may be A or P or T or V, X8 may be S or T, X9 may be F or Y, X10 may be A or N or S or T, Xll may be F or I, X12 may be E or G or K or N or S or T, X13 may be E or Q, X14 may be I or M or V, X15 may be A or G, X16 may be A or P or T, X17 may be G or R, X18 may be I or R, X19 may be L or M, X20 may be E or K, X21 may be T or V, X22 may be E or Q, X23 may be F or Y, X24 may be D or N. CDRL1-CDRL3 and CDRH1-CDRH3 may be inserted in the same positions as discussed above numbered relative to SEQ ID NO:8.

[0056] The amino acid sequence of the scaffold protein may be at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 10. The scaffold protein may comprise the amino acid sequence:XiXzXsX XsAPPDQTVXsVGETVTLTWX XgXgGXwXnXijXiaWVRQAPGGPLEWXMXisRFTITSDTSSNTASLTITNVQV GDTATYYAXisX WGEGTKLTVPASEEELKEARXigERKEEREELIKXigGEIIGLTPEKATVTVALGGTATLTVWYKQAPG QPPELLIX20GVPSRFSGSGSGTDFTLTITDVQX21EDEATYYAFSEGTKVVIL (SEQ ID NO:94), wherein XI may be D or E or G or P or Q, X2 may be A or V, X3 may be A or H or K or Q or R, X4 may be L or V, X5 may be D or Q or T, X6 may be A or K, X7 may be A or K or T or V, X8 may be A or P or T or V, X9 may be S or T, X10 may be F or Y, Xll may be A or N or S or T, X12 may be F or I, X13 may be G or K or N or S or T, X14 may be I or M or V, X15 may be A or G, X16 may be A or P or T, X17 may be G or R, X18 may be E or K, X19 may be E or R, X20 may be F or Y, X21 may be E or P. CDRL1-CDRL3 and CDRH1-CDRH3 may be inserted in the same positions as discussed above numbered relative to SEQ ID NO:8.

[0057] The amino acid sequence of the scaffold protein may be at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 11. The scaffold protein may comprise the amino acid sequence:XiX2X3X4X5QSPDQT EEGSTVTLTAX6X7X8GX9XioXiiXi2WIREYLDGSLEWXi3Xi4RFSITRDTSKNQFYLTITNLTKLDT ATYYAX15XI6WGQGTKLTVGELSEEEKEELIKERKERRKQYYKEHPNVIHMSVDQKVVKVKLGETAVIRVWYKQKPGQP PQLUX17GVPERISGSGSGTDFTLTITNVQEEDAATYYAFSEPVKLVIE (SEQ ID NO:95), wherein XI may be D or G or P or Q, X2 may be A or V, X3 may be A or H or K or R, X4 may be L or V, X5 may be D or Q or T, X6 may be A or K or T or V, X7 may be A or P or T or V, X8 may be S or T, X9 may be F or Y, X10 may be A or N or S or T, Xll may be F or I, X12 may be G or K or S or T, X13 may be I or M or V, X14 may be A or G, X15Atty Dkt. No.: MOBI-015WOmay be A or P or T, X16 may be G or R, X17 may be F or Y, and wherein CDRL1-CDRL3 and CDRH1-CDRH3 may be inserted in the same manner as discussed above numbered relative to SEQ ID NO:8.

[0058] The amino acid sequence of the scaffold protein may be at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12. The scaffold protein may comprises the amino acid sequence:DGX1VX2LX3ESPDQEVEVGETVTLTAX4X5X6GX7X8X9X10WVRQPPGGPLEWX11X12RFSISRDDSKSSVSLTITNVRIEDH ATYYFX13X14LGKGTKLTVKADPEELEEALRKYHEELKTREVPGQVRMTADKTTVTVKEGETATLKFWYKQAPGEPPRVL IX15GVPSRISGSGSGTDFTLTITDVQPEDEATYYAFSEGTKLVIE (SEQ ID NO:96), wherein DG may be present or absent, XI may be D or G or K or P or Q, X2 may be A or H or K or R or V, X3 may be D or Q or T, X4 may be K or T or V, X5 may be A or P or T or V, X6 may be S or T, X7 may be F or Y, X8 may be A or N or S or T, X9 may be F or I, X10 may be G or K or S or T, Xll may be I or M or V, X12 may be A or G, X13 may be A or P or T, X14 may be G or R, X15 may be F or K or Y, and wherein CDRL1-CDRL3 and CDRH1-CDRH3 may be inserted in the same manner as discussed above numbered relative to SEQ ID NO:8.

[0059] In some embodiments, the VHVL type scaffold proteins described above may include one of the following sets of CDRs (each set including CDRL1-CDRL3 and CDRH1-CDRH3) for binding to, e.g., CRP, D-Dimer, Hemoglobin, PCT, TSH, sFLT-1, FITC, IL-6, His-Tag, or Hemagglutinin (HA), as found in Table 2 below:Table 2: CDR Sets for VHVL Framework SequencesCDRL1 SASSSVSYMY (SEQ ID NO:13)CDRL2 RTSNLAS (SEQ ID NO:14)CDRL3 QQYHSYPPT (SEQ ID NO:15)Set 1: CRP-2702CDRH1 HYSLY fSEQ ID NO:16)CDRH2 EINPRNDGTKFNEKFKS (SEQ ID NO:17)CDRH3 SGTTYDLALDY (SEQ ID NO:18)CDRL1 KASQNVGTPVA (SEQ ID NO:19)CDRL2 STSTRYP (SEQ ID NQ:20)CDRL3 QQYSLYPLT (SEQ ID NO:21)Set 2: DDimer-3302CDRH1 SDYAWN (SEQ ID NO:22)CDRH2 YITYSGTTSYNPSLTS (SEQ ID NO:23)CDRH3 EWFPYYFDY (SEQ ID NO:24)CDRL1 RASEGIYHWLA (SEQ ID NO:25)CDRL2 KASSLAS (SEQ ID NO:26)Set 3: Hemoglobin-3885 CDRL3 QQYSNYPLT (SEQ ID NO:27)CDRH1 NYAMS (SEQ ID NO:28)CDRH2 AISGSGGSTYYADSVKG (SEQ ID NO:29)Atty Dkt. No.: MOBI-015WOCDRH3 YYGDGMDV (SEQ ID NO:30)CDRL1 RSSQSLVHINGNTYVH (SEQ ID N0:31)CDRL2 KVSNRFS (SEQ ID NO:32)CDRL3 SQSTHVPLT (SEQ ID NO:33)Set 4: PCT-3322CDRH1 DTFIH (SEQ ID NO:34)CDRH2 RIDPANGNIIYDPRFQG (SEQ ID NO:35)CDRH3 VGDASLYFDY (SEQ ID NO:36)CDRL1 RASQSVSSSSYSYMH (SEQ ID NO:37)CDRL2 FASNLES (SEQ ID NO:38)CDRL3 QHTWEIPRT (SEQ ID NO:39)Set 5: TSH-2508CDRH1 LYWMS (SEQ ID N0:40)CDRH2 EIDPESNTINYTPSLKD (SEQ ID N0:41)CDRH3 SSMDY (SEQ ID NO:42)CDRL1 KASQSVGTAVA (SEQ ID NO:43)CDRL2 SASNRYT (SEQ ID NO:44)CDRL3 QQYFTYPYT (SEQ ID NO:45)Set 6: sFLTl-4129CDRH1 SYWMN (SEQ ID NO:46)CDRH2 QIYPGDGDTNYNGKFRG (SEQ ID NO:47)CDRH3 DDGYEGFDY (SEQ ID NO:48)CDRL1 RASQSVSSSYLA (SEQ ID NO:49)CDRL2 GASSRAT (SEQ ID NQ:50)CDRL3 QQYGSSPLT (SEQ ID N0:51)Set 7: sFLTl-4131CDRH1 SYGMH (SEQ ID NO:52)CDRH2 VIWYDGSNKYYADSVRG (SEQ ID NO:53)CDRH3 DHYGSGVHHYFYYGLDV (SEQ ID NO:54)CDRL1 RSSQSLVHSNGNTYLR (SEQ ID NO:55)CDRL2 KVSNRVS (SEQ ID NO:56)CDRL3 SQSTHVPWT (SEQ ID NO:57)Set 8: FITC-6486CDRH1 HYWMN (SEQ ID NO:58)CDRH2 QFRNKPYNYETYYSDSVKG (SEQ ID NO:59)CDRH3 ASYGMEY (SEQ ID N0:60)CDRL1 KASQDINSYLS (SEQ ID NO:61)CDRL2 RADRLVD (SEQ ID NO:62)CDRL3 LQYDEFPLT (SEQ ID NO:63)Set 9: CRP-5809CDRH1 DTYIH (SEQ ID NO:54)CDRH2 RIDPANGHTRYAPKFQG (SEQ ID NO:65)CDRH3 IVWYSGGYAMDY (SEQ ID NO:66)CDRL1 GLSSGSVTASNYPG (SEQ ID NO:245)Set 10: IL6-2418 CDRL2 STNDRHS (SEQ ID NO:246)CDRL3 ALDIGDITE (SEQ ID NO:247)Atty Dkt. No.: MOBI-015WOCDRH1 SYRMY (SEQ ID NO:248)CDRH2 AISAGGGSTYYGDSVKG (SEQ ID NO:249)CDRH3 RAGWGMGDY (SEQ ID NQ:250)CDRL1 KSSQSLFNSGHQKNYLA (SEQ ID NO:256)CDRL2 GASTRES (SEQ ID NO:257)CDRL3 QNDHRYPLT (SEQ ID NO:258)Set 11: HisTag-6446CDRH1 DYNMD (SEQ ID NO:259)CDRH2 DINPNNGGPIYNQNFRG (SEQ ID NQ:260)CDRH3 DWSTAMDY (SEQ ID NO:261)CDRL1 KSSQSLFNSGKRKNFLT (SEQ ID NO:239)CDRL2 WASTRES (SEQ ID NQ:240)CDRL3 QNDYSHPLT (SEQ ID NO:241)Set 12: HA-6107CDRH1 SFGMS (SEQ ID NO:242)CDRH2 TISNGGGYTYYQDSVKG (SEQ ID NO:243)CDRH3 RERYDEKGFAY (SEQ ID NO:244)IL6 Antigen Binding Polypeptides

[0060] The present disclosure provides IL6 binding polypeptides in scFv format comprising a scaffold protein as described herein and CDRsl-6 of an anti-l L6 antibody, e.g., an anti-human IL-6 antibody.

[0061] An IL6 antigen binding polypeptide of the present disclosure includes, from N-terminus to C-terminus, three light chain CDRs (e.g., CDRL1-CDRL3) followed by three heavy chain CDRs (e.g., CDRH1-CDRH3) and may be produced, e.g., using any of the above VLVH type scaffold proteins (e.g., SEQ ID NOs:l-7). In these instances, the IL6 antigen binding polypeptide comprises an amino acid sequence, including the CDRs, which amino acid sequence is at least 70% identical to one of the amino acid sequences:QTVVTMDAKEVTVKLGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSGSGTDFTLTISN VEPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEKKLEEAREERRKELAERRANSPVKLTQSPDITVKEGETATITVAASGF TFSSYRMYWVKQAPGGPLEWVSAISAGGGSTYYGDSVKGKFTISADTSKNTAYLTIKNLTKEDTATYYAANRAGWGM GDYWGEGTKLTVE (SEQ. ID NO:169), DIVMTVDAKEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSGSGTDFTLTISNV EPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEELLEEARERRRKRLAERRANSPVKLTQSPDITVKEGETATLTVKASGFT FTSYRMYWVKQAPGGPLEWIGAISAGGGSTYYGDSVKGRFTISRDTSKNTAYLTITNLTKEDTATYYAARRAGWGMGD YWGEGTKLTVE (SEQ ID N0:170),QTVVTVDAKEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSGSGTDFTLTISNVAtty Dkt. No.: MOBI-015WOEPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEKLLEEAREERRKELAERRANSPVKLTQSPDITVKEGETATLTVAASGFT FSSYRMYWVKQAPGGPLEWVSAISAGGGSTYYGDSVKGRFTISRDTSKNTAYLTITNLTKEDTATYYAANRAGWGMG DYWGEGTKLTVE (SEQ ID NO:171), QTVVVDAKEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSISGNKATLTISNVE PEDEATYYAALDIGDITEFSEGTKLLIVPTPETEELLEEARERRRKRLAERRANSPVKLTQSPDITVKEGETATLTVAASGFTF SSYRMYWVKQAPGGPLEWVSAISAGGGSTYYGDSVKGRFTISRDNAKNTVYLTITNLTKEDTATYYAANRAGWGMG DYWGEGTKLTVE (SEQ. ID NO:172), QTVVDDAKEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFTGSISGNKASLTISNVE PEDEATYYAALDIGDITEFSEGTKLLIVPTPETEELLEEARERRRKRLAERRANSPVKLTQSPDITVKEGETATLTVAASGFTF SSYRMYWVKQAPGGPLEFVSAISAGGGSTYYGDSVKGRFTISRDNAKNTVSLTITNLTKEDTATYYAANRAGWGMGD YWGEGTKLTVE (SEQ ID NO:173), QTVVTDDKAEVTVELGETATITVGLSSGSVTASNYPGWYRQFPGEPPELLIYSTNDRHSGVPDRISGSGSGTDFTLTIKNV EPEDEATYYAALDIGDITEFSSGTKLLLVPTPETEEELEEARRERERELAERRKNSPVKLTQSPDLTVKEGETATLTAAASGF TFSSYRMYWVRQAPGGPLEWVSAISAGGGSTYYGDSVKGRFSISRDTSKNTLYLTISNLTPEDTATYYAANRAGWGMG DYWGEGTKLTVE (SEQ ID NO:174), QTVVTVDKAEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRISGSGSGTDFTLTISNV EPEDEATYYAALDIGDITEFSQGTKLLLVPTPETEEELEEARRERAERLAERRKNSPVKLTQSPDLTVKEGETATLTAAASG FTFSSYRMYWVRQAPGGPLEWVSAISAGGGSTYYGDSVKGRFEISRDTSKNTLYLTIKNLTKEDTATYYAANRAGWGM GDYWGEGTKLTVE (SEQ ID NO:175), QIMLSVDKPEVVVEEGETAEVKVGLSSGSVTASNYPGWYRQFPGKPPEALVYSTNDRHSGVPDRISGSGSGTEFTLTIK NVEPEDVATYYAALDIGDITEFSSGTKLLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKEGETATLTLTVS GFSLTSYRMYWVKQAPGGPLQWLGAISAGGGSTYYGDSVKGRFTISRDTSKSQFYLTITNLKKEDTATYYAARRAGWG MGDYWGQGTKLTVE (SEQ ID NO:176), QTVVTVDKSEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSGSGTDFTLTISNV EPEDEATYYAALDIGDITEFSSGTKLLIVPTPETEEELEEAREERARELAERRKNSPVKLTQSPDLTVKEGETATLTAAASGF TFSSYRMYWVRQAPGGPLQWVSAISAGGGSTYYGDSVKGRFSISRDTSKNTFYLTISNLTKEDTATYYAANRAGWGM GDYWGEGTKLTVE (SEQ ID NO:177), QTVVVDKPEVVVEEGETAEVKVGLSSGSVTASNYPGWYRQFPGKPPEALIYSTNDRHSGVPDRISGSISGNKATLTIKNV EPEDVATYYAALDIGDITEFSSGTKLLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKEGETATLTLAASGF TFSSYRMYWVKQAPGGPLQWVSAISAGGGSTYYGDSVKGRFTISRDNAKNTVYLTITNLKKEDTATYYAANRAGWGM GDYWGQGTKLTVE (SEQ ID NO:178), orQTVVVDKPEVVVEEGETAEVSVGLSSGSVTASNYPGWYRQFPGKPPELLIYSTNDRHSGVPDRISGSISGNKAVLTIKNVAtty Dkt. No.: MOBI-015WOEPEDVATYYAALDIGDITEFSEGTKLLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKEGETATLTLAASGF TFSSYRMYWVKQAPGGPLEFVSAISAGGGSTYYGDSVKGRFTISRDNAKNTVTLTITNLKKEDTATYYAANRAGWGMG DYWGQGTKLTVE (SEQ ID NO:179).

[0062] The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:169. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NQ:170. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:171. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:172. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:173. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:174. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:175. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:176. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:177. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:178. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:179.

[0063] The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence:Atty Dkt. No.: MOBI-015WOXiXjVXjX^XsDAKEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFXsGSXySGXgXgXio XuLTISNVEPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEXuLLEEAREXuRRKXuLAERRANSPVKLTQSPDITVKEGE TATLTVX15ASGFTFX16SYRMYWVKQAPGGPLEX17X18X19AISAGGGSTYYGDSVKGRFTISRDX20X21KNTX22X23LTITN LTKEDTATYYAAX24RAGWGMGDYWGEGTKLTVE (SEQ ID NO:251), wherein XI may be D or Q, X2 may be I or T, X3 may be M or V, X4 may be T or X, X5 may be D or V, X6 may be S or T, X7 may be G or I, X8 may be N or T, X9 may be D or K, X10 may be A or F, Xll may be S or T, X12 may be E or K, X13 may be E or R, X14 may be E or R, X15 may be A or K, X16 may be S or T, X17 may be F or W, X18 may be I or V, X19 may be G or S, X20 may be N or T, X21 may be A or S, X22 may be A or V, X23 may be S or Y, and X24 may be N or R.

[0064] An IL6 antigen binding polypeptide of the present disclosure includes, from N-terminus to C-terminus, three heavy chain CDRs (e.g., CDRH1-CDRH3), followed by three light chain CDRs (e.g., CDRL1-CDRL3) and may be produced, e.g., using any of the above VHVL type scaffold proteins (e.g., SEQ ID NOs:8-12). In these instances, IL6 antigen binding polypeptide comprises an amino acid sequence, including the CDRs, which amino acid sequence is at least 70% identical to one of the amino acid sequences:PVKLTQSPDQTVEEGSTATLTAAASGFTFSSYRMYWVKEDLDGSLEWVSAISAGGGSTYYGDSVKGRFTITSDTSSNTA YLTITNLTKSDTATYYAANRAGWGMGDYWGQGTKLTVGELSEEEKEELIKERKERREEYYKENPDVVKMTVEKETVTVK LGETATIKVGLSSGSVTASNYPGWYKQKPGQPPQLLIYSTNDRHSGVPSRISGSGSGTDFTLTITNVQPEDEATYYAALDI GDITEFSDPVKLIIE (SEQ ID N0:180), QVQLQQSPDQTVEVGETVTLSAKASGFNIESYRMYWVRQPPGGPLQWIGAISAGGGSTYYGDSVKGRFTITADTSSNR VSLTITNVRIEDTATYYATRRAGWGMGDYWGQGTKLTVKADPEEREKALKEYLERLKTEKRPGQVRLTPEKKTVKVKLG ETATLKFGLSSGSVTASNYPGWYKQAPGEPPQLLIYSTNDRHSGVPSRISGSGSGTDFTLTITNVQPEDEATYYAALDIGD ITEFSEGTKLVIE (SEQ ID NO:181), PVKLTQSPDQTVEVGETVTLSAAASGFTFSSYRMYWVRQPPGGPLEWVSAISAGGGSTYYGDSVKGRFTITADTSSNR VSLTITNVRIEDTATYYAANRAGWGMGDYWGQGTKLTVKADPEEREKALKEYLERLKTEKIPGQVRMTPEEKVVKVKL GETATLKFGLSSGSVTASNYPGWYKQAPGQPPQLLIYSTNDRHSGVPSRISGSGSGTDFTLTITDVQPEDEATYYAALDI GDITEFSEGTKLVIE (SEQ ID NO:182), EVQLVQSPDQTVEVGETVTLSAAASGFTFSSYRMYWVRQPPGGPLEWVSAISAGGGSTYYGDSVKGRFTISRDNAKNT VSLTITNVRIEDTATYYAANRAGWGMGDYWGQGTKLTVKADPEEREKALKEYLERLKTEKIPGQVRMTPEEKVVKVKL GETATLKFGLSSGSVTASNYPGWYKQAPGQPPQLLIYSTNDRHSGVPSRISGSISGNKATLTITDVQPEDEATYYAALDIG DITEFSEGTKLVIE (SEQ ID NO:183),EVQLVQSPDQTVEVGETVTLTAAASGFTFSSYRMYWVRQPPGGPLEFVSAISAGGGSTYYGDSVKGRFTISRDNAKNTAtty Dkt. No.: MOBI-015WOVSLTITNVRIEDTATYYAANRAGWGMGDYWGQGTKLTVKADPEEREKALKEYLERLKTEKIPGQNRLLPEEKVVKVKLG ETATLSFGLSSGSVTASNYPGWYKQAPGQPPTQLIYSTNDRHSGVPSRISGSISGNKAVLTITDVQPEDEATYYAALDIGD ITEFGEGTKLVIE (SEQ ID NO:184), EVQLQAPPDQTVAVGETVTLTWTASGFNIKSYRMYWVRQAPGGPLEWIGAISAGGGSTYYGDSVKGRFTITSDTSSNT ASLTITNVQVGDTATYYAARRAGWGMGDYWGEGTKLTVPASEEELKEAREERKEEREELIKRGEIIGLTPEKATVTVALG GTATLTVGLSSGSVTASNYPGWYKQAPGQPPELLIYSTNDRHSGVPSRFSGSGSGTDFTLTITDVQEEDEATYYAALDIG DITEFSEGTKVVIL (SEQ. ID NO:185), PVKLTAPPDQTVKVGETVTLTWAASGFTFSSYRMYWVRQAPGGPLEWVSAISAGGGSTYYGDSVKGRFTITSDTSSNT ASLTITNVQVGDTATYYAANRAGWGMGDYWGEGTKLTVPASEEELKEARKERKEEREELIKEGEIIGLTPEKATVTVALG GTATLTVGLSSGSVTASNYPGWYKQAPGQPPELLIYSTNDRHSGVPSRFSGSGSGTDFTLTITDVQPEDEATYYAALDIG DITEFSEGTKVVIL (SEQ ID NO:186), EVQLVAPPDQTVKVGETVTLTWAASGFTFSSYRMYWVRQAPGGPLEWVSAISAGGGSTYYGDSVKGRFTISRDNAKN TVSLTITNVQVGDTATYYAANRAGWGMGDYWGEGTKLTVPASEEELKEARKERKEEREELIKEGEIIGLTPEKATVTVAL GGTATLTVGLSSGSVTASNYPGWYKQAPGQPPELLIYSTNDRHSGVPSRFSGSISGNKATLTITDVQPEDEATYYAALDI GDITEFSEGTKVVIL (SEQ ID NO:187), EVQLVPPPDQTVKVGETVTLTWAASGFTFSSYRMYWVRQAPGGPLEFVSAISAGGGSTYYGDSVKGRFTISRDNAKNT VSLTITNVQVGDTATYYAANRAGWGMGDYWGQGTKLTVPASEEELKEARKERKEEREELIKEGEITGLYPDKATVTVAL GGTATLTVGLSSGSVTASNYPGWYKQAPGQPPQLLIYSTNDRHSGVPSRFSGSISGNKAVLTITDVQPEDEATYYAALDI GDITEFSEGTKVVIL (SEQ ID NO:188), or PVKLTQSPDQTVEEGSTVTLTAAASGFTFSSYRMYWIREYLDGSLEWVSAISAGGGSTYYGDSVKGRFSITRDTSKNQFY LTITNLTKLDTATYYAANRAGWGMGDYWGQGTKLTVGELSEEEKEELIKERKERRKQYYKEHPNVIHMSVDQKVVKVK LGETAVIRVGLSSGSVTASNYPGWYKQKPGQPPQLLIYSTNDRHSGVPERISGSGSGTDFTLTITNVQEEDAATYYAALDI GDITEFSEPVKLVIE (SEQ ID NO:189).

[0065] The ILS antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NQ:180. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:181. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:182. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%,Atty Dkt. No.: MOBI-015WOat least 99%, or 100% identical to SEQ ID NO:183. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:184. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:185. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:186. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:187. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:188. The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:189.

[0066] The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence:X1VX2LX3QSPDQTVEVGET LX4AX5ASGFX6X7X8SYRMYWVRQPPGGPLX9X10X11X12AISAGGGSTYYGDSVKGRFTI X13X14DX15X16X17NX18 SLTITNVRIEDTATYYAX19X2ORAGWGMGDYWGQGTKLTVKADPEEREKALKEYLERLKTEKX 21PGQX22RX23X24PEX25KX26VKVKLGETATLX27FGLSSGSVTASNYPGWYKQAPGX28PPX29X30LIYSTNDRHSGVPSRIS GSX31SGX32X33X34X35LTITX36 QPEDEATYYAALDIGDITEFX37EGTKLVIE (SEQ ID NO:252), wherein XI may be E or P or Q, X2 may be K or Q, X3 may be Q or T or V, X4 may be S or T, X5 may be A or K, X6 may be N or T, X7 may be F or I, X8 may be E or S, X9 may be E or Q, X10 may be F or W, Xll may be I or V, X12 may be G or S, X13 may be S or T, X14 may be A or R, X15 may be N or T, X16 may be A or S, X17 may be K or S, X18 may be R or T, X19 may be A or T, X20 may be N or R, X21 may be I or R, X22 may be N or V, X23 may be L or M, X24 may be L or T, X25 may be E or K, X26 may be T or V, X27 may be K or S, X28 may be E or Q, X29 may be Q or T, X30 may be L or Q, X31 may be G or I, X32 may be N or T, X33 may be D or K, X34 may be A or F, X35 may be T or V, X36 may be D or N, and X37 may be G or S.

[0067] The IL6 antigen binding polypeptide may comprise an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence:Atty Dkt. No.: MOBI-015WOXiVX2LX3X4PPDQTVX5VGETVTLTWXsASGFX7X8X9SYRMYWVRQAPGGPLEXioXiiXi2AISAGGGSTYYGDSVKGRFT IXisXMDXisXieXivNTXisSLTITNVQVGDTATYYAAXigRAGWGMGDYWGXzoGTKLTVPASEEELKEARXziERKEEREEL IKX22GEIX23GLX24PX25KATVTVALGGTATLTVGLSSGSVTASNYPGWYKQAPGQPPX2SLLIYSTNDRHSG PSRFSGSX2 7SGX28X29X3OX3ILTITD QX32EDEATYYAALDIGDITEFSEGTKVVIL (SEQ ID NO:253), wherein XI may be E or P, X2 may be K or Q, X3 may be Q or T or V, X4 may be A or P, X5 may be A or K, X6 may be A or T, X7 may be N or T, X8 may be F or I, X9 may be K or S, X10 may be F or W, Xll may be I or V, X12 may be G or S, X13 may be S or T, X14 may be R or S, X15 may be N or T, X16 may be A or S, X17 may be K or S, X18 may be A or V, X19 may be N or R, X20 may be E or Q, X21 may be E or K, X22 may be E or R, X23 may be I or T, X24 may be T or Y, X25 may be D or E, X25 may be E or Q, X27 may be G or I, X28 may be N or T, X29 may be D or K, X30 may be A or F, X31 may be T or V, and X32 may be E or P.PfRh5 Antigen Binding Polypeptides

[0068] The present disclosure provides Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRh5) binding polypeptides in scFv format comprising a scaffold protein as described herein and CDRsl-6 of an anti-PfRh5 antibody.

[0069] A PfRh5 antigen binding polypeptide of the disclosure includes, from N-terminus to C-terminus, three light chain CDRs (e.g., CDRL1-CDRL3) followed by three heavy chain CDRs (e.g., CDRH1-CDRH3). In some embodiments, the VLVH0230-S scaffold protein may be used to produce the PfRh5 antigen binding polypeptide. In these instances, the PfRh5 antigen binding polypeptide, including the CDRs, may comprise an amino acid sequence that is at least 70% identical (e.g. at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to the amino acid sequence:DIVLTVDAKEVTVELGETATITVRASESVEYYGTSLMQWYRQYPGEPPELLIHGASNVQSGVPSRFSGSGSGTDFTLTISN VEPEDEATYYAQQSTKVPWTFSEGTKLLIVPTPETEKLLEEAREERRKELAERRANSPVKLTQSPDITVKEGETATLTVAAS GFTFSDYGMAWVKQAPGGPLEWVTFISNMAYSIYYADTVTGRFTISRENAKNTLYLTITNLTKEDTATYYATRAIFDYAG YWYFDVWGEGTKLTVE (SEQ. ID NO:228), or DIVLTVDAKEVTVELGETATITVRASQSVSTSSYTYFHWYRQYPGEPPELLIRYASNLESGVPSRFSGSGSGTDFTLTISNVE PEDEATYYAQHSWEIPYTFSEGTKLLIVPTPETEKLLEEAREERRKELAERRANSPVKLTQSPDITVKEGETATLTVAASGFT FSDFYMYWVKQAPGGPLEWVATISDGDSYIYYPDSVRGRFTISRDNAKNILYLTITNLTKEDTATYYAARDGNGKDGGD AMDYWGEGTKLTVE (SEQ ID NO:229).

[0070] The amino acid sequence may be at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:228.Atty Dkt. No.: MOBI-015WOThe amino acid sequence may be at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:229.

[0071] A PfRh5 antigen binding polypeptide of the disclosure includes, from N-terminus to C-terminus, three heavy chain CDRs (e.g., CDRH1-CDRH3), followed by three light chain CDRs (e.g., CDRL1-CDRL3). In some embodiments, the VHVL4742 or the VHVL4739 scaffold protein may be used to produce the PfRh5 antigen binding polypeptide. In these instances, the PfRh5 antigen binding polypeptide, including the CDRs, may comprise an amino acid sequence that is at least 70% identical (e.g., at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to the amino acid sequence:GVKLVQSPDQTVKVGETVTLTWAASGFTFSDYGMAWVRQAPGGPLEWVTFISNMAYSIYYADTVTGRFTISRENAKN TLSLTITNVQVGDTATYYATRAIFDYAGYWYFDVWGEGTKLTVPASEEELKEARKERKEEREEUKEGEIIGLTPEKATVTV ALGGTATLTVRASESVEYYGTSLMQWYKQAPGQPPELLIHGASNVQSGVPSRFSGSGSGTDFTLTITDVQPEDEATYYA QQSTKVPWTFSEGTKVVIL (SEQ ID NO:231), or VKLVQSPDQTVEVGETVTLTAAASGFTFSDYGMAWVRQPPGGPLEFVTFISNMAYSIYYADTVTGRFTISRENAKNTLS LTITNVRIEDTATYYATRAIFDYAGYWYFDVWGQGTKLTVKADPEEREKALKEYLERLKTEKRPGVITLTPEEKVVKVKLG ETATLKFRASESVEYYGTSLMQWFKQAPGQPPQLLIHGASNVQSGVPSRISGSGSGTDFTLTITDVQPEDEATYYAQQS TKVPWTFSEGTKLVIE (SEQ ID NO:233).

[0072] The amino acid sequence may be at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:231. The amino acid sequence may be at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:233.Conjugated Polypeptides

[0073] The polypeptides disclosed herein, e.g., scaffold proteins and antigen binding polypeptides comprising a scaffold protein and a set of CDRs, may be conjugated to another moiety. The moiety may be a small molecule, peptide, polypeptide, nucleic acid, or lipid. The polypeptides may also be tagged with a sequence for localization to a cellular compartment, cell membrane, for secretion, detection, or purification. The polypeptides disclosed herein can be used as biosensors by conjugating a detectable moiety to the N-terminus, the C-terminus, or between the N- and the C-terminus. The detectable moiety may be a radioisotope, an enzyme which generates a detectable product, a fluorescent protein, and the like.Atty Dkt. No.: MOBI-015WO

[0074] The moiety may be conjugated directly to the polypeptides, e.g., via a peptide bond to the N-terminus and / or the C-terminus and / or to an amino acid side chain or may be conjugated to the polypeptide via a linker. The linker may be a polymer, e.g., an amino acid linker or a sugar linker. The moiety may be conjugated to the side chain of the amino acid at the N-terminus and / or the side chain of the amino acid at the C-terminus and / or to an interior amino acid side chain of the polypeptides disclosed herein. In certain examples, an amino acid, e.g., a cysteine or a lysine may be introduced at the N-terminus and / or the C-terminus and / or in between the N- and C-terminus of the polypeptides disclosed herein to serve as a chemical handle for conjugating a moiety.

[0075] A variety of linkers may be used and may include alkyl groups, methylene carbon chains, ether, polyether, alkyl amide linker, a peptide linker, a modified peptide linker, a Polyethylene glycol) (PEG) linker, a streptavidin-biotin or avidin-biotin linker, polyaminoacids (e.g., polylysine), functionalized PEG, polysaccharides, glycosaminoglycans, oligonucleotide linker, phospholipid derivatives, alkenyl chains, alkynyl chains, disulfide, or a combination thereof. In some embodiments, the linker is cleavable (e.g., enzymatically (e.g., TEV protease site), chemically, photoinduced cleavage, etc.).

[0076] In certain aspects, the moiety may be a heterologous amino acid sequence. In certain aspects, the moiety is conjugated to the polypeptide post-translationally. In certain aspects, the moiety is conjugated to the polypeptide during translation, e. g., a nucleic acid may encode a fusion protein comprising the polypeptide and the moiety. As used herein, the term "heterologous amino acid sequence" means an amino acid sequence that is not part of a polypeptide's sequence prior to the conjugation or fusion. Heterologous amino sequences of interest include amino acid sequences of a polypeptide that interact with another polypeptide either directly or via another moiety.

[0077] In certain aspects, the heterologous amino acid sequence includes a protein binding domain, such as one that binds IL-17RA, e.g., IL-17A, or the IL-17A binding domain of IL-17RA, Jun binding domain of Erg, or the EG binding domain of Jun; a potassium channel voltage sensing domain, e.g., one useful to detect protein conformational changes, the GTPase binding domain of a Cdc42 or rac target, or other GTPase binding domains, domains associated with kinase or phosphotase activity, e.g., regulatory myosin light chain, PKC6, pleckstrin containing PH and DEP domains, other phosphorylation recognition domains and substrates; glucose binding protein domains, glutamate / aspartate binding protein domains, PKA or a cAMP-dependent binding substrate, lnsP3 receptors, GKI, PDE, estrogen receptor ligand binding domains, apoKl-er, or calmodulin binding domains.

[0078] In certain aspects, a fusion protein comprising a polypeptide fused to a heterologous amino acid sequence may be a biosensor. The biosensor is useful to detect a GTPase, e.g., binding ofAtty Dkt. No.: MOBI-015WOCdc42 or Rac to an EBFP, EGFP PAK fragment, Raichu-Rac, Raichu-Cdc42, integrin alphavbeta3, IBB of importin-a, DMCA or NBD-Ras of CRafl (for Ras activation), binding domain of Ras / Rap Rai RBD with Ras prenylation sequence. In one embodiment, the biosensor detects PI(4,5)P2 (e.g., using PH-PCLdeltal, PH-GRP1), PI(4,5)P2 or PI(4)P (e.g., PH-OSBP), PI(3,4,5)P3 (e.g., using PH-ARNO, or PH-BTK, or PH-Cytohesinl), PI(3,4,5)P3 or PI(3,4)P2 (e.g., using PH Akt), PI(3)P (e.g., using FYVE-EEA1), or Ca2+ (cytosolic) (e.g., using calmodulin, or C2 domain of PKC.

[0079] In one aspect, a fusion protein comprising a polypeptide is fused to a protein domain. In one embodiment, the domain is one with a phosphorylated tyrosine (e.g., in Src, Abl and EGFR), that detects phosphorylation of ErbB2, phosphorylation of tyrosine in Src, Abl and EGFR, activation of MKA2 (e.g., using MK2), cAMP induced phosphorylation, activation of PKA, e.g., using KID of CREG, phosphorylation of Crkll, e.g., using SH2 domain pTyr peptide, binding of bZIP transcription factors and REL proteins, e.g., bFos and bJun ATF2 and Jun, or p65 NFkappaB, or microtubule binding, e.g., using kinesin.

[0080] A first antigen binding polypeptide generated using a subject scaffold and a first set of CDRs and may be conjugated (e.g., post-translationally) to a second antigen binding polypeptide. The second antigen binding polypeptide may be an antibody, e.g., a scFv, to generate a bispecific antibody comprising two scFvs. The second antigen binding polypeptide may be a second antigen binding polypeptide generated using a subject scaffold and a second set of CDRs to generate a bispecific antibody comprising two scFvs. A plurality (e.g., three or more) of different antigen binding polypeptides generated using scaffolds of the present disclosure may be assembled (e.g., by fusion) into a multispecific molecule (e.g., a trispecific antibody) to simultaneously bind to multiple epitopes.

[0081] An antigen binding polypeptide generated using a subject scaffold and a set of CDRs may be in a scFv format and may be fused to an immunoglobulin G (IgG) Fc sequence, e.g. human IgG 1 Fc sequence.

[0082] An antigen binding polypeptide of the present disclosure may be used in a manner similar to the source antibody for the CDRs. Thus, if the source antibody is used in an assay, diagnostic, or treatment, the antigen binding polypeptide, generated from a subject scaffold and the CDRs of the source antibody, can also be used in the assay, diagnostic, or treatment.NUCLEIC ACIDS

[0083] The present disclosure provides nucleic acids comprising nucleotide sequences encoding the polypeptides described herein. These nucleic acids may be used for a cell-free transcription andAtty Dkt. No.: MOBI-015WOtranslation. A nucleotide sequence encoding a subject polypeptide can be operably linked to one or more regulatory elements, such as a promoter and enhancer, that allow expression of the nucleotide sequence in a recombinant cell that is genetically modified to produce the polypeptide.

[0084] Suitable promoter and enhancer elements are known in the art. For expression in a bacterial cell, suitable promoters include, but are not limited to, lacl, lacZ, T3, T7, gpt, lambda P and trc. For expression in a eukaryotic cell, suitable promoters include, but are not limited to, cytomegalovirus immediate early promoter; herpes simplex virus thymidine kinase promoter; early and late SV40 promoters; promoter present in long terminal repeats from a retrovirus; mouse metallothionein-l promoter; and the like.

[0085] A nucleotide sequence encoding a subject polypeptide can be present in an expression vector and / or a cloning vector. An expression vector can include a selectable marker, an origin of replication, and other features that provide for replication and / or maintenance of the vector. Large numbers of suitable vectors and promoters are known to those of skill in the art; many are commercially available for generating a subject recombinant construct. The following vectors are provided by way of example. Bacterial: pBs, phagescript, PsiX174, pBluescript SK, pBs KS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene, La Jolla, Calif., USA); pTrc99A, pKK223-3, pKK233-3, pDR540, and pRIT5 (Pharmacia, Uppsala, Sweden). Eukaryotic: pWLneo, pSV2cat, pOG44, PXR1, pSG (Stratagene) pSVK3, pBPV, pMSG and pSVL (Pharmacia). Expression vectors generally have convenient restriction sites located near the promoter sequence to provide for the insertion of nucleic acid sequences encoding polypeptides. A selectable marker operative in the expression host cell may be present.

[0086] Nucleic acids, e.g., as described herein, may, in some instances, be introduced into a cell, e.g., by contacting the cell with the nucleic acid. Cells with introduced nucleic acids will generally be referred to herein as genetically modified cells. Various methods of nucleic acid delivery may be employed including, but not limited to e.g., naked nucleic acid delivery, viral delivery, chemical transfection, biolistics, and the like.

[0087] The nucleic acids of the present disclosure may be provided in a kit. The kit may include additional components such as reconstitution buffer for resuspending the nucleic acid provided in the kit in a lyophilized form.HOST CELLS

[0088] The present disclosure provides isolated genetically modified cells (e.g., in vitro cells, ex vivo cells, cultured cells, etc.) that are genetically modified with a subject nucleic acid. In some aspects, aAtty Dkt. No.: MOBI-015WOsubject isolated genetically modified cell can produce a subject polypeptide. In some instances, a genetically modified cell may be used in the screening and / or discovery of protein-protein interaction; protein-drug interactions; protein-nucleic acid interaction, etc.

[0089] Suitable cells include eukaryotic cells, such as a mammalian cell (e.g., HEK 293 cells or CHO cells), an insect cell, a yeast cell; and prokaryotic cells, such as a bacterial cell (e.g., E. coli).Introduction of a subject nucleic acid into the host cell can be affected, for example by calcium phosphate precipitation, DEAE dextran mediated transfection, liposome-mediated transfection, electroporation, or other known methods. The scaffolds of the present disclosure allow generation of antigen binding polypeptides with scFv like format while avoiding need for disulfide bond mediated folding, allowing expression of the antigen binding polypeptides based on the scaffolds described herein in prokaryotic cells.KITS

[0090] Aspects of the present disclosure include kits comprising one or more antigen binding polypeptides as disclosed herein. In one aspect, the kit comprises (i) the polypeptide as disclosed herein, or (ii) the nucleic acid comprising a nucleotide sequence encoding the polypeptide as disclosed herein or the vector including the nucleic acid.METHODS

[0091] Methods disclosed herein include methods of producing a scaffold protein comprising three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, and three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3. In certain aspects, methods of interest include: in silico grafting CDRL1-CDRL3 and CDRH1-CDRH3 from a parental antibody into the amino acid sequence of a scaffold protein according to any one of the scaffold proteins as described herein (see, e.g., VLVH type scaffold sequences [e.g., VLVH type scaffold comprising an amino acid sequence having at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to one of SEQ ID NOs:l-7 and 85-91] and VHVL type scaffold sequences [e.g., e.g., VHVL type scaffold comprising an amino acid sequence having at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to one of SEQ ID NOs:8-12 and 92-96] above) to generate a first scaffold protein; in silico modeling the conformation of the first scaffold protein and comparing to theAtty Dkt. No.: MOBI-015WOconformation of the parental antibody, wherein when the conformations match, producing the first scaffold protein.

[0092] In some embodiments wherein the conformations (i.e., of the first scaffold protein and the parental antibody) do not match, the method further comprises in silico grafting 3-5 amino acids from (i) the N-terminus of the variable light chain of the parental antibody and / or 2-8 amino acids adjacent to one or more of the CDRL1-CDRL3 and the CDRH1-CDRH3 in the parental antibody into the corresponding region in the first VLVH type scaffold protein or (ii) the N-terminus of the variable heavy chain of the parental antibody and / or 2-8 amino acids adjacent to one or more of the CDRL1-CDRL3 and the CDRH1-CDRH3 in the parental antibody into the corresponding region in the first VHVL type scaffold protein to generate a second scaffold protein. In these instances, the method may further comprise in silico modeling the conformation of the second scaffold protein and comparing the second scaffold protein conformation to the conformation of the parental antibody and, wherein when the conformations match, producing the second scaffold protein.

[0093] In some embodiments wherein the conformations (i.e., of the second scaffold protein and the parental antibody) do not match, the method further comprises in silico grafting additional-loops from the parental antibody that are within 20 amino acids or less (such as, e.g., 10 amino acids or less) of one or more of CDRL1-CDRL3 and CDRH1-CDRH3 into the corresponding region in the second scaffold protein to generate a third scaffold protein. In these instances, the method may further comprise in silico modeling the conformation of the third scaffold protein and comparing the third scaffold protein conformation to the conformation of the parental antibody and, wherein when the conformations match, producing the third scaffold protein.

[0094] In some embodiments wherein the conformations (i.e., of the third scaffold protein and the parental antibody) do not match, the method further comprises in silico grafting additional-loops from the parental antibody that are within 20 amino acids or less (such as, e.g., 10 amino acids or less) of one or more of CDRL1-CDRL3 and CDRH1-CDRH3 into the corresponding region in the second scaffold protein to generate a third scaffold protein. In these instances, the method may further comprise redesigning (e.g., in silico) residues of the third scaffold protein which have sidechain (Cβ) contacts with grafted residues to alleviate boundary discrepancies to generate a fourth scaffold protein. In these instances, the method may further comprise in silico modeling the conformation of the fourth scaffold protein and comparing the fourth scaffold protein conformation to the conformation of the parental antibody and, wherein when the conformations match, producing the fourth scaffold protein.Atty Dkt. No.: MOBI-015WO

[0095] VLVH type scaffold sequences (e.g., SEQ ID NOs:l-7 and 85-91) and VHVL type scaffold sequences (e.g., SEQ ID NOs:8-12 and 92-96) disclosed herein can be optimized for a set of CDRs to be inserted into the scaffold. Optimization of the scaffold sequences may be performed as described for methods of producing a scaffold protein. In addition, consensus sequences derived from the scaffolds and disclosed in SEQ ID Nos: 85-96 can also be used as guides for which amino acids can be substituted to optimize the scaffold. Alignment of SEQ ID Nos: 85-96 provide guidance for amino acid substitutions for optimization of a given scaffold protein.

[0096] Any standard structure prediction algorithm, such as, AlphaFold2 or AlphaFold3, may be used for modeling and comparing scaffold protein conformations. Comparing scaffold conformations may involve comparing the folded structure of the CDRs (e.g., all CDRs or just the HCDRs or just the HCDR3 or HCDR3 and LCDR3) or the structure of the entire scaffold to the structure of a scFv chain of the parental antibody. Redesigning (e.g., in silico) residues of the third scaffold protein which have sidechain (Cβ) contacts with grafted residues to alleviate boundary discrepancies to generate a fourth scaffold may utilize algorithms, such as, ProteinMPNN. In addition, the amino acid sequences of the scaffolds provided herein may be used to guide selection of amino acids and motifs for testing in conjunction with a set of CDRs.

[0097] Examples of the N-terminus region, 2-8 amino acids adjacent to one or more of the CDRL1-CDRL3 and the CDRH1-CDRH3, and additional-loops are shown in FIG. 1A and IB. One or more amino acids in the N-terminus region of a scaffold protein may be replaced with the one or more amino acids in the N-terminus region of the parental antibody. 2-8 amino acids adjacent to one or more of the CDRL1-CDRL3 and the CDRH1-CDRH3 may be replaced with the 2-8 amino acids adjacent to one or more of the CDRL1-CDRL3 and the CDRH1-CDRH3 of the parental antibody. One or more amino acids in the additional loops close to the CDRs as shown in Figs. 1A and IB may be replaced with one or more amino acids in the additional loops close to the CDRs in the parental antibody.

[0098] The method may also be performed by simultaneously starting with two or more of the scaffold proteins as described herein. In addition, the method may be performed simultaneously for multiple sets of CDRL1-CDRL3 and CDRH1-CDRH3 from different parental antibodies.EXAMPLES OF NON-LIMITING ASPECTS OF THE DISCLOSURE

[0099] Aspects, including embodiments, of the present subject matter described above may be beneficial alone or in combination, with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the disclosure are provided below. As will beAtty Dkt. No.: MOBI-015WOapparent to those of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for all such combinations of aspects and is not limited to combinations of aspects explicitly provided below:1. A scaffold protein comprising an amino acid sequence that is at least 70% identical to > VLVH0230-S DIVMTVDAKEVTVELGETATITVWYRQYPGEPPELLIYGVPSRFSGSGSGTDFTLTISNVEPEDEATYYAFSEGTK LLIVPTPETEELLEEARERRRKRLAERRANSPVKLTQSPDITVKEGETATLTVKASGFTFTWVKQAPGGPLEWIGR FTISRDTSKNTAYLTITNLTKEDTATYYAARWGEGTKLTVE (SEQ ID NO: 1),> VLVH0230-B DIVMTVDAKEVTVKLGETATITVWYRQYPGEPPELLIYGVPSRISGSGSGTDFTLTISNVEPEDEATYYAFSEGTKL LIVPTPETEKKLEEARERRRKRLAERRANSPVKLTQSPDITVKEGETATLTVAASGFTFTWVKQAPGGPLEWIGR FTISADTSKNTAYLTITNLTKEDTATYYAARWGEGTKLTVE (SEQ ID NO: 2),> VLVH0230-T5 DIQMTDDKAEVTVELGETATITVWYRQFPGEPPELLIYGVPDRISGSGSGTDFTLTIKNVEPEDEATYYAFSSGTK LLLVPTPETEEELEEARRRRERRLAERRKNSPVKLTQSPDLTVKEGETATLTVAASGFSFTWVRQAPGGPLEWIG RFSISRDTSKNTLYLTISNLTPEDTATYYAARWGEGTKLTVE (SEQ ID NO: 3),> VLVH4721-1 DIVMTVDKSEVTVELGETATITVWYRQYPGEPPELLIYGVPSRFSGSGSGTDFTLTISNVEPEDEATYYAFSSGTKL LIVPTPETEEELEEARERRARRLAERRKNSPVKLTQSPDLTVKEGETATLTAAASGFAFSWVRQAPGGPLQWIGR FSISRDTSKNTFYLTISNLTKEDTATYYAARWGEGTKLTVE (SEQ ID NO: 4), or> VLVH4717 DIVMTVDKAEVTVELGETATITVWYRQYPGEPPELLIYGVPSRISGSGSGTDFTLTISNVEPEDEATYYAFSQGTK LLLVPTPETEEELEEARRERAERLAERRKNSPVKLTQSPDLTVKEGETATLTATVTGYSITWVRQAPGGPLEWMG RFEISRDTSKNTLYLTIKNLTKEDTATYYAARWGEGTKLTVE (SEQ ID NO: 5),wherein the amino acid sequence can comprise three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, and three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3,whereinCDRL1 is inserted between positions 20 and 27,CDRL2 is inserted between positions 35 and 42,CDRL3 is inserted between positions 67 and 74,Atty Dkt. No.: MOBI-015WOCDRH1 is inserted between positions 134 and 141,CDRH2 is inserted between positions 148 and 155,CDRH3 is inserted between positions 180 and 187,wherein positions are numbered relative to SEQ ID NO:1 andwherein the CDRL1-CDRL3 and CDRH1-CDRH3 are disregarded when calculating sequence identity of the scaffold protein.The scaffold protein of aspect 1, wherein the amino acid sequence is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 1.The scaffold protein of aspect 1, wherein the amino acid sequence is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 2.The scaffold protein of aspect 1, wherein the amino acid sequence is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 3.The scaffold protein of aspect 1, wherein the amino acid sequence is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 4.The scaffold protein of aspect 1, wherein the amino acid sequence is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 5.A scaffold protein comprising an amino acid sequence that is at least 70% identical to > VLVH6727 DIELTVDKKEIVVEEGEPVTIKVWFQQYEGEPPRTLIYGVPERISGSGSGQDYTLTITKVEPEDEATYYAFSEGIKLR IKRTPEVEEKLAKAREERRRRLAEERRNAPVRLTQSPDITVKEGETATLTVTPSGFNIKWVKQAPGKGLEWIGKF ELTADASSNTAYLTIKNLTKEDTATYYAPRWGEGTKLTVE (SEQ ID NO:6),wherein the amino acid sequence can comprise three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, and three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3,whereinCDRL1 is inserted between positions 20 and 1,CDRL2 is inserted between positions 35 and 42,Atty Dkt. No.: MOBI-015WOCDRL3 is inserted between positions 67 and 74,CDRH1 is inserted between positions 134 and 141,CDRH2 is inserted between positions 148 and 155,CDRH3 is inserted between positions 180 and 187,wherein positions are numbered relative to SEQ ID NO:6 andwherein the CDRL1-CDRL3 and CDRH1-CDRH3 are disregarded when calculating sequence identity of the scaffold protein.A scaffold protein comprising an amino acid sequence that is at least 70% identical to > VLVH4721-2 QIMLSVDKPEVVVEEGETAEVKVWYRQFPGKPPEALVYGVPDRISGSGSGTEFTLTIKNVEPEDVATYYAFSSGT KLLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKEGETATLTLTVSGFSLTWVKQAPGGPLQWLG RFTISRDTSKSQFYLTITNLKKEDTATYYAARWGQGTKLTVE (SEQ ID NO:7),wherein the amino acid sequence can comprise three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, and three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3,whereinCDRL1 is inserted between positions 20 and 27,CDRL2 is inserted between positions 35 and 42,CDRL3 is inserted between positions 67 and 74,CDRH1 is inserted between positions 134 and 141,CDRH2 is inserted between positions 148 and 155,CDRH3 is inserted between positions 180 and 187,wherein positions are numbered relative to SEQ ID NO:7 andwherein the CDRL1-CDRL3 and CDRH1-CDRH3 are disregarded when calculating sequence identity of the scaffold protein.The scaffold protein of any one of aspects 1-8, comprising one of the following sets of CDRL1- CDRL3 and CDRH1-CDRH3:Set 1: CRP-2702CDRL1 SASSSVSYMY (SEQ ID NO:13)CDRL2 RTSNLAS (SEQ ID NO: 14)CDRL3 QQYHSYPPT (SEQ ID NO:15)CDRH1 HYSLY (SEQ ID NO:16)CDRH2 EINPRNDGTKFNEKFKS (SEQ ID NO:17)CDRH3 SGTTYDLALDY (SEQ ID NO:18)Atty Dkt. No.: MOBI-015WOSet 2: DDimer-3302CDRL1 KASQNVGTPVA (SEQ ID NO:19)CDRL2 STSTRYP (SEQ. ID NO:20)CDRL3 QQYSLYPLT (SEQ ID NO:21)CDRH1 SDYAWN (SEQ ID NO:22)CDRH2 YITYSGTTSYNPSLTS (SEQ ID NO:23)CDRH3 EWFPYYFDY (SEQ ID NO:24)Set 3: Hemoglobin-3885CDRL1 RASEGIYHWLA (SEQ ID NO:25)CDRL2 KASSLAS (SEQ ID NO:26)CDRL3 QQYSNYPLT (SEQ ID NO:27)CDRH1 NYAMS (SEQ ID NO:28)CDRH2 AISGSGGSTYYADSVKG (SEQ ID NO:29)CDRH3 YYGDGMDV (SEQ ID NO:30)Set 4: PCT-3322CDRL1 RSSQSLVHINGNTYVH (SEQ ID NO:31)CDRL2 KVSNRFS (SEQ ID NO:32)CDRL3 SQSTHVPLT (SEQ ID NO:33)CDRH1 DTFIH (SEQ ID NO:34)CDRH2 RIDPANGNIIYDPRFQG (SEQ ID NO:35)CDRH3 VGDASLYFDY (SEQ ID NO:36)Set 5: TSH-2508CDRL1 RASQSVSSSSYSYMH (SEQ ID NO:37)CDRL2 FASNLES (SEQ ID NO:38)CDRL3 QHTWEIPRT (SEQ ID NO:39)CDRH1 LYWMS (SEQ ID NO:40)CDRH2 EIDPESNTINYTPSLKD (SEQ ID NO:41)CDRH3 SSMDY (SEQ ID NO:42)Set 6: sFLTl-4129CDRL1 KASQSVGTAVA (SEQ ID NO:43)CDRL2 SASNRYT (SEQ ID NO:44)CDRL3 QQYFTYPYT (SEQ ID NO:45)CDRH1 SYWMN (SEQ ID NO:46)CDRH2 QIYPGDGDTNYNGKFRG (SEQ ID NO:47)CDRH3 DDGYEGFDY (SEQ ID NO:48)Set 7: sFLTl-4131CDRL1 RASQSVSSSYLA (SEQ ID NO:49)CDRL2 GASSRAT (SEQ ID NQ:50)Atty Dkt. No.: MOBI-015WOCDRL3 QQYGSSPLT (SEQ ID NO:51)CDRH1 SYGMH (SEQ ID NO:52)CDRH2 VIWYDGSNKYYADSVRG (SEQ ID NO:53)CDRH3 DHYGSGVHHYFYYGLDV (SEQ ID NO:54)Set 8: FITC-6486CDRL1 RSSQSLVHSNGNTYLR (SEQ ID NO:55)CDRL2 KVSNRVS (SEQ ID NO:56)CDRL3 SQSTHVPWT (SEQ ID NO:57)CDRH1 HYWMN (SEQ ID NO:58)CDRH2 QFRNKPYNYETYYSDSVKG (SEQ ID NO:59)CDRH3 ASYGMEY (SEQ ID NQ:60)Set 9: CRP-5809CDRL1 KASQDINSYLS (SEQ ID NO:61)CDRL2 RADRLVD (SEQ ID NO:62)CDRL3 LQYDEFPLT (SEQ ID NO:63)CDRH1 DTYIH (SEQ ID NO:64)CDRH2 RIDPANGHTRYAPKFQG (SEQ ID NO:65)CDRH3 IVWYSGGYAMDY (SEQ ID NO:66)Set 10: IL6-2418CDRL1 GLSSGSVTASNYPG (SEQ ID NO:245)CDRL2 STNDRHS (SEQ ID NO:246)CDRL3 ALDIGDITE (SEQ ID NO:247)CDRH1 SYRMY (SEQ ID NO:248)CDRH2 AISAGGGSTYYGDSVKG (SEQ ID NO:249)CDRH3 RAGWGMGDY (SEQ ID NQ:250)Set 11: HisTag-6446CDRL1 KSSQSLFNSGHQKNYLA (SEQ ID NO:256)CDRL2 GASTRES (SEQ ID NO:257)CDRL3 QNDHRYPLT (SEQ ID NO:258)CDRH1 DYNMD (SEQ ID NO:259)CDRH2 DINPNNGGPIYNQNFRG (SEQ ID N0:260)CDRH3 DWSTAMDY (SEQ ID NO:251)10. The scaffold protein of aspect 9, comprising the consensus sequence:> VLVH0230-B derived consensus DXXXTXDAKEVTVKLGETATITVWYRQYPGEPPELXIYGVPSRXSGSGSGTDFTLTISNVEPEDEATYYAFSEGTK LLIVPTPETEKKLEEAREXRRKXLAERRANSPVKLTQSPDITVKEGETATXTVXXXGXXXXWVKQAPGGPLEWXX XFTISADTSKNTAYLTIXNLTKEDTATYYAXXWGEGTKLTVE (SEQ ID NO:85),> VLVH0230-S derived consensusAtty Dkt. No.: MOBI-015WOXXXXXVDAKEVTVELGETATITVWYRQYPGEPPELXIXGVPSRFSGSGSGTDFTLTISNVEPEDEATYYAFSEGTK LLIVPTPETEXLLEEAREXRRKXLAERRANSPVKLTQSPDITVKEGETATLTVXXXGXXXXWVKQAPGGPLEWXX RFTISRDTSKNTAYLTITNLTKEDTATYYAXXWGEGTKLTVE (SEQ ID NO:86),> VLVH0230-T5 derived consensus DXXMTDDKAEVTVELGETATITVWYRQFPGEPPELLIYGVPDRISGSGSGTDFTLTIKNVEPEDEATYYAFSSGTK LLLVPTPETEEELEEARRXRERXLAERRKNSPVKLTQSPDLTVKEGETATLTXXXXGXXXXWVRQAPGGPLEWXX RFSISRDTSKNTLYLTISNLTPEDTATYYAXXWGEGTKLTVE (SEQ ID NO:87),> VLVH4717 derived consensus DXXXTVDKAEVTVELGETATITVWYRQYPGEPPELLIXGVPSRISGSGSGTDFTLTISNVEPEDEATYYAFSQGTKL LLVPTPETEEELEEARRERAERLAERRKNSPVKLTQSPDLTVKEGETATLTAXXXGXXXXWVRQAPGGPLEWXXR FEISRDTSKNTLYLTIKNLTKEDTATYYAXXWGEGTKLTVE (SEQ ID NO:88),> VLVH4721-1 derived consensus XXXXTVDKSEVTVELGETATITVWYRQYPGEPPELLIXGVPSRFSGSGSGTDFTLTISNVEPEDEATYYAFSSGTKL LIVPTPETEEELEEAREXRARXLAERRKNSPVKLTQSPDLTVKEGETATLTAXXXGXXXXWVRQAPGGPLQWXX RFSISRDTSKNTFYLTISNLTKEDTATYYAXXWGEGTKLTVE (SEQ ID NO:89),> VLVH4721-2 derived consensus XXXXXVDKPEVVVEEGETAEVKVWYRQFPGKPPEALXXGVPDRISGSGSGTEFTLTIKNVEPEDVATYYAFSSGT KLLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKEGETATLTLXXXGXXXXWVKQAPGGPLQWX XRFTISRDTSKSQFYLTITNLKKEDTATYYAXXWGQGTKLTVE (SEQ ID NQ:90), or> VLVH6727 derived consensus XXXXXVDKKEIVVEEGEPVTIKVWFQQYEGEPPRTLIXGVPERISGSGSGQDYTLTITKVEPEDEATYYAFSEGIKL RIKRTPEVEEKLAKAREERRRRLAEERRNAPVRLTQSPDITVKEGETATLTVXXXGXXXXWVKQAPGKGLEWXX KFELTADASSNTAYLTIKNLTKEDTATYYAXXWGEGTKLTVE (SEQ ID NO:91),wherein the CDRL1-CDRL3 and CDRH1-CDRH3 are not included in the consensus sequence. A scaffold protein comprising an amino acid sequence that is at least 85% identical to:> VHVL4736 EVQLQQSPDQTVEEGSTATLTATASGFNITWVKEDLDGSLEWIGRFTITSDTSSNTAYLTITNLTKADTATYYAAR WGQGTKLTVGELSEEEKEELIKERKERREEYYKENPDVVKMTVEKETVTVKLGETATIKVWYKQKPGQPPQLLI YGVPSRISGSGSGTDFTLTITNVQPEDEATYYAFSDPVKLIIE (SEQ ID NO:8),> VHVL4739Atty Dkt. No.: MOBI-015WOQVQLQQSPDQTVEVGETVTLSAKASGFNIEWVRQPPGGPLQWIGRFTITADTSSNRVSLTITNVRIEDTATYYA TRWGQGTKLTVKADPEEREKALKEYLERLKTEKRPGQVRLTPEKKTVKVKLGETATLKFWYKQAPGEPPQLLIY GVPSRISGSGSGTDFTLTITNVQPEDEATYYAFSEGTKLVIE (SEQ ID NO:9),> VHVL4742 EVQLQAPPDQTVAVGETVTLTWTASGFNIKWVRQAPGGPLEWIGRFTITSDTSSNTASLTITNVQVGDTATYYA ARWGEGTKLTVPASEEELKEAREERKEEREELIKRGEIIGLTPEKATVTVALGGTATLTVWYKQAPGQPPELLIYGV PSRFSGSGSGTDFTLTITDVQEEDEATYYAFSEGTKVVIL (SEQ. ID NO:10),> VHVL6375 DVHLQQSPDQTVEEGSTVTLTATVTGYSITWIREYLDGSLEWMGRFSITRDTSKNQFYLTITNLTKLDTATYYAAR WGQGTKLTVGELSEEEKEELIKERKERRKQYYKEHPNVIHMSVDQKVVKVKLGETAVIRVWYKQKPGQPPQLL IYGVPERISGSGSGTDFTLTITNVQEEDAATYYAFSEPVKLVIE (SEQ ID NO:11), or> VHVL6486 DGGVKLDESPDQEVEVGETVTLTAVTSGFTFGWVRQPPGGPLEWVARFSISRDDSKSSVSLTITNVRIEDHATY YFTGLGKGTKLTVKADPEELEEALRKYHEELKTREVPGQVRMTADKTTVTVKEGETATLKFWYKQAPGEPPRVL IYGVPSRISGSGSGTDFTLTITDVQPEDEATYYAFSEGTKLVIE (SEQ ID NO:12),wherein the amino acid sequence can comprise three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3 and three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3,whereinCDRH1 is inserted between positions 27 and 34,CDRH2 is inserted between positions 41 and 48,CDRH3 is inserted between positions 73 and 80,CDRL1 is inserted between positions 133 and 140,CDRL2 is inserted between positions 148 and 155,CDRL3 is inserted between positions 180 and 187,wherein positions are numbered relative to SEQ ID NO:8, andwherein the CDRL1-CDRL3 and CDRH1-CDRH3 are disregarded when calculating sequence identity of the scaffold protein.The scaffold protein of aspect 11, comprising one of the following sets of CDRL1-CDRL3 and CDRH1-CDRH3:Set 1: CRP-2702CDRL1 SASSSVSYMY (SEQ ID NO:13)Atty Dkt. No.: MOBI-015WOCDRL2 RTSNLAS (SEQ ID NO: 14)CDRL3 QQYHSYPPT (SEQ ID NO:15)CDRH1 HYSLY (SEQ ID NO:16)CDRH2 EINPRNDGTKFNEKFKS (SEQ ID NO:17)CDRH3 SGTTYDLALDY (SEQ ID NO:18)Set 2: DDimer-3302CDRL1 KASQNVGTPVA (SEQ ID NO:19)CDRL2 STSTRYP (SEQ ID NQ:20)CDRL3 QQYSLYPLT (SEQ ID NO:21)CDRH1 SDYAWN (SEQ ID NO:22)CDRH2 YITYSGTTSYNPSLTS (SEQ ID NO:23)CDRH3 EWFPYYFDY (SEQ ID NO:24)Set 3: Hemoglobin-3885CDRL1 RASEGIYHWLA (SEQ ID NO:25)CDRL2 KASSLAS (SEQ ID NO:26)CDRL3 QQYSNYPLT (SEQ ID NO:27)CDRH1 NYAMS (SEQ ID NO:28)CDRH2 AISGSGGSTYYADSVKG (SEQ ID NO:29)CDRH3 YYGDGMDV (SEQ ID NO:30)Set 4: PCT-3322CDRL1 RSSQSLVHINGNTYVH (SEQ ID NO:31)CDRL2 KVSNRFS (SEQ ID NO:32)CDRL3 SQSTHVPLT (SEQ ID NO:33)CDRH1 DTFIH (SEQ ID NO:34)CDRH2 RIDPANGNIIYDPRFQG (SEQ ID NO:35)CDRH3 VGDASLYFDY (SEQ ID NO:36)Set 5: TSH-2508CDRL1 RASQSVSSSSYSYMH (SEQ ID NO:37)CDRL2 FASNLES (SEQ ID NO:38)CDRL3 QHTWEIPRT (SEQ ID NO:39)CDRH1 LYWMS (SEQ ID NO:40)CDRH2 EIDPESNTINYTPSLKD (SEQ ID NO:41)CDRH3 SSMDY (SEQ ID NO:42)Set 6: sFLTl-4129CDRL1 KASQSVGTAVA (SEQ ID NO:43)CDRL2 SASNRYT (SEQ ID NO:44)CDRL3 QQYFTYPYT (SEQ ID NO:45)CDRH1 SYWMN (SEQ ID NO:46)CDRH2 QIYPGDGDTNYNGKFRG (SEQ ID NO:47)CDRH3 DDGYEGFDY (SEQ ID NO:48)Atty Dkt. No.: MOBI-015WOSet 7: sFLTl-4131CDRL1 RASQSVSSSYLA (SEQ ID NO:49)CDRL2 GASSRAT (SEQ ID N0:50)CDRL3 QQYGSSPLT (SEQ ID NO:51)CDRH1 SYGMH (SEQ ID NO:52)CDRH2 VIWYDGSNKYYADSVRG (SEQ ID NO:53)CDRH3 DHYGSGVHHYFYYGLDV (SEQ ID NO:54)Set 8: FITC-6486CDRL1 RSSQSLVHSNGNTYLR (SEQ ID NO:55)CDRL2 KVSNRVS (SEQ ID NO:56)CDRL3 SQSTHVPWT (SEQ ID NO:57)CDRH1 HYWMN (SEQ ID NO:58)CDRH2 QFRNKPYNYETYYSDSVKG (SEQ ID NO:59)CDRH3 ASYGMEY (SEQ ID NQ:60)Set 9: CRP-5809CDRL1 KASQDINSYLS (SEQ ID NO:61)CDRL2 RADRLVD (SEQ ID NO:52)CDRL3 LQYDEFPLT (SEQ ID NO:63)CDRH1 DTYIH (SEQ ID NO:64)CDRH2 RIDPANGHTRYAPKFQG (SEQ ID NO:65)CDRH3 IVWYSGGYAMDY (SEQ ID NO:66)Set 10: IL6-2418CDRL1 GLSSGSVTASNYPG (SEQ ID NO:245)CDRL2 STNDRHS (SEQ ID NO:246)CDRL3 ALDIGDITE (SEQ ID NO:247)CDRH1 SYRMY (SEQ ID NO:248)CDRH2 AISAGGGSTYYGDSVKG (SEQ ID NO:249)CDRH3 RAGWGMGDY (SEQ ID NQ:250)Set 11: HisTag-6446CDRL1 KSSQSLFNSGHQKNYLA (SEQ ID NO:256)CDRL2 GASTRES (SEQ ID NO:257)CDRL3 QNDHRYPLT (SEQ ID NO:258)CDRH1 DYNMD (SEQ ID NO:259)CDRH2 DINPNNGGPIYNQNFRG (SEQ ID NQ:260)CDRH3 DWSTAMDY (SEQ ID NO:261)Set 12: HA-6107CDRL1 KSSQSLFNSGKRKNFLT (SEQ ID NO:239)CDRL2 WASTRES (SEQ ID NQ:240)Atty Dkt. No.: MOBI-015WOCDRL3 QNDYSHPLT (SEQ ID NO:241)CDRH1 SFGMS (SEQ ID NO:242)CDRH2 TISNGGGYTYYQDSVKG (SEQ ID NO:243)CDRH3 RERYDEKGFAY (SEQ ID NO:244)13. The scaffold protein of aspect 12, comprising the consensus sequence:> VHVL4736-S derived consensus XXXXXQSPDQTVEEGSTATLTAXXXGXXXXWVKEDLDGSLEWXXRFTITSDTSSNTAYLTITNLTKXDTATYYAXX WGQGTKLTVGELSEEEKEELIKERKERREEYYKENPDVVKMTVEKETVTVKLGETATIKVWYKQKPGQPPQLLI XGVPSRISGSGSGTDFTLTITNVQPEDEATYYAFSDPVKLIIE (SEQ ID NO:92),> VHVL 4739-S derived consensus XXXXXQSPDQTVEVGETVTLSAXXXGXXXXWVRQPPGGPLXWXXRFTITADTSSNRVSLTITNVRIEDTATYYAX XWGQGTKLTVKADPEEREKALKEYLERLKTEKXPGQVRXTPEXKXVKVKLGETATLKFWYKQAPGXPPQLLIXG VPSRISGSGSGTDFTLTITXVQPEDEATYYAFSEGTKLVIE (SEQ ID NO:93),> VHVL 4742-S derived consensus XXXXXAPPDQTVXVGETVTLTWXXXGXXXXWVRQAPGGPLEWXXRFTITSDTSSNTASLTITNVQVGDTATYY AXXWGEGTKLTVPASEEELKEARXERKEEREELIKXGEIIGLTPEKATVTVALGGTATLTVWYKQAPGQPPELLIXG VPSRFSGSGSGTDFTLTITDVQXEDEATYYAFSEGTKVVIL (SEQ ID NO:94),> VHVL 6375 derived consensus XXXXXQSPDQTVEEGSTVTLTAXXXGXXXXWIREYLDGSLEWXXRFSITRDTSKNQFYLTITNLTKLDTATYYAXX WGQGTKLTVGELSEEEKEELIKERKERRKQYYKEHPNVIHMSVDQKVVKVKLGETAVIRVWYKQKPGQPPQLL IXGVPERISGSGSGTDFTLTITNVQEEDAATYYAFSEPVKLVIE (SEQ ID NO:95), or> VHVL 6486 derived consensus DGXVXLXESPDQEVEVGETVTLTAXXXGXXXXWVRQPPGGPLEWXXRFSISRDDSKSSVSLTITNVRIEDHATYY FXXLGKGTKLTVKADPEELEEALRKYHEELKTREVPGQVRMTADKTTVTVKEGETATLKFWYKQAPGEPPRVLI XGVPSRISGSGSGTDFTLTITDVQPEDEATYYAFSEGTKLVIE (SEQ ID NO:96),wherein the CDRL1-CDRL3 and CDRH1-CDRH3 are not included in the consensus sequence and X is any amino acid.14. The scaffold protein of any one of aspects 1-13 conjugated to a moiety.15. The scaffold protein of aspect 14, wherein the moiety is an amino acid sequence, nucleic acid sequence, or a small molecule.16. The scaffold protein of aspect 15, wherein the scaffold protein is conjugated to an immunoglobulin G (IgG) Fc sequence.Atty Dkt. No.: MOBI-015WO17. The scaffold protein of aspect 15, wherein the scaffold protein is conjugated to another scaffold protein.18. The scaffold protein of aspect 17, wherein the other scaffold protein is a scaffold protein according to any one of aspects 1-17.19. The scaffold protein of aspect 15, wherein the scaffold protein is conjugated to another scFv. 20. A polypeptide that specifically binds to human IL-6, the polypeptide comprising an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence:QTVVTMDAKEVTVKLGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSGSGTDF TLTISNVEPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEKKLEEAREERRKELAERRANSPVKLTQSPDITVKEGE TATITVAASGFTFSSYRMYWVKQAPGGPLEWVSAISAGGGSTYYGDSVKGKFTISADTSKNTAYLTIKNLTKEDT ATYYAANRAGWGMGDYWGEGTKLTVE (SEQ ID NO:169), DIVMTVDAKEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSGSGTDFT LTISNVEPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEELLEEARERRRKRLAERRANSPVKLTQSPDITVKEGET ATLTVKASGFTFTSYRMYWVKQAPGGPLEWIGAISAGGGSTYYGDSVKGRFTISRDTSKNTAYLTITNLTKEDTA TYYAARRAGWGMGDYWGEGTKLTVE (SEQ. ID NO:170), QTVVTVDAKEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSGSGTDFT LTISNVEPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEKLLEEAREERRKELAERRANSPVKLTQSPDITVKEGET ATLTVAASGFTFSSYRMYWVKQAPGGPLEWVSAISAGGGSTYYGDSVKGRFTISRDTSKNTAYLTITNLTKEDTA TYYAANRAGWGMGDYWGEGTKLTVE (SEQ. ID NO:171), QTVVVDAKEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSISGNKATL TISNVEPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEELLEEARERRRKRLAERRANSPVKLTQSPDITVKEGET ATLTVAASGFTFSSYRMYWVKQAPGGPLEWVSAISAGGGSTYYGDSVKGRFTISRDNAKNTVYLTITNLTKEDT ATYYAANRAGWGMGDYWGEGTKLTVE (SEQ ID NO:172), QTVVDDAKEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFTGSISGNKASL TISNVEPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEELLEEARERRRKRLAERRANSPVKLTQSPDITVKEGET ATLTVAASGFTFSSYRMYWVKQAPGGPLEFVSAISAGGGSTYYGDSVKGRFTISRDNAKNTVSLTITNLTKEDTA TYYAANRAGWGMGDYWGEGTKLTVE (SEQ ID NO:173), QTVVTDDKAEVTVELGETATITVGLSSGSVTASNYPGWYRQFPGEPPELLIYSTNDRHSGVPDRISGSGSGTDF TLTIKNVEPEDEATYYAALDIGDITEFSSGTKLLLVPTPETEEELEEARRERERELAERRKNSPVKLTQSPDLTVKEG ETATLTAAASGFTFSSYRMYWVRQAPGGPLEWVSAISAGGGSTYYGDSVKGRFSISRDTSKNTLYLTISNLTPED TATYYAANRAGWGMGDYWGEGTKLTVE (SEQ ID NO:174),Atty Dkt. No.: MOBI-015WOQTVVTVDKAEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRISGSGSGTDFT LTISNVEPEDEATYYAALDIGDITEFSQGTKLLLVPTPETEEELEEARRERAERLAERRKNSPVKLTQSPDLTVKEGE TATLTAAASGFTFSSYRMYWVRQAPGGPLEWVSAISAGGGSTYYGDSVKGRFEISRDTSKNTLYLTIKNLTKEDT ATYYAANRAGWGMGDYWGEGTKLTVE (SEQ ID NO:175), QIMLSVDKPEVVVEEGETAEVKVGLSSGSVTASNYPGWYRQFPGKPPEALVYSTNDRHSGVPDRISGSGSGTE FTLTIKNVEPEDVATYYAALDIGDITEFSSGTKLLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKE GETATLTLTVSGFSLTSYRMYWVKQAPGGPLQWLGAISAGGGSTYYGDSVKGRFTISRDTSKSQFYLTITNLKKE DTATYYAARRAGWGMGDYWGQGTKLTVE (SEQ ID NO:176), QTVVTVDKSEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSGSGTDFT LTISNVEPEDEATYYAALDIGDITEFSSGTKLLIVPTPETEEELEEAREERARELAERRKNSPVKLTQSPDLTVKEGE TATLTAAASGFTFSSYRMYWVRQAPGGPLQWVSAISAGGGSTYYGDSVKGRFSISRDTSKNTFYLTISNLTKEDT ATYYAANRAGWGMGDYWGEGTKLTVE (SEQ ID NO:177), QTVVVDKPEVVVEEGETAEVKVGLSSGSVTASNYPGWYRQFPGKPPEALIYSTNDRHSGVPDRISGSISGNKAT LTIKNVEPEDVATYYAALDIGDITEFSSGTKLLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKEGE TATLTLAASGFTFSSYRMYWVKQAPGGPLQWVSAISAGGGSTYYGDSVKGRFTISRDNAKNTVYLTITNLKKED TATYYAANRAGWGMGDYWGQGTKLTVE (SEQ ID NO:178), or QTVVVDKPEVVVEEGETAEVSVGLSSGSVTASNYPGWYRQFPGKPPELLIYSTNDRHSGVPDRISGSISGNKAV LTIKNVEPEDVATYYAALDIGDITEFSEGTKLLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKEGE TATLTLAASGFTFSSYRMYWVKQAPGGPLEFVSAISAGGGSTYYGDSVKGRFTISRDNAKNTVTLTITNLKKEDT ATYYAANRAGWGMGDYWGQGTKLTVE (SEQ ID NO:179), wherein the sequences of the CDRs are not changed.A polypeptide that specifically binds to human IL-6, the polypeptide comprising an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence PVKLTQSPDQTVEEGSTATLTAAASGFTFSSYRMYWVKEDLDGSLEWVSAISAGGGSTYYGDSVKGRFTITSDT SSNTAYLTITNLTKSDTATYYAANRAGWGMGDYWGQGTKLTVGELSEEEKEELIKERKERREEYYKENPDVVKM TVEKETVTVKLGETATIKVGLSSGSVTASNYPGWYKQKPGQPPQLLIYSTNDRHSGVPSRISGSGSGTDFTLTITN VQPEDEATYYAALDIGDITEFSDPVKLIIE (SEQ ID NQ:180), QVQLQQSPDQTVEVGETVTLSAKASGFNIESYRMYWVRQPPGGPLQWIGAISAGGGSTYYGDSVKGRFTITA DTSSNRVSLTITNVRIEDTATYYATRRAGWGMGDYWGQGTKLTVKADPEEREKALKEYLERLKTEKRPGQVRLT PEKKTVKVKLGETATLKFGLSSGSVTASNYPGWYKQAPGEPPQLLIYSTNDRHSGVPSRISGSGSGTDFTLTITNV QPEDEATYYAALDIGDITEFSEGTKLVIE (SEQ ID NO:181),Atty Dkt. No.: MOBI-015WOPVKLTQSPDQTVEVGETVTLSAAASGFTFSSYRMYWVRQPPGGPLEWVSAISAGGGSTYYGDSVKGRFTITAD TSSNRVSLTITNVRIEDTATYYAANRAGWGMGDYWGQGTKLTVKADPEEREKALKEYLERLKTEKIPGQVRMT PEEKWKVKLGETATLKFGLSSGSVTASNYPGWYKQAPGQPPQLLIYSTNDRHSGVPSRISGSGSGTDFTLTITD VQPEDEATYYAALDIGDITEFSEGTKLVIE (SEQ ID NO:182), EVQLVQSPDQTVEVGETVTLSAAASGFTFSSYRMYWVRQPPGGPLEWVSAISAGGGSTYYGDSVKGRFTISR DNAKNTVSLTITNVRIEDTATYYAANRAGWGMGDYWGQGTKLTVKADPEEREKALKEYLERLKTEKIPGQVR MTPEEKVVKVKLGETATLKFGLSSGSVTASNYPGWYKQAPGQPPQLLIYSTNDRHSGVPSRISGSISGNKATLTI TDVQPEDEATYYAALDIGDITEFSEGTKLVIE (SEQ. ID NO:183), EVQLVQSPDQTVEVGETVTLTAAASGFTFSSYRMYWVRQPPGGPLEFVSAISAGGGSTYYGDSVKGRFTISRD NAKNTVSLTITNVRIEDTATYYAANRAGWGMGDYWGQGTKLTVKADPEEREKALKEYLERLKTEKIPGQNRLL PEEKVVKVKLGETATLSFGLSSGSVTASNYPGWYKQAPGQPPTQLIYSTNDRHSGVPSRISGSISGNKAVLTITD VQPEDEATYYAALDIGDITEFGEGTKLVIE (SEQ ID NO:184), EVQLQAPPDQTVAVGETVTLTWTASGFNIKSYRMYWVRQAPGGPLEWIGAISAGGGSTYYGDSVKGRFTITS DTSSNTASLTITNVQVGDTATYYAARRAGWGMGDYWGEGTKLTVPASEEELKEAREERKEEREELIKRGEIIGLT PEKATVTVALGGTATLTVGLSSGSVTASNYPGWYKQAPGQPPELLIYSTNDRHSGVPSRFSGSGSGTDFTLTITD VQEEDEATYYAALDIGDITEFSEGTKVVIL (SEQ ID NO:185), PVKLTAPPDQTVKVGETVTLTWAASGFTFSSYRMYWVRQAPGGPLEWVSAISAGGGSTYYGDSVKGRFTITS DTSSNTASLTITNVQVGDTATYYAANRAGWGMGDYWGEGTKLTVPASEEELKEARKERKEEREELIKEGEIIGLT PEKATVTVALGGTATLTVGLSSGSVTASNYPGWYKQAPGQPPELLIYSTNDRHSGVPSRFSGSGSGTDFTLTITD VQPEDEATYYAALDIGDITEFSEGTKWIL (SEQ ID NO:186), EVQLVAPPDQTVKVGETVTLTWAASGFTFSSYRMYWVRQAPGGPLEWVSAISAGGGSTYYGDSVKGRFTISR DNAKNTVSLTITNVQVGDTATYYAANRAGWGMGDYWGEGTKLTVPASEEELKEARKERKEEREEUKEGEIIGL TPEKATVTVALGGTATLTVGLSSGSVTASNYPGWYKQAPGQPPELLIYSTNDRHSGVPSRFSGSISGNKATLTITD VQPEDEATYYAALDIGDITEFSEGTKWIL (SEQ ID NO:187), EVQLVPPPDQTVKVGETVTLTWAASGFTFSSYRMYWVRQAPGGPLEFVSAISAGGGSTYYGDSVKGRFTISRD NAKNTVSLTITNVQVGDTATYYAANRAGWGMGDYWGQGTKLTVPASEEELKEARKERKEEREELIKEGEITGLY PDKATVTVALGGTATLTVGLSSGSVTASNYPGWYKQAPGQPPQLLIYSTNDRHSGVPSRFSGSISGNKAVLTITD VQPEDEATYYAALDIGDITEFSEGTKWIL (SEQ ID NO:188), or PVKLTQSPDQTVEEGSTVTLTAAASGFTFSSYRMYWIREYLDGSLEWVSAISAGGGSTYYGDSVKGRFSITRDTS KNQFYLTITNLTKLDTATYYAANRAGWGMGDYWGQGTKLTVGELSEEEKEEUKERKERRKQYYKEHPNVIHM SVDQKVVKVKLGETAVIRVGLSSGSVTASNYPGWYKQKPGQPPQLLIYSTNDRHSGVPERISGSGSGTDFTLTITAtty Dkt. No.: MOBI-015WONVQEEDAATYYAALDIGDITEFSEPVKLVIE (SEQ ID NO:189), wherein the sequences of the CDRs are not changed.22. A polypeptide that specifically binds to PfRh5, the polypeptide comprising an amino acid sequence at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to:DIVLTVDAKEVTVELGETATITVRASESVEYYGTSLMQWYRQYPGEPPELUHGASNVQSGVPSRFSGSGSGTD FTLTISNVEPEDEATYYAQQSTKVPWTFSEGTKLLIVPTPETEKLLEEAREERRKELAERRANSPVKLTQSPDITVK EGETATLTVAASGFTFSDYGMAWVKQAPGGPLEWVTFISNMAYSIYYADTVTGRFTISRENAKNTLYLTITNLTK EDTATYYATRAIFDYAGYWYFDVWGEGTKLTVE (SEQ. ID NO:228), or DIVLTVDAKEVTVELGETATITVRASQSVSTSSYTYFHWYRQYPGEPPELLIRYASNLESGVPSRFSGSGSGTDFTL TISNVEPEDEATYYAQHSWEIPYTFSEGTKLLIVPTPETEKLLEEAREERRKELAERRANSPVKLTQSPDITVKEGE TATLTVAASGFTFSDFYMYWVKQAPGGPLEWVATISDGDSYIYYPDSVRGRFTISRDNAKNILYLTITNLTKEDTA TYYAARDGNGKDGGDAMDYWGEGTKLTVE (SEQ ID NO:229), wherein the sequences of the CDRs are not changed.23. A polypeptide that specifically binds to PfRh5, the polypeptide comprising an amino acid sequence at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to:GVKLVQSPDQTVKVGETVTLTWAASGFTFSDYGMAWVRQAPGGPLEWVTFISNMAYSIYYADTVTGRFTISR ENAKNTLSLTITNVQVGDTATYYATRAIFDYAGYWYFDVWGEGTKLTVPASEEELKEARKERKEEREELIKEGEII GLTPEKATVTVALGGTATLTVRASESVEYYGTSLMQWYKQAPGQPPELLIHGASNVQSGVPSRFSGSGSGTDFT LTITDVQPEDEATYYAQQSTKVPWTFSEGTKVVIL (SEQ ID NO:231), or VKLVQSPDQTVEVGETVTLTAAASGFTFSDYGMAWVRQPPGGPLEFVTFISNMAYSIYYADTVTGRFTISRENA KNTLSLTITNVRIEDTATYYATRAIFDYAGYWYFDVWGQGTKLTVKADPEEREKALKEYLERLKTEKRPGVITLTPE EKVVKVKLGETATLKFRASESVEYYGTSLMQWFKQAPGQPPQLLIHGASNVQSGVPSRISGSGSGTDFTLTITD VQPEDEATYYAQQSTKVPWTFSEGTKLVIE (SEQ ID NO:233), wherein the sequences of the CDRs are not changed.24. A method for producing a scaffold protein comprising three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, and three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3, the method comprising:in silico grafting CDRL1-CDRL3 and CDRH1-CDRH3 from a parental antibody into the amino acid sequence of a scaffold protein according to any one of aspects 1-8 to generate a first scaffold protein;Atty Dkt. No.: MOBI-015WOin silico modeling the conformation of the first scaffold protein and comparing to the conformation of the parental antibody,wherein when the conformations match, producing the first scaffold protein, wherein when the conformations do not match, in silico grafting 3-5 amino acids from the N-terminus of the variable light chain or the variable heavy chain of the parental antibody and 2-8 amino acids adjacent to one or more of the CDRL1-CDRL3 and the CDRH1-CDRH3 in the parental antibody into the corresponding region in the first scaffold protein to generate a second scaffold protein;in silico modeling the conformation of the second scaffold protein and comparing to the conformation of the parental antibody,wherein when the conformations match, producing the second scaffold protein, wherein when the conformations do not match, in silico grafting additional-loops from the parental antibody that are within 10 amino acids of one or more of CDRL1-CDRL3 and CDRH1-CDRH3 into the corresponding region in the second scaffold protein to generate a third scaffold protein;in silico modeling the conformation of the third scaffold protein and comparing to the conformation of the parental antibody,wherein when the conformations match, producing the third scaffold protein.The method of aspect 24, wherein when the conformations do not match, redesigning residues of the third scaffold protein which have sidechain (cp) contacts with grafted residues to alleviate boundary discrepancies to generate a fourth scaffold protein.The method of aspect 25, wherein the method further comprises in silico modeling the conformation of the fourth scaffold protein and comparing to the conformation of the parental antibody, wherein when the conformations match, producing the fourth scaffold protein.The method of aspect 24, wherein at least one of the first polypeptide, the second polypeptide, or the third polypeptide binds to the same antigen bound by the parental antibody with a comparable or higher affinity than the parental antibody.Atty Dkt. No.: MOBI-015WO28. The method of aspect 25 or 26, wherein at least one of the first polypeptide, the second polypeptide, the third polypeptide, or the fourth polypeptide bind to the same antigen bound by the parental antibody with a comparable or higher affinity.29. A method comprising:in silico grafting CDRH1-CDRH3 and CDRL1-CDRL3 from a parental antibody into the amino acid sequence of a scaffold protein according to claim 11 or 13 to generate a first polypeptide;in silico modeling the conformation of the first polypeptide and comparing to the conformation of the parental antibody,wherein when the conformations match, producing the first polypeptide, wherein when the conformations do not match, in silico grafting 3-5 amino acids from the N-terminus of the variable heavy chain of the parental antibody and 2-8 amino acids adjacent to one or more of the CDRL1-CDRL3 and the CDRH1-CDRH3 in the parental antibody into the corresponding region in the first polypeptide to generate a second polypeptide;in silico modeling the conformation of the second polypeptide and comparing to the conformation of the parental antibody,wherein when the conformations match, producing the second polypeptide, wherein when the conformations do not match, in silico grafting additional-loops from the parental antibody that are within 10 amino acid of one or more of CDRL1-CDRL3 and CDRH1- CDRH3 into the corresponding region in the second polypeptide to generate a third polypeptide;in silico modeling the conformation of the third polypeptide and comparing to the conformation of the parental antibody,wherein when the conformations match, producing the third polypeptide.30. The method of aspect 29, wherein when the conformations do not match, redesigning residues of the third polypeptide which have sidechain (Cβ) contacts with grafted residues to alleviate boundary discrepancies to generate a fourth polypeptide.31. The method of aspect 30, wherein the method further comprises in silico modeling the conformation of the fourth polypeptide and comparing to the conformation of the parental antibody, wherein when the conformations match, producing the fourth polypeptide.Atty Dkt. No.: MOBI-015WOThe method of aspect 29, wherein at least one of the first polypeptide, the second polypeptide, or the third polypeptide binds to the same antigen bound by the parental antibody with a comparable or higher affinity than the parental antibody.The method of aspect 30 or 31, wherein at least one of the first polypeptide, the second polypeptide, the third polypeptide, or the fourth polypeptide bind to the same antigen bound by the parental antibody with a comparable or higher affinity.Atty Dkt. No.: MOBI-015WOEXAMPLES[OO1OO] The following examples are offered to illustrate, but not to limit any embodiments provided by the present disclosure. The following examples are not intended to represent that the experiments below are all or the only experiments performed.e 1: Scaffold

[0101] Various scaffold protein sequences in VHVL or VLVH format were screened with different CDR sets to identify scaffold protein sequences that effectively supported target antigen binding. The SEQ ID # corresponds to an amino acid sequence comprising the indicated framework regions / sequence of the Scaffold column in combination with a CDR set targeting the antigen of the Target column. Similarly, the MBIO number corresponds to the identification number given to a specific antigen binding polypeptide sequence generated.

[0102] Antigen binding polypeptides generated using the scaffolds and CDR sets were expressed in E. coli cells and evaluated for expression, stability, and binding affinities using multiple methods. More specifically, the VHVL4736 scaffold (SEQ ID NO:8) was used to produce antigen binding polypeptides for FITC, CRP, PCT, and sFLT-1 antigens (see, e.g., SEQ ID NOs:137-141 of Table 3, below); the VHVL4739 scaffold (SEQ ID NO:9) was used to produce antigen binding polypeptides for FITC, CRP, DDimer, PCT, sFLT-1, IL6, and PfRh5 antigens (see, e.g., SEQ ID NOs:144-150, 183-184 and 233 of Table 3, below); the VHVL4742 scaffold (SEQ ID NO:10) was used to produce antigen binding polypeptides for FITC, CRP, sFLT-1, PfRh5, and HisTag antigens (see, e.g., SEQ ID NOs:152-153, 156-157, 231, and 255 of Table 3, below); the VHVL6375 scaffold (SEQ ID NO:11) was used to produce antigen binding polypeptides for FITC, CRP, HA-tag, and sFLT-1 antigens (see, e.g., SEQ ID NOs:164-168 of Table 3, below); the VHVL6486 scaffold (SEQ ID NO:12) was used to produce antigen binding polypeptides for FITC, CRP, and sFLT-1 antigens (see, e.g., SEQ ID NOs:159-161 of Table 3, below); the VLVH0230-S scaffold (SEQ ID NO:1) was used to produce antigen binding polypeptides for CRP, Hemoglobin, TSH, sFLT-1, FITC, IL6, PfRh5, and HisTag antigens (see, e.g, SEQ ID NOs:102, 104, 106-110, 172-173, 228-229, and 254 of Table 3, below); the VLVH4717 scaffold (SEQ ID NO:5) was used to produce antigen binding polypeptides for CRP, DDimer, Hemoglobin, PCT, TSH, and sFLT-1 antigens (see, e.g, SEQ ID NOs:235, 118-122, and 236 of Table 3, below); the VLVH4721-1 scaffold (SEQ ID NO:4) was used to produce antigen binding polypeptides for CRP, DDimer, Hemoglobin, PCT, TSH, and sFLT-1 antigens (see, e.g, SEQ ID NOs:237,123, and 126-128 of Table 3, below); the VLVH4721-2 scaffold (SEQ ID NO:7) was used to produce antigen binding polypeptides for FITC, CRP, and IL6 antigens (see, e.g, SEQ ID NOs:129-Atty Dkt. No.: MOBI-015WO130,176, and 178-179 of Table 3, below); the VLVH6727 scaffold (SEQ ID NO:6) was used to produce antigen binding polypeptides for FITC, CRP, PCT, and sFLT-1 antigens (see, e.g., SEQ ID NOs:132-135 of Table 3, below); the VLVH0230-B scaffold (SEQ ID NO:2) was used to produce antigen binding polypeptides for CRP, DDimer, Hemoglobin, PCT, and sFLT-1 antigens (see, e.g., SEQ ID NOs:97-101 of Table 3, below); and the VLVH0230-T5 scaffold (SEQ ID NO:3) was used to produce antigen binding polypeptides for DDimer, Hemoglobin, PCT, and sFLT-1 antigens (see, e.g., SEQ ID NOs:114-117, and 238 of Table 3, below).

[0103] Whole Cell Expression (Whole Cell Exp.) was quantitated using an SDS-PAGE gel. A score of 2 indicates high expression level, 1 indicates good expression level, and 0 indicates low or negligible expression level. Antigen binding polypeptides generated using the scaffolds and CDR sets were expressed with a poly-histidine tag. To evaluate yield and stability, small-scale Immobilized Metal Affinity Chromatography (IMAC) was performed from 1 ml of auto-induced E.coli culture. The SDS-PAGE results were analyzed to determine both the total protein yield and the presence of protein truncations, which reflect stability. A score of 2 indicates a high yield and stability, 1 indicates good yield and stability, and 0 indicates a low yield and / or stability. Expression levels of the antigen polypeptides was also assessed by Bio-layer Interferometry (BLI) using a GatorBio instrument. Gator loading (gator load.) was quantitated by the magnitude of the shift which correlates to the change in optical signal (in nanometers) caused by the his-tagged protein from the lysate binding to the anti-his probes. A score of 2 indicates a > 0.9 nm shift which indicates high concentration of the antigen binding polypeptide in the lysate, a score of 1 indicates a 0.2-0.9 nm shift suggesting moderate concentration, and a score of 0 indicates a < 0.2 nm shift which implies little to no concentration.

[0104] Additionally, the binding affinities of the expressed polypeptides or their parent antibody was measured through the dissociation constant Kd (as measured by BLI on a GatorBio instrument). The Kd values were reported in nanomolars (nM). The Kd was determined from a multipoint titration, using a global fit binding model for the parent, whereas for the screened polypeptides a single-point was fitted using a local full fit binding model. If no parent antibody was available to be screened in-house with the same parameters then the parent Kd was denoted by NA.

[0105] Table 3: Screening for Effective Scaffold - CDR Set PairsSEQ Whole Gator Parent Scaffold Target MBIO IMAC Kd (nM)ID # Cell Exp. Load. Kd (nM)FITC 137 6900 1 2 1 <0.10 6.51 VHVL4736CRP 138 6908 0 1 0 NA 2.27Atty Dkt. No.: MOBI-015WOPCT 139 6950 1 2 1 NA 19.5 sFLT-1 140 6962 0 2 0 NA <0.001 sFLT-1 141 6968 0 2 0 NA 40.8 FITC 144 6901 1 2 0 <0.10 1.48 CRP 145 6909 0 2 0 NA 0.432 D-Dimer 146 6923 0 2 0 NA 64.8 PCT 148 6951 1 2 2 NA 33.5 VHVL4739 sFLT-1 149 6963 2 2 2 NA 2.11 sFLT-1 150 6969 0 2 0 NA 7.53 IL-6 183 7117 2 1 1 NA 4.04 IL-6 184 7118 2 2 2 NA 9.76 PfRh5 233 7370 1 2 0 0.802 12.40 FITC 152 6902 2 2 0 <0.10 2.52 CRP 153 6910 0 2 1 NA 0.125 sFLT-1 156 6964 0 2 0 NA 1.59 VHVL4742sFLT-1 157 6970 0 2 0 NA 2.01 PfRh5 231 7373 0 1 0 0.802 0.63 HisTag 255 7193 2 2 2 NA 272.0 FITC 164 6903 2 2 0 <0.10 6.2 CRP 165 6911 0 1 0 NA 18.2 VHVL6375 HA-tag 166 6931 0 2 0 NA 134 sFLT-1 167 6965 0 2 1 NA 3.69 sFLT-1 168 6971 0 2 0 NA 10.6 FITC 159 6904 2 1 0 <0.10 10.7 VHVL6486 CRP 160 6912 0 2 0 NA 3.93 sFLT-1 161 6966 1 2 1 NA 3.47 CRP 102 6652 1 2 1 NA 25.46 Hemoglobin 104 6670 1 2 1 NA 282 TSH 106 6694 1 2 1 NA 98.9 sFLT-1 107 6706 2 2 2 NA 2.1142 sFLT-1 108 6712 1 2 0 NA 5.695 VLVH0230- FITC 109 6905 2 2 0 <0.10 4.45 soluble-consensus CRP 110 6913 2 2 2 NA 0.928IL-6 172 7123 0 2 1 NA 31.5 IL-6 173 7124 2 2 1 NA 111 PfRh5 228 7375 1 2 0 0.807 7.45 PfRh5 229 7384 1 2 0 1.57 26.40 HisTag 254 7195 2 2 2 NA 4.0 CRP 235 6655 0 2 0 NA 20.58 VLVH4717D-Dimer 118 6667 2 2 2 NA 157.2Atty Dkt. No.: MOBI-015WOHemoglobin 119 6673 2 2 2 NA 471 PCT 120 6685 1 2 1 NA 110.9 TSH 121 6697 2 2 1 NA 19.3 sFLT-1 122 6709 2 2 2 NA 2.6875 sFLT-1 236 6715 0 2 0 NA 5.84 CRP 237 6656 0 2 0 NA 15.21 D-Dimer 123 6668 2 2 2 NA 153 VLVH4721-1 TSH 126 6698 1 2 1 NA 31.45 sFLT-1 127 6710 2 2 2 NA 2.2435 sFLT-1 128 6716 0 1 0 NA 3.14 FITC 129 6906 2 2 0 <0.10 35.3 CRP 130 6914 2 2 2 NA 138 VLVH4721-2 IL-6 176 7125 2 2 0 NA 7 IL-6 178 7126 2 1 1 NA 4.6 IL-6 179 7127 2 2 0 NA 10 FITC 132 6907 2 2 0 <0.10 1.14 CRP 133 6915 2 2 2 NA 0.226 VLVH6727PCT 134 6955 2 2 2 NA 36.8 sFLT-1 135 6967 2 2 2 NA 0.96 CRP 97 6653 1 2 1 NA 21.83 D-Dimer 98 6665 2 2 1 NA 85.7 VLVH0230-binder- Hemoglobin 99 6671 2 2 1 NA 313 consensusPCT 100 6683 1 2 1 NA 35.15 sFLT-1 101 6707 2 2 2 NA 2.203 D-Dimer 114 6666 2 2 2 NA 182.5 VLVH0230- Hemoglobin 115 6672 2 2 2 NA 686 top5expression- PCT 116 6684 1 2 1 NA 93.95 consensus sFLT-1 117 6708 2 2 2 NA 2.975sFLT-1 238 6714 1 2 0 NA 27.07Example 2: Scaffold Sequence Screening

[0106] Various scaffold protein sequences in VHVL or VLVH format were screened above from different CDR sets to identify scaffold protein sequences that effectively supported target antigen binding. The identified lead polypeptides were subsequently expressed and purified at a larger scale for further characterization (including, e.g., determining binding parameters of polypeptides to target antigens). Their characteristics are summarized in Table 4.

[0107] The binding parameters— including dissociation constant (Kd), association rate (Kon), and dissociation rate (Koff)— were determined using Bio-layer Interferometry (GatorBio). In these experiments, scaffold proteins containing the described sequences were loaded onto His-tag or Strep-Atty Dkt. No.: MOBI-015WOTactin XT probes at a concentration of 100 nM, and the analyte of interest was titrated. In cases where the parent antibody (i.e., the CDR source) was not available for in-house testing, the Kd value for the parent antibody was marked as NA. PCT: Procalcitonin; FITC: fluorescein; IL6: Interleukin-6; sFLT-1: soluble fms-like tyrosine kinase-1. The SEQ ID # corresponds to an amino acid sequence comprising an optimized scaffold protein produced from the scaffold protein of the indicated Scaffold column (e.g., as discussed above) in combination with a CDR set targeting the antigen of the Target column.Table 4: Screening for Effective Scaffold - CDR Set PairsSEQ Kon Koff Parent BLI Scaffold Target MBIO Kd ID # (1 / Ms) (1 / s) (Kd)D-Dimer 103 6664 3.95 E+4 1.78 E-3 NA 45 nM Hemoglobin 104 6670 6.85 E+3 3.38 E-4 NA 65 nM VLVH 0230-soluble- PCT 105 6682 2.23 E+5 1.35 E-3 6 nM consensus NAsFLT-1 107 6706 8.81 E+4 <1 E-6 NA <1 pM HisTag 254 7195 7.00 E+4 1.15 E-3 NA 16.5 nM D-Dimer 123 6668 5.14 E+3 1.64 E-2 NA 32 nM Hemoglobin 124 6674 2.97 E+3 1.34 E-3 NA 425 nM PCT 125 6686 2.20 E+4 5.53 E-3 NA 25 nM VLVH 4721-1sFLT-1 127 6710 8.22 E+4 <1 E-6 NA <1 pM IL-6 178 7126 158000 0.000272 NA 1.7 nM IL-6 179 7127 234000 0.000294 NA 1.3 nM FITC 144 6901 205000 0.0000857 <10 pM 0.48 nM VHVL 4739IL-6 184 7118 147000 0.000268 NA 1.8 nM FITC 152 6902 151000 0.000188 <10 pM 1.25 nM VHVL 4742HisTag 255 7193 1.13 E+3 1.16 E-3 NA 1020 nM

[0108] While the subject proteins have been particularly shown and described with references to certain embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

Atty Dkt. No.: MOBI-015WOCLAIMSWhat is claimed is:

1. A scaffold protein comprising an amino acid sequence that is at least 70% identical to > VLVH0230-S DIVMTVDAKEVTVELGETATITVWYRQYPGEPPELLIYGVPSRFSGSGSGTDFTLTISNVEPEDEATYYAFSEGT KLLIVPTPETEELLEEARERRRKRLAERRANSPVKLTQSPDITVKEGETATLTVKASGFTFTWVKQAPGGPLEWI GRFTISRDTSKNTAYLTITNLTKEDTATYYAARWGEGTKLTVE (SEQ ID NO: 1),> VLVH0230-B DIVMTVDAKEVTVKLGETATITVWYRQYPGEPPELLIYGVPSRISGSGSGTDFTLTISNVEPEDEATYYAFSEGT KLLIVPTPETEKKLEEARERRRKRLAERRANSPVKLTQSPDITVKEGETATLTVAASGFTFTWVKQAPGGPLEWI GRFTISADTSKNTAYLTITNLTKEDTATYYAARWGEGTKLTVE (SEQ ID NO: 2),> VLVH0230-T5 DIQMTDDKAEVTVELGETATITVWYRQFPGEPPELLIYGVPDRISGSGSGTDFTLTIKNVEPEDEATYYAFSSGT KLLLVPTPETEEELEEARRRRERRLAERRKNSPVKLTQSPDLTVKEGETATLTVAASGFSFTWVRQAPGGPLEW IGRFSISRDTSKNTLYLTISNLTPEDTATYYAARWGEGTKLTVE (SEQ ID NO: 3),> VLVH4721-1 DIVMTVDKSEVTVELGETATITVWYRQYPGEPPELLIYGVPSRFSGSGSGTDFTLTISNVEPEDEATYYAFSSGT KLLIVPTPETEEELEEARERRARRLAERRKNSPVKLTQSPDLTVKEGETATLTAAASGFAFSWVRQAPGGPLQW IGRFSISRDTSKNTFYLTISNLTKEDTATYYAARWGEGTKLTVE (SEQ ID NO: 4), or> VLVH4717 DIVMTVDKAEVTVELGETATITVWYRQYPGEPPELLIYGVPSRISGSGSGTDFTLTISNVEPEDEATYYAFSQGT KLLLVPTPETEEELEEARRERAERLAERRKNSPVKLTQSPDLTVKEGETATLTATVTGYSITWVRQAPGGPLEW MGRFEISRDTSKNTLYLTIKNLTKEDTATYYAARWGEGTKLTVE (SEQ ID NO: 5),wherein the amino acid sequence can comprise three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, and three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3,whereinCDRL1 is inserted between positions 20 and 27,CDRL2 is inserted between positions 35 and 42,CDRL3 is inserted between positions 67 and 74,CDRH1 is inserted between positions 134 and 141,Atty Dkt. No.: MOBI-015WOCDRH2 is inserted between positions 148 and 155,CDRH3 is inserted between positions 180 and 187,wherein positions are numbered relative to SEQ ID NO:1 andwherein the CDRL1-CDRL3 and CDRH1-CDRH3 are disregarded when calculating sequence identity of the scaffold protein.

2. The scaffold protein of claim 1, wherein the amino acid sequence is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 1.

3. The scaffold protein of claim 1, wherein the amino acid sequence is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 2.

4. The scaffold protein of claim 1, wherein the amino acid sequence is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 3.

5. The scaffold protein of claim 1, wherein the amino acid sequence is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 4.

6. The scaffold protein of claim 1, wherein the amino acid sequence is at least 70%, at least 75%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 5.

7. A scaffold protein comprising an amino acid sequence that is at least 70% identical to > VLVH6727 DIELTVDKKEIVVEEGEPVTIKVWFQQYEGEPPRTLIYGVPERISGSGSGQDYTLTITKVEPEDEATYYAFSEGIKL RIKRTPEVEEKLAKAREERRRRLAEERRNAPVRLTQSPDITVKEGETATLTVTPSGFNIKWVKQAPGKGLEWIG KFELTADASSNTAYLTIKNLTKEDTATYYAPRWGEGTKLTVE (SEQ ID NO:6),Atty Dkt. No.: MOBI-015WOwherein the amino acid sequence can comprise three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, and three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3,whereinCDRL1 is inserted between positions 20 and 27,CDRL2 is inserted between positions 35 and 42,CDRL3 is inserted between positions 67 and 74,CDRH1 is inserted between positions 134 and 141,CDRH2 is inserted between positions 148 and 155,CDRH3 is inserted between positions 180 and 187,wherein positions are numbered relative to SEQ ID NO:6 andwherein the CDRL1-CDRL3 and CDRH1-CDRH3 are disregarded when calculating sequence identity of the scaffold protein.

8. A scaffold protein comprising an amino acid sequence that is at least 70% identical to > VLVH4721-2 QIMLSVDKPEVWEEGETAEVKVWYRQFPGKPPEALVYGVPDRISGSGSGTEFTLTIKNVEPEDVATYYAFSSG TKLLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKEGETATLTLTVSGFSLTWVKQAPGGPLQW LGRFTISRDTSKSQFYLTITNLKKEDTATYYAARWGQGTKLTVE (SEQ ID NO:7),wherein the amino acid sequence can comprise three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3, and three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3,whereinCDRL1 is inserted between positions 20 and 27,CDRL2 is inserted between positions 35 and 42,CDRL3 is inserted between positions 67 and 74,CDRH1 is inserted between positions 134 and 141,CDRH2 is inserted between positions 148 and 155,CDRH3 is inserted between positions 180 and 187,wherein positions are numbered relative to SEQ ID NO:7 andwherein the CDRL1-CDRL3 and CDRH1-CDRH3 are disregarded when calculating sequence identity of the scaffold protein.Atty Dkt. No.: MOBI-015WO9. The scaffold protein of any one of claims 1-8, comprising one of the following sets of CDRL1- CDRL3 and CDRH1-CDRH3:Set 1: CRP-2702CDRL1 SASSSVSYMY (SEQ ID NO:13)CDRL2 RTSNLAS (SEQ ID NO:14)CDRL3 QQYHSYPPT (SEQ ID NO:15)CDRH1 HYSLY (SEQ ID NO:16)CDRH2 EINPRNDGTKFNEKFKS (SEQ ID NO:17)CDRH3 SGTTYDLALDY (SEQ ID NO:18)Set 2: DDimer-3302CDRL1 KASQNVGTPVA (SEQ ID NO:19)CDRL2 STSTRYP (SEQ ID NO:20)CDRL3 QQYSLYPLT (SEQ ID NO:21)CDRH1 SDYAWN (SEQ ID NO:22)CDRH2 YITYSGTTSYNPSLTS (SEQ ID NO:23)CDRH3 EWFPYYFDY (SEQ ID NO:24)Set 3: Hemoglobin-3885CDRL1 RASEGIYHWLA (SEQ ID NO:25)CDRL2 KASSLAS (SEQ ID NO:26)CDRL3 QQYSNYPLT (SEQ ID NO:27)CDRH1 NYAMS (SEQ ID NO:28)CDRH2 AISGSGGSTYYADSVKG (SEQ ID NO:29)CDRH3 YYGDGMDV (SEQ ID NO:30)Set 4: PCT-3322CDRL1 RSSQSLVHINGNTYVH (SEQ ID NO:31)CDRL2 KVSNRFS (SEQ ID NO:32)CDRL3 SQSTHVPLT (SEQ ID NO:33)CDRH1 DTFIH (SEQ ID NO:34)CDRH2 RIDPANGNIIYDPRFQG (SEQ ID NO:35)CDRH3 VGDASLYFDY (SEQ ID NO:36)Set 5: TSH-2508CDRL1 RASQSVSSSSYSYMH (SEQ ID NO:37)CDRL2 FASNLES (SEQ ID NO:38)CDRL3 QHTWEIPRT (SEQ ID NO:39)CDRH1 LYWMS (SEQ ID NO:40)CDRH2 EIDPESNTINYTPSLKD (SEQ ID NO:41)CDRH3 SSMDY (SEQ ID NO:42)Atty Dkt. No.: MOBI-015WOSet 6: sFLTl-4129CDRL1 KASQSVGTAVA (SEQ ID NO:43)CDRL2 SASNRYT (SEQ ID NO:44)CDRL3 QQYFTYPYT (SEQ. ID NO:45)CDRH1 SYWMN (SEQ ID NO:46)CDRH2 QIYPGDGDTNYNGKFRG (SEQ ID NO:47)CDRH3 DDGYEGFDY (SEQ ID NO:48)Set 7: sFLTl-4131CDRL1 RASQSVSSSYLA (SEQ ID NO:49)CDRL2 GASSRAT (SEQ ID NQ:50)CDRL3 QQYGSSPLT (SEQ ID NO:51)CDRH1 SYGMH (SEQ ID NO:52)CDRH2 VIWYDGSNKYYADSVRG (SEQ ID NO:53)CDRH3 DHYGSGVHHYFYYGLDV (SEQ ID NO:54)Set 8: FITC-6486CDRL1 RSSQSLVHSNGNTYLR (SEQ ID NO:55)CDRL2 KVSNRVS (SEQ ID NO:56)CDRL3 SQSTHVPWT (SEQ ID NO:57)CDRH1 HYWMN (SEQ ID NO:58)CDRH2 QFRNKPYNYETYYSDSVKG (SEQ ID NO:59)CDRH3 ASYGMEY (SEQ ID NQ:60)Set 9: CRP-5809CDRL1 KASQDINSYLS (SEQ ID NO:61)CDRL2 RADRLVD (SEQ ID NO:62)CDRL3 LQYDEFPLT (SEQ ID NO:63)CDRH1 DTYIH (SEQ ID NO:64)CDRH2 RIDPANGHTRYAPKFQG (SEQ ID NO:65)CDRH3 IVWYSGGYAMDY (SEQ ID NO:66)Set 10: IL6-2418CDRL1 GLSSGSVTASNYPG (SEQ ID NO:245)CDRL2 STNDRHS (SEQ ID NO:246)CDRL3 ALDIGDITE (SEQ ID NO:247)CDRH1 SYRMY (SEQ ID NO:248)CDRH2 AISAGGGSTYYGDSVKG (SEQ ID NO:249)CDRH3 RAGWGMGDY (SEQ ID NQ:250)Set 11: HisTag-6446CDRL1 KSSQSLFNSGHQKNYLA (SEQ ID NO:256)CDRL2 GASTRES (SEQ ID NO:257)CDRL3 QNDHRYPLT (SEQ ID NO:258)CDRH1 DYNMD (SEQ ID NO:259)CDRH2 DINPNNGGPIYNQNFRG (SEQ ID NQ:260)Atty Dkt. No.: MOBI-015WOCDRH3 DWSTAMDY (SEQ ID NO:261)10. The scaffold protein of claim 9, comprising the consensus sequence:> VLVH0230-B derived consensus DXXXTXDAKEVTVKLGETATITVWYRQYPGEPPELXIYGVPSRXSGSGSGTDFTLTISNVEPEDEATYYAFSEGT KLLIVPTPETEKKLEEAREXRRKXLAERRANSPVKLTQSPDITVKEGETATXTVXXXGXXXXWVKQAPGGPLEW XXXFTISADTSKNTAYLTIXNLTKEDTATYYAXXWGEGTKLTVE (SEQ ID NO:85),> VLVH0230-S derived consensus XXXXXVDAKEVTVELGETATITVWYRQYPGEPPELXIXGVPSRFSGSGSGTDFTLTISNVEPEDEATYYAFSEGT KLLIVPTPETEXLLEEAREXRRKXLAERRANSPVKLTQSPDITVKEGETATLTVXXXGXXXXWVKQAPGGPLEW XXRFTISRDTSKNTAYLTITNLTKEDTATYYAXXWGEGTKLTVE (SEQ ID NO:86),> VLVH0230-T5 derived consensus DXXMTDDKAEVTVELGETATITVWYRQFPGEPPELLIYGVPDRISGSGSGTDFTLTIKNVEPEDEATYYAFSSGT KLLLVPTPETEEELEEARRXRERXLAERRKNSPVKLTQSPDLTVKEGETATLTXXXXGXXXXWVRQAPGGPLEW XXRFSISRDTSKNTLYLTISNLTPEDTATYYAXXWGEGTKLTVE (SEQ ID NO:87),> VLVH4717 derived consensus DXXXTVDKAEVTVELGETATITVWYRQYPGEPPELLIXGVPSRISGSGSGTDFTLTISNVEPEDEATYYAFSQGT KLLLVPTPETEEELEEARRERAERLAERRKNSPVKLTQSPDLTVKEGETATLTAXXXGXXXXWVRQAPGGPLEW XXRFEISRDTSKNTLYLTIKNLTKEDTATYYAXXWGEGTKLTVE (SEQ ID NO:88),> VLVH4721-1 derived consensus XXXXTVDKSEVTVELGETATITVWYRQYPGEPPELLIXGVPSRFSGSGSGTDFTLTISNVEPEDEATYYAFSSGTK LLIVPTPETEEELEEAREXRARXLAERRKNSPVKLTQSPDLTVKEGETATLTAXXXGXXXXWVRQAPGGPLQWX XRFSISRDTSKNTFYLTISNLTKEDTATYYAXXWGEGTKLTVE (SEQ ID NO:89),> VLVH4721-2 derived consensus XXXXXVDKPEVVVEEGETAEVKVWYRQFPGKPPEALXXGVPDRISGSGSGTEFTLTIKNVEPEDVATYYAFSSG TKLLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKEGETATLTLXXXGXXXXWVKQAPGGPLQ WXXRFTISRDTSKSQFYLTITNLKKEDTATYYAXXWGQGTKLTVE (SEQ ID NQ:90), or> VLVH6727 derived consensus XXXXXVDKKEIVVEEGEPVTIKVWFQQYEGEPPRTLIXGVPERISGSGSGQDYTLTITKVEPEDEATYYAFSEGIK LRIKRTPEVEEKLAKAREERRRRLAEERRNAPVRLTQSPDITVKEGETATLTVXXXGXXXXWVKQAPGKGLEW XXKFELTADASSNTAYLTIKNLTKEDTATYYAXXWGEGTKLTVE (SEQ ID NO:91),wherein the CDRL1-CDRL3 and CDRH1-CDRH3 are not included in the consensus sequence.Atty Dkt. No.: MOBI-015WO11. A scaffold protein comprising an amino acid sequence that is at least 70% identical to:> VHVL4736 EVQLQQSPDQTVEEGSTATLTATASGFNITWVKEDLDGSLEWIGRFTITSDTSSNTAYLTITNLTKADTATYYA ARWGQGTKLTVGELSEEEKEELIKERKERREEYYKENPDVVKMTVEKETVTVKLGETATIKVWYKQKPGQPPQ LLIYGVPSRISGSGSGTDFTLTITNVQPEDEATYYAFSDPVKLIIE (SEQ ID NO:8),> VHVL4739 QVQLQQSPDQTVEVGETVTLSAKASGFNIEWVRQPPGGPLQWIGRFTITADTSSNRVSLTITNVRIEDTATYY ATRWGQGTKLTVKADPEEREKALKEYLERLKTEKRPGQVRLTPEKKTVKVKLGETATLKFWYKQAPGEPPQLLI YGVPSRISGSGSGTDFTLTITNVQPEDEATYYAFSEGTKLVIE (SEQ ID NO:9),> VHVL4742 EVQLQAPPDQTVAVGETVTLTWTASGFNIKWVRQAPGGPLEWIGRFTITSDTSSNTASLTITNVQVGDTATY YAARWGEGTKLTVPASEEELKEAREERKEEREELIKRGEIIGLTPEKATVTVALGGTATLTVWYKQAPGQPPELL IYGVPSRFSGSGSGTDFTLTITDVQEEDEATYYAFSEGTKVVIL (SEQ ID NO:10),> VHVL6375 DVHLQQSPDQTVEEGSTVTLTATVTGYSITWIREYLDGSLEWMGRFSITRDTSKNQFYLTITNLTKLDTATYYA ARWGQGTKLTVGELSEEEKEELIKERKERRKQYYKEHPNVIHMSVDQKVVKVKLGETAVIRVWYKQKPGQPP QLLIYGVPERISGSGSGTDFTLTITNVQEEDAATYYAFSEPVKLVIE (SEQ ID NO:11), or> VHVL6486 DGGVKLDESPDQEVEVGETVTLTAVTSGFTFGWVRQPPGGPLEWVARFSISRDDSKSSVSLTITNVRIEDHAT YYFTGLGKGTKLTVKADPEELEEALRKYHEELKTREVPGQVRMTADKTTVTVKEGETATLKFWYKQAPGEPPR VUYGVPSRISGSGSGTDFTLTITDVQPEDEATYYAFSEGTKLVIE (SEQ ID NO:12),wherein the amino acid sequence can comprise three heavy chain complementarity determining regions, CDRH1, CDRH2, and CDRH3 and three light chain complementarity determining regions, CDRL1, CDRL2, and CDRL3,whereinCDRH1 is inserted between positions 27 and 34,CDRH2 is inserted between positions 41 and 48,CDRH3 is inserted between positions 73 and 80,CDRL1 is inserted between positions 133 and 140,CDRL2 is inserted between positions 148 and 155,CDRL3 is inserted between positions 180 and 187,wherein positions are numbered relative to SEQ ID NO:8, andAtty Dkt. No.: MOBI-015WOwherein the CDRL1-CDRL3 and CDRH1-CDRH3 are disregarded when calculating sequence identity of the scaffold protein.

12. The scaffold protein of claim 11, comprising one of the following sets of CDRL1-CDRL3 and CDRH1-CDRH3:Set 1: CRP-2702CDRL1 SASSSVSYMY (SEQ ID NO:13)CDRL2 RTSNLAS (SEQ ID NO:14)CDRL3 QQYHSYPPT (SEQ ID NO:15)CDRH1 HYSLY (SEQ ID NO:16)CDRH2 EINPRNDGTKFNEKFKS (SEQ ID NO:17)CDRH3 SGTTYDLALDY (SEQ ID NO:18)Set 2: DDimer-3302CDRL1 KASQNVGTPVA (SEQ ID NO:19)CDRL2 STSTRYP (SEQ ID NO:20)CDRL3 QQYSLYPLT (SEQ ID NO:21)CDRH1 SDYAWN (SEQ ID NO:22)CDRH2 YITYSGTTSYNPSLTS (SEQ ID NO:23)CDRH3 EWFPYYFDY (SEQ ID NO:24)Set 3: Hemoglobin-3885CDRL1 RASEGIYHWLA (SEQ ID NO:25)CDRL2 KASSLAS (SEQ ID NO:26)CDRL3 QQYSNYPLT (SEQ ID NO:27)CDRH1 NYAMS (SEQ ID NO:28)CDRH2 AISGSGGSTYYADSVKG (SEQ ID NO:29)CDRH3 YYGDGMDV (SEQ ID NO:30)Set 4: PCT-3322CDRL1 RSSQSLVHINGNTYVH (SEQ ID NO:31)CDRL2 KVSNRFS (SEQ ID NO:32)CDRL3 SQSTHVPLT (SEQ ID NO:33)CDRH1 DTFIH (SEQ ID NO:34)CDRH2 RIDPANGNIIYDPRFQG (SEQ ID NO:35)CDRH3 VGDASLYFDY (SEQ ID NO:36)Set 5: TSH-2508CDRL1 RASQSVSSSSYSYMH (SEQ ID NO:37)CDRL2 FASNLES (SEQ ID NO:38)CDRL3 QHTWEIPRT (SEQ ID NO:39)CDRH1 LYWMS (SEQ ID NO:40)CDRH2 EIDPESNTINYTPSLKD (SEQ ID NO:41)CDRH3 SSMDY (SEQ ID NO:42)Atty Dkt. No.: MOBI-015WOSet 6: sFLTl-4129CDRL1 KASQSVGTAVA (SEQ ID NO:43)CDRL2 SASNRYT (SEQ ID NO:44)CDRL3 QQYFTYPYT (SEQ. ID NO:45)CDRH1 SYWMN (SEQ ID NO:46)CDRH2 QIYPGDGDTNYNGKFRG (SEQ ID NO:47)CDRH3 DDGYEGFDY (SEQ ID NO:48)Set 7: sFLTl-4131CDRL1 RASQSVSSSYLA (SEQ ID NO:49)CDRL2 GASSRAT (SEQ ID NQ:50)CDRL3 QQYGSSPLT (SEQ ID NO:51)CDRH1 SYGMH (SEQ ID NO:52)CDRH2 VIWYDGSNKYYADSVRG (SEQ ID NO:53)CDRH3 DHYGSGVHHYFYYGLDV (SEQ ID NO:54)Set 8: FITC-6486CDRL1 RSSQSLVHSNGNTYLR (SEQ ID NO:55)CDRL2 KVSNRVS (SEQ ID NO:56)CDRL3 SQSTHVPWT (SEQ ID NO:57)CDRH1 HYWMN (SEQ ID NO:58)CDRH2 QFRNKPYNYETYYSDSVKG (SEQ ID NO:59)CDRH3 ASYGMEY (SEQ ID NQ:60)Set 9: CRP-5809CDRL1 KASQDINSYLS (SEQ ID NO:61)CDRL2 RADRLVD (SEQ ID NO:62)CDRL3 LQYDEFPLT (SEQ ID NO:63)CDRH1 DTYIH (SEQ ID NO:64)CDRH2 RIDPANGHTRYAPKFQG (SEQ ID NO:65)CDRH3 IVWYSGGYAMDY (SEQ ID NO:66)Set 10: IL6-2418CDRL1 GLSSGSVTASNYPG (SEQ ID NO:245)CDRL2 STNDRHS (SEQ ID NO:246)CDRL3 ALDIGDITE (SEQ ID NO:247)CDRH1 SYRMY (SEQ ID NO:248)CDRH2 AISAGGGSTYYGDSVKG (SEQ ID NO:249)CDRH3 RAGWGMGDY (SEQ ID NQ:250)Set 11: HisTag-6446CDRL1 KSSQSLFNSGHQKNYLA (SEQ ID NO:256)CDRL2 GASTRES (SEQ ID NO:257)CDRL3 QNDHRYPLT (SEQ ID NO:258)CDRH1 DYNMD (SEQ ID NO:259)Atty Dkt. No.: MOBI-015WOCDRH2 DINPNNGGPIYNQNFRG (SEQ ID N0:260)CDRH3 DWSTAMDY (SEQ ID NO:261)Set 12: HA-6107CDRL1 KSSQSLFNSGKRKNFLT (SEQ ID NO:239)CDRL2 WASTRES (SEQ ID N0:240)CDRL3 QNDYSHPLT (SEQ ID NO:241)CDRH1 SFGMS (SEQ ID NO:242)CDRH2 TISNGGGYTYYQDSVKG (SEQ ID NO:243)CDRH3 RERYDEKGFAY (SEQ ID NO:244)13. The scaffold protein of claim 12, comprising the consensus sequence:> VHVL4736-S derived consensus XXXXXQSPDQTVEEGSTATLTAXXXGXXXXWVKEDLDGSLEWXXRFTITSDTSSNTAYLTITNLTKXDTATYYA XXWGQGTKLTVGELSEEEKEELIKERKERREEYYKENPDVVKMTVEKETVTVKLGETATIKVWYKQKPGQPPQ LLIXGVPSRISGSGSGTDFTLTITNVQPEDEATYYAFSDPVKLIIE (SEQ ID NO:92),> VHVL 4739-S derived consensus XXXXXQSPDQTVEVGETVTLSAXXXGXXXXWVRQPPGGPLXWXXRFTITADTSSNRVSLTITNVRIEDTATYY AXXWGQGTKLTVKADPEEREKALKEYLERLKTEKXPGQVRXTPEXKXVKVKLGETATLKFWYKQAPGXPPQLL IXGVPSRISGSGSGTDFTLTITXVQPEDEATYYAFSEGTKLVIE (SEQ ID NO:93),> VHVL 4742-S derived consensus XXXXXAPPDQTVXVGETVTLTWXXXGXXXXWVRQAPGGPLEWXXRFTITSDTSSNTASLTITNVQVGDTATY YAXXWGEGTKLTVPASEEELKEARXERKEEREELIKXGEIIGLTPEKATVTVALGGTATLTVWYKQAPGQPPELL IXGVPSRFSGSGSGTDFTLTITDVQXEDEATYYAFSEGTKVVIL (SEQ ID NO:94),> VHVL 6375 derived consensus XXXXXQSPDQTVEEGSTVTLTAXXXGXXXXWIREYLDGSLEWXXRFSITRDTSKNQFYLTITNLTKLDTATYYAX XWGQGTKLTVGELSEEEKEELIKERKERRKQYYKEHPNVIHMSVDQKVVKVKLGETAVIRVWYKQKPGQPPQ LLIXGVPERISGSGSGTDFTLTITNVQEEDAATYYAFSEPVKLVIE (SEQ ID NO:95), or> VHVL 6486 derived consensus DGXVXLXESPDQEVEVGETVTLTAXXXGXXXXWVRQPPGGPLEWXXRFSISRDDSKSSVSLTITNVRIEDHATY YFXXLGKGTKLTVKADPEELEEALRKYHEELKTREVPGQVRMTADKTTVTVKEGETATLKFWYKQAPGEPPRV LIXGVPSRISGSGSGTDFTLTITDVQPEDEATYYAFSEGTKLVIE (SEQ ID NO:96),wherein the CDRL1-CDRL3 and CDRH1-CDRH3 are not included in the consensus sequence.

14. The scaffold protein of any one of claims 1-13 conjugated to a moiety.Atty Dkt. No.: MOBI-015WO15. The scaffold protein of claim 14, wherein the moiety is an amino acid sequence, nucleic acid sequence, or a small molecule.

16. The scaffold protein of claim 15, wherein the scaffold protein is conjugated to an immunoglobulin G (IgG) Fc sequence.

17. The scaffold protein of claim 15, wherein the scaffold protein is conjugated to another scaffold protein.

18. The scaffold protein of claim 17, wherein the other scaffold protein is a scaffold protein according to any one of claims 1-17.

19. The scaffold protein of claim 15, wherein the scaffold protein is conjugated to an scFv.

20. A polypeptide that specifically binds to human IL-6, the polypeptide comprising the amino acid sequence:QTWTMDAKEVTVKLGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSGSGTD FTLTISNVEPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEKKLEEAREERRKELAERRANSPVKLTQSPDITVKE GETATITVAASGFTFSSYRMYWVKQAPGGPLEWVSAISAGGGSTYYGDSVKGKFTISADTSKNTAYLTIKNLTK EDTATYYAANRAGWGMGDYWGEGTKLTVE (SEQ ID NO:169), DIVMTVDAKEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSGSGTDF TLTISNVEPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEELLEEARERRRKRLAERRANSPVKLTQSPDITVKEG ETATLTVKASGFTFTSYRMYWVKQAPGGPLEWIGAISAGGGSTYYGDSVKGRFTISRDTSKNTAYLTITNLTKE DTATYYAARRAGWGMGDYWGEGTKLTVE (SEQ ID N0:170), QTVVTVDAKEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSGSGTDF TLTISNVEPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEKLLEEAREERRKELAERRANSPVKLTQSPDITVKEG ETATLTVAASGFTFSSYRMYWVKQAPGGPLEWVSAISAGGGSTYYGDSVKGRFTISRDTSKNTAYLTITNLTKE DTATYYAANRAGWGMGDYWGEGTKLTVE (SEQ ID NO:171), QTVVVDAKEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSISGNKAT LTISNVEPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEELLEEARERRRKRLAERRANSPVKLTQSPDITVKEGE TATLTVAASGFTFSSYRMYWVKQAPGGPLEWVSAISAGGGSTYYGDSVKGRFTISRDNAKNTVYLTITNLTKEAtty Dkt. No.: MOBI-015WODTATYYAANRAGWGMGDYWGEGTKLTVE (SEQ ID NO:172), QTVVDDAKEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFTGSISGNKAS LTISNVEPEDEATYYAALDIGDITEFSEGTKLLIVPTPETEELLEEARERRRKRLAERRANSPVKLTQSPDITVKEGE TATLTVAASGFTFSSYRMYWVKQAPGGPLEFVSAISAGGGSTYYGDSVKGRFTISRDNAKNTVSLTITNLTKED TATYYAANRAGWGMGDYWGEGTKLTVE (SEQ ID NO:173), QTVVTDDKAEVTVELGETATITVGLSSGSVTASNYPGWYRQFPGEPPELLIYSTNDRHSGVPDRISGSGSGTDF TLTIKNVEPEDEATYYAALDIGDITEFSSGTKLLLVPTPETEEELEEARRERERELAERRKNSPVKLTQSPDLTVKE GETATLTAAASGFTFSSYRMYWVRQAPGGPLEWVSAISAGGGSTYYGDSVKGRFSISRDTSKNTLYLTISNLTP EDTATYYAANRAGWGMGDYWGEGTKLTVE (SEQ ID NO:174), QTVVTVDKAEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRISGSGSGTDF TLTISNVEPEDEATYYAALDIGDITEFSQGTKLLLVPTPETEEELEEARRERAERLAERRKNSPVKLTQSPDLTVKE GETATLTAAASGFTFSSYRMYWVRQAPGGPLEWVSAISAGGGSTYYGDSVKGRFEISRDTSKNTLYLTIKNLTK EDTATYYAANRAGWGMGDYWGEGTKLTVE (SEQ ID NO:175), QIMLSVDKPEVVVEEGETAEVKVGLSSGSVTASNYPGWYRQFPGKPPEALVYSTNDRHSGVPDRISGSGSGT EFTLTIKNVEPEDVATYYAALDIGDITEFSSGTKLLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVK EGETATLTLTVSGFSLTSYRMYWVKQAPGGPLQWLGAISAGGGSTYYGDSVKGRFTISRDTSKSQFYLTITNLK KEDTATYYAARRAGWGMGDYWGQGTKLTVE (SEQ ID NO:176), QTVVTVDKSEVTVELGETATITVGLSSGSVTASNYPGWYRQYPGEPPELLIYSTNDRHSGVPSRFSGSGSGTDF TLTISNVEPEDEATYYAALDIGDITEFSSGTKLLIVPTPETEEELEEAREERARELAERRKNSPVKLTQSPDLTVKEG ETATLTAAASGFTFSSYRMYWVRQAPGGPLQWVSAISAGGGSTYYGDSVKGRFSISRDTSKNTFYLTISNLTKE DTATYYAANRAGWGMGDYWGEGTKLTVE (SEQ ID NO:177), QTVVVDKPEVVVEEGETAEVKVGLSSGSVTASNYPGWYRQFPGKPPEALIYSTNDRHSGVPDRISGSISGNKA TLTIKNVEPEDVATYYAALDIGDITEFSSGTKLLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKE GETATLTLAASGFTFSSYRMYWVKQAPGGPLQWVSAISAGGGSTYYGDSVKGRFTISRDNAKNTVYLTITNLK KEDTATYYAANRAGWGMGDYWGQGTKLTVE (SEQ ID NO:178), or QTVVVDKPEVVVEEGETAEVSVGLSSGSVTASNYPGWYRQFPGKPPELLIYSTNDRHSGVPDRISGSISGNKA VLTIKNVEPEDVATYYAALDIGDITEFSEGTKLLLKKTPEVEEKLKEAEKEREERLAERRKNSPVKLTQSPDITVKE GETATLTLAASGFTFSSYRMYWVKQAPGGPLEFVSAISAGGGSTYYGDSVKGRFTISRDNAKNTVTLTITNLKK EDTATYYAANRAGWGMGDYWGQGTKLTVE (SEQ ID NO:179).

21. A polypeptide that specifically binds to human IL-6, the polypeptide comprising the amino acid sequence:Atty Dkt. No.: MOBI-015WOPVKLTQSPDQTVEEGSTATLTAAASGFTFSSYRMYWVKEDLDGSLEWVSAISAGGGSTYYGDSVKGRFTITSD TSSNTAYLTITNLTKSDTATYYAANRAGWGMGDYWGQGTKLTVGELSEEEKEELIKERKERREEYYKENPDVV KMTVEKETVTVKLGETATIKVGLSSGSVTASNYPGWYKQKPGQPPQLLIYSTNDRHSGVPSRISGSGSGTDFTL TITNVQPEDEATYYAALDIGDITEFSDPVKLIIE (SEQ ID NO:180), QVQLQQSPDQTVEVGETVTLSAKASGFNIESYRMYWVRQPPGGPLQWIGAISAGGGSTYYGDSVKGRFTIT ADTSSNRVSLTITNVRIEDTATYYATRRAGWGMGDYWGQGTKLTVKADPEEREKALKEYLERLKTEKRPGQV RLTPEKKTVKVKLGETATLKFGLSSGSVTASNYPGWYKQAPGEPPQLLIYSTNDRHSGVPSRISGSGSGTDFTLT ITNVQPEDEATYYAALDIGDITEFSEGTKLVIE (SEQ. ID NO:181), PVKLTQSPDQTVEVGETVTLSAAASGFTFSSYRMYWVRQPPGGPLEWVSAISAGGGSTYYGDSVKGRFTITA DTSSNRVSLTITNVRIEDTATYYAANRAGWGMGDYWGQGTKLTVKADPEEREKALKEYLERLKTEKIPGQVR MTPEEKWKVKLGETATLKFGLSSGSVTASNYPGWYKQAPGQPPQLLIYSTNDRHSGVPSRISGSGSGTDFTL TITDVQPEDEATYYAALDIGDITEFSEGTKLVIE (SEQ ID NO:182), EVQLVQSPDQTVEVGETVTLSAAASGFTFSSYRMYWVRQPPGGPLEWVSAISAGGGSTYYGDSVKGRFTISR DNAKNTVSLTITNVRIEDTATYYAANRAGWGMGDYWGQGTKLTVKADPEEREKALKEYLERLKTEKIPGQVR MTPEEKVVKVKLGETATLKFGLSSGSVTASNYPGWYKQAPGQPPQLLIYSTNDRHSGVPSRISGSISGNKATLT ITDVQPEDEATYYAALDIGDITEFSEGTKLVIE (SEQ ID NO:183), EVQLVQSPDQTVEVGETVTLTAAASGFTFSSYRMYWVRQPPGGPLEFVSAISAGGGSTYYGDSVKGRFTISRD NAKNTVSLTITNVRIEDTATYYAANRAGWGMGDYWGQGTKLTVKADPEEREKALKEYLERLKTEKIPGQNRL LPEEKVVKVKLGETATLSFGLSSGSVTASNYPGWYKQAPGQPPTQLIYSTNDRHSGVPSRISGSISGNKAVLTIT DVQPEDEATYYAALDIGDITEFGEGTKLVIE (SEQ ID NO:184), EVQLQAPPDQTVAVGETVTLTWTASGFNIKSYRMYWVRQAPGGPLEWIGAISAGGGSTYYGDSVKGRFTITS DTSSNTASLTITNVQVGDTATYYAARRAGWGMGDYWGEGTKLTVPASEEELKEAREERKEEREELIKRGEIIGL TPEKATVTVALGGTATLTVGLSSGSVTASNYPGWYKQAPGQPPELLIYSTNDRHSGVPSRFSGSGSGTDFTLTI TDVQEEDEATYYAALDIGDITEFSEGTKVVIL (SEQ ID NO:185), PVKLTAPPDQTVKVGETVTLTWAASGFTFSSYRMYWVRQAPGGPLEWVSAISAGGGSTYYGDSVKGRFTITS DTSSNTASLTITNVQVGDTATYYAANRAGWGMGDYWGEGTKLTVPASEEELKEARKERKEEREELIKEGEIIG LTPEKATVTVALGGTATLTVGLSSGSVTASNYPGWYKQAPGQPPELLIYSTNDRHSGVPSRFSGSGSGTDFTLT ITDVQPEDEATYYAALDIGDITEFSEGTKWIL (SEQ ID NO:186), EVQLVAPPDQTVKVGETVTLTWAASGFTFSSYRMYWVRQAPGGPLEWVSAISAGGGSTYYGDSVKGRFTIS RDNAKNTVSLTITNVQVGDTATYYAANRAGWGMGDYWGEGTKLTVPASEEELKEARKERKEEREELIKEGEII GLTPEKATVTVALGGTATLTVGLSSGSVTASNYPGWYKQAPGQPPELLIYSTNDRHSGVPSRFSGSISGNKATL TITDVQPEDEATYYAALDIGDITEFSEGTKVVIL (SEQ ID NO:187),Atty Dkt. No.: MOBI-015WOEVQLVPPPDQTVKVGETVTLTWAASGFTFSSYRMYWVRQAPGGPLEFVSAISAGGGSTYYGDSVKGRFTISR DNAKNTVSLTITNVQVGDTATYYAANRAGWGMGDYWGQGTKLTVPASEEELKEARKERKEEREELIKEGEIT GLYPDKATVTVALGGTATLTVGLSSGSVTASNYPGWYKQAPGQPPQLLIYSTNDRHSGVPSRFSGSISGNKAV LTITDVQPEDEATYYAALDIGDITEFSEGTKVVIL (SEQ ID NO:188), or PVKLTQSPDQTVEEGSTVTLTAAASGFTFSSYRMYWIREYLDGSLEWVSAISAGGGSTYYGDSVKGRFSITRDT SKNQFYLTITNLTKLDTATYYAANRAGWGMGDYWGQGTKLTVGELSEEEKEELIKERKERRKQYYKEHPNVIH MSVDQKVVKVKLGETAVIRVGLSSGSVTASNYPGWYKQKPGQPPQLLIYSTNDRHSGVPERISGSGSGTDFTL TITNVQEEDAATYYAALDIGDITEFSEPVKLVIE (SEQ ID NO:189).

22. A polypeptide that specifically binds to PfRh5, the polypeptide comprising the amino acid sequence:DIVLTVDAKEVTVELGETATITVRASESVEYYGTSLMQWYRQYPGEPPELLIHGASNVQSGVPSRFSGSGSGTD FTLTISNVEPEDEATYYAQQSTKVPWTFSEGTKLLIVPTPETEKLLEEAREERRKELAERRANSPVKLTQSPDITV KEGETATLTVAASGFTFSDYGMAWVKQAPGGPLEWVTFISNMAYSIYYADTVTGRFTISRENAKNTLYLTITN LTKEDTATYYATRAIFDYAGYWYFDVWGEGTKLTVE (SEQ ID NO:228), or DIVLTVDAKEVTVELGETATITVRASQSVSTSSYTYFHWYRQYPGEPPELLIRYASNLESGVPSRFSGSGSGTDFT LTISNVEPEDEATYYAQHSWEIPYTFSEGTKLLIVPTPETEKLLEEAREERRKELAERRANSPVKLTQSPDITVKEG ETATLTVAASGFTFSDFYMYWVKQAPGGPLEWVATISDGDSYIYYPDSVRGRFTISRDNAKNILYLTITNLTKE DTATYYAARDGNGKDGGDAMDYWGEGTKLTVE (SEQ ID NO:229).

23. A polypeptide that specifically binds to PfRh5, the polypeptide comprising the amino acid sequence:GVKLVQSPDQTVKVGETVTLTWAASGFTFSDYGMAWVRQAPGGPLEWVTFISNMAYSIYYADTVTGRFTIS RENAKNTLSLTITNVQVGDTATYYATRAIFDYAGYWYFDVWGEGTKLTVPASEEELKEARKERKEEREELIKEG EIIGLTPEKATVTVALGGTATLTVRASESVEYYGTSLMQWYKQAPGQPPELLIHGASNVQSGVPSRFSGSGSGT DFTLTITDVQPEDEATYYAQQSTKVPWTFSEGTKVVIL (SEQ ID NO:231), or VKLVQSPDQTVEVGETVTLTAAASGFTFSDYGMAWVRQPPGGPLEFVTFISNMAYSIYYADTVTGRFTISREN AKNTLSLTITNVRIEDTATYYATRAIFDYAGYWYFDVWGQGTKLTVKADPEEREKALKEYLERLKTEKRPGVITL TPEEKVVKVKLGETATLKFRASESVEYYGTSLMQWFKQAPGQPPQLLIYGASNVQSGVPSRISGSGSGTDFTL TITDVQPEDEATYYAQQSTKVPWTFSEGTKLVIE (SEQ ID NO:233).

24. A method comprising:Atty Dkt. No.: MOBI-015WOin silico grafting CDRL1-CDRL3 and CDRH1-CDRH3 from a parental antibody into the amino acid sequence of a scaffold protein according to any one of claims 1-8 to generate a first polypeptide;in silico modeling the conformation of the first polypeptide and comparing to the conformation of the parental antibody,wherein when the conformations match, producing the first polypeptide, wherein when the conformations do not match, in silico grafting 3-5 amino acids from the N-terminus of the variable light chain of the parental antibody and 2-8 amino acids adjacent to one or more of the CDRL1-CDRL3 and the CDRH1-CDRH3 in the parental antibody into the corresponding region in the first polypeptide to generate a second polypeptide;in silico modeling the conformation of the second polypeptide and comparing to the conformation of the parental antibody,wherein when the conformations match, producing the second polypeptide, wherein when the conformations do not match, in silico grafting additional-loops from the parental antibody that are within 10 amino acid of one or more of CDRL1-CDRL3 and CDRH1- CDRH3 into the corresponding region in the second polypeptide to generate a third polypeptide;in silico modeling the conformation of the third polypeptide and comparing to the conformation of the parental antibody,wherein when the conformations match, producing the third polypeptide.

25. The method of claim 24, wherein when the conformations do not match, redesigning residues of the third polypeptide which have sidechain (Cβ) contacts with grafted residues to alleviate boundary discrepancies to generate a fourth polypeptide.

26. The method of claim 25, wherein the method further comprises in silico modeling the conformation of the fourth polypeptide and comparing to the conformation of the parental antibody, wherein when the conformations match, producing the fourth polypeptide.

27. The method of claim 24, wherein at least one of the first polypeptide, the second polypeptide, or the third polypeptide binds to the same antigen bound by the parental antibody with a comparable or higher affinity than the parental antibody.Atty Dkt. No.: MOBI-015WO28. The method of claim 25 or 26, wherein at least one of the first polypeptide, the second polypeptide, the third polypeptide, or the fourth polypeptide bind to the same antigen bound by the parental antibody with a comparable or higher affinity.

29. A method comprising:in silico grafting CDRH1-CDRH3 and CDRL1-CDRL3 from a parental antibody into the amino acid sequence of a scaffold protein according to claim 11 or 13 to generate a first polypeptide;in silico modeling the conformation of the first polypeptide and comparing to the conformation of the parental antibody,wherein when the conformations match, producing the first polypeptide, wherein when the conformations do not match, in silico grafting 3-5 amino acids from the N-terminus of the variable heavy chain of the parental antibody and 2-8 amino acids adjacent to one or more of the CDRL1-CDRL3 and the CDRH1-CDRH3 in the parental antibody into the corresponding region in the first polypeptide to generate a second polypeptide;in silico modeling the conformation of the second polypeptide and comparing to the conformation of the parental antibody,wherein when the conformations match, producing the second polypeptide, wherein when the conformations do not match, in silico grafting additional-loops from the parental antibody that are within 10 amino acid of one or more of CDRL1-CDRL3 and CDRH1- CDRH3 into the corresponding region in the second polypeptide to generate a third polypeptide;in silico modeling the conformation of the third polypeptide and comparing to the conformation of the parental antibody,wherein when the conformations match, producing the third polypeptide.

30. The method of claim 29, wherein when the conformations do not match, redesigning residues of the third polypeptide which have sidechain (Cβ) contacts with grafted residues to alleviate boundary discrepancies to generate a fourth polypeptide.Atty Dkt. No.: MOBI-015WO31. The method of claim 30, wherein the method further comprises in silico modeling the conformation of the fourth polypeptide and comparing to the conformation of the parental antibody, wherein when the conformations match, producing the fourth polypeptide.

32. The method of claim 29, wherein at least one of the first polypeptide, the second polypeptide, or the third polypeptide binds to the same antigen bound by the parental antibody with a comparable or higher affinity than the parental antibody.

33. The method of claim 30 or 31, wherein at least one of the first polypeptide, the second polypeptide, the third polypeptide, or the fourth polypeptide bind to the same antigen bound by the parental antibody with a comparable or higher affinity.

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