CN117651565A - Combination therapy with antifolate receptor conjugates and bevacizumab - Google Patents

Combination therapy with antifolate receptor conjugates and bevacizumab Download PDF

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CN117651565A
CN117651565A CN202280050428.XA CN202280050428A CN117651565A CN 117651565 A CN117651565 A CN 117651565A CN 202280050428 A CN202280050428 A CN 202280050428A CN 117651565 A CN117651565 A CN 117651565A
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V·德阿尔梅达
C·L·亚伯拉罕
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Sutro Biopharma Inc
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Abstract

The present invention relates to combination therapies using antibody conjugates with binding specificity for folate receptor alpha (FOLR 1) and subtypes and homologs thereof. The invention also provides methods for use in combination with antibody conjugates and compositions thereof, e.g., in therapeutic and diagnostic methods.

Description

Combination therapy with antifolate receptor conjugates and bevacizumab
Cross Reference to Related Applications
The present application claims and enjoys priority from U.S. provisional application number 63/190,743 filed on day 2021, 5, 19, and U.S. provisional application number 63/291,297 filed on day 2021, 12, 17; each of which is incorporated by reference in its entirety into this application for all purposes.
Technical Field
The present invention provides combination therapies using antibody conjugates with binding specificity for folate receptor alpha (folra or FolR 1) and compositions, including pharmaceutical compositions, for administration thereof. The combination therapies are useful in methods of treating and preventing cell proliferation and cancer. The combination therapy is also useful in methods of treating and preventing autoimmune, infectious and inflammatory diseases.
Background
Folate receptors or Folate Binding Proteins (FBPs) include single chain glycoproteins that can bind and facilitate in vivo turnover of folic acid and other compounds. Elwood,1989, J.biol. Chem.264:14893-14901. Some folate receptors are single chain glycoproteins that have high affinity binding sites for folic acid and other compounds (e.g., methotrexate). Elwood, p.14893. The human FOLR1 gene encodes an adult folate receptor, a 30kDa polypeptide of approximately 257 amino acids, with three potential N-linked glycosylation sites. Elwood, p.14893; lacey et al, 1989, J.Clin.Invest.84:715-720. Homologous genes and polypeptides have been identified in several tens of species.
Mature folate receptor glycoprotein is about 42kDa in size and has been observed to be involved in internalizing folic acid and antifolate into cells. Elwood et al 1997,Biochemistry 36:1467-1478. Expression has been observed in human cerebellum and kidney cells and human cancer cell lines. Elwood et al, 1997, p.1467. In addition to folate internalization, folate receptors have been demonstrated to be an important cofactor for viruses, particularly Marburg (Marburg) and Ebola (Ebola) viruses, into cells. Chan et al 2001,Cell 106:117-126. Because of these internalizing properties, folate receptors have been proposed as targets for diagnostic and therapeutic agents. For example, diagnostic and therapeutic agents are linked to folic acid for internalization into cells expressing the folate receptor. See, e.g., leamon,2008,Curr.Opin.Investig.Drugs 9:1277-1286; paulos et al 2004,Adv.Drug Del.Rev.56:1205-1217.
Folate receptor alpha (folra or FolR 1) is a cell surface glycoprotein linked to glycosyl phosphatidylinositol, which has a high affinity for folic acid. Except for lower levels in the kidneys and lungs, most normal tissues do not express FOLR1, but high levels of FOLR1 are found in serous and endometrioid epithelial ovarian cancer, endometrial adenocarcinoma, non-small cell lung cancer (NSCLC) of the adenocarcinoma subtype, and Triple Negative Breast Cancer (TNBC). FOLR1 expression is maintained in metastatic and recurrent carcinoma in ovarian cancer patients, and FOLR1 expression has been observed following chemotherapy for epithelial ovarian cancer and endometrial cancer. These properties, as well as the highly restricted expression of FOLR1 on normal tissues, make FOLR1 a very promising target for cancer treatment. Thus, the folate receptor provides a potential target for diagnostic and therapeutic agents for cancer and inflammatory diseases. In addition to the need for novel antibodies that specifically bind to and target these folate receptors, combination therapies with other anti-cancer agents or agents that target cell division and/or cell differentiation provide another avenue of search for the treatment of diseases and conditions associated with FOLR1 overexpression and/or FOLR1 signaling hyperactivity.
There is a need for improved methods to modulate the immunomodulation of folate receptor alpha (FOLR 1) and downstream signaling processes activated by folate receptor alpha (FOLR 1) that can be enhanced or improved in combination with administered anticancer agents or therapeutic agents that modulate cell division and/or cell differentiation. Such therapeutic agents, in combination with anti-FOLR 1 antibody conjugates that can deliver therapeutic or diagnostic payload moieties to target cells expressing folate receptor alpha, are useful in the treatment of diseases in which FOLR1 is expressed or overexpressed.
Summary of the invention
The present invention provides antibody conjugates that selectively bind to folate receptor alpha (FOLR 1) for use in combination with a second therapeutic agent that modulates angiogenesis. The antibody conjugates comprise an antibody that binds folate receptor alpha (FOLR 1) linked to one or more payload moiety. The antibody may be directly attached to the payload by a covalent bond or indirectly attached to the payload by a linker. The present invention details folate receptor alpha (FOLR 1) antibodies, as well as useful payload group moieties and useful linkers. In certain embodiments, the second therapeutic agent is an inhibitor of Vascular Endothelial Growth Factor (VEGF) activity.
In one aspect, the invention provides methods of using anti-FOLRl antibody conjugates in combination with a second therapeutic agent that modulates angiogenesis. In some embodiments, the second therapeutic agent is a VEGF inhibitor. In some embodiments, the VEGF inhibitor is bevacizumab (bevacizumab) or a bevacizumab anti-biological analog. In some embodiments, the amount of the one or more VEGF-A inhibitors is about 15mg/kg. In certain embodiments, the method is a method of treatment. In certain embodiments, the combination is for use in treating a disease or disorder. In certain embodiments, the disease or disorder is cancer.
In some embodiments, the administration is by Intravenous (IV) administration. In some embodiments, the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered separately on the same day. In some embodiments, the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered simultaneously on the same day. In some embodiments, the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered about once every 3 weeks or more for the remainder of the treatment. In some embodiments, the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered about once every 3 weeks. In some embodiments, the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered about once every 4 weeks.
In some embodiments, the amount of the antibody conjugate is about 3.5mg/kg or more. In some embodiments, the amount of the antibody conjugate is about 4.3mg/kg. In some embodiments, the amount of the antibody conjugate is about 5.2mg/kg. In some embodiments, the method further comprises administering the antibody conjugate to the subject at a reduced dose. In some embodiments, the reduced dose is about 4.3mg/kg or less. In some embodiments, the reduced dose is about 4.3mg/kg. In some embodiments, the reduced dose is about 3.5mg/kg. In some embodiments, the reduced dose is about 2.9mg/kg. In some embodiments, the antibody conjugate is administered to the subject at a first dose for 1 to 5 cycles prior to the reduced dose, wherein each cycle is about 3 weeks or more. In some embodiments, the antibody conjugate is administered to the subject in a first dose for 1 to 3 cycles prior to the reduced dose, wherein each cycle is about 3 weeks or more. In some embodiments, the antibody conjugate is administered to the subject at a first dose for 2 to 4 cycles prior to the reduced dose, wherein each cycle is about 3 weeks or more.
In another aspect, the invention provides a kit or composition comprising the anti-FOLR 1 antibody conjugate and a second therapeutic agent that modulates angiogenesis. In certain embodiments, the anti-FOLR 1 antibody conjugate and the second therapeutic agent are in separate pharmaceutical compositions. In certain embodiments, the anti-FOLR 1 antibody conjugate and the second therapeutic agent are administered separately. In certain embodiments, the anti-FOLR 1 antibody conjugate and the second therapeutic agent are administered cyclically.
In certain embodiments, the composition is a pharmaceutical composition. Any suitable pharmaceutical composition may be used. In certain embodiments, the pharmaceutical composition of the anti-FOLR 1 antibody conjugate is a composition useful for Intravenous (IV) administration. In certain embodiments, the pharmaceutical composition of the second therapeutic agent is a composition useful for IV administration. In certain embodiments, the second therapeutic agent is a VEGF antagonist. In certain embodiments, the second therapeutic agent is bevacizumab or a bevacizumab anti-biological analogue.
The methods, kits and compositions disclosed herein are useful for treating diseases or conditions. In certain embodiments, the disease or disorder is cancer. In certain embodiments, the cancer is endometrial or ovarian cancer. In certain embodiments, the combinations, kits, and compositions provided herein are useful in therapy. In certain embodiments, the invention provides combinations, kits and compositions for use in the treatment of cancer.
In some embodiments, the antibody conjugate binds to human folate receptor alpha. In some embodiments, the antibody conjugate also binds to a homolog of human folate receptor alpha. In some aspects, the antibody conjugate also binds to a cynomolgus monkey and/or a homolog of the mouse folate receptor alpha.
Brief description of the drawings
FIG. 1 provides tumor size changes over time and body weight changes over time following administration of 2.5mg/kg conjugate A, 5.0mg/kg VEGF trap, and a combination of 2.5mg/kg conjugate A and 5.0mg/kg bevacizumab for an OV-90 mouse tumor model.
FIG. 2A provides in vivo efficacy of conjugate A as 5mg/kg monotherapy and in combination with 5mg/kg bevacizumab in an OV-90 tumor model. Figure 2B provides the percent change in body weight calculated relative to the body weight of the animals at the beginning of the study.
Detailed Description
1. Definition of the definition
Unless defined otherwise, all technical terms, symbolic descriptions and other scientific terms used herein are intended to have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. In many instances, words having a commonly understood meaning are defined herein for clarity and/or ease of reference, and the inclusion of such definitions in this disclosure should not be taken to represent differences from those ordinarily skilled in the art. The techniques and procedures described or referred to in this invention are generally well understood by those of ordinary skill in the art and are often employed using conventional methods such as, for example, the molecular cloning methods described in the widely used Sambrook et al, molecular Cloning: A Laboratory Manual 2nd ed. (1989) Cold Spring Harbor Laboratory Press, cold Spring Harbor, NY. Methods involving the use of commercially available kits and reagents, where appropriate, are generally performed according to manufacturer-defined protocols and conditions/parameters, unless otherwise indicated.
It should be understood that aspects, cases, and embodiments described herein as "comprising" or "including" include embodiments that "consist of" and "consist essentially of.
As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
The term "about" means and encompasses the indicated values as well as ranges above and below such values. In certain embodiments, the term "about" means the specified value ± 10%, ±5% or ± 1%. In certain embodiments, the term "about" means the specified value ± one standard deviation of the value.
The term "combinations thereof includes various possible combinations of elements to which the term refers. For example, expressed as "if alpha 2 A is A, then alpha 3 Is not D; alpha 5 Is not S; or alpha 6 Is not S; or a combination thereof "includes the following combinations: when alpha is 2 When A is: (1) Alpha 3 Is not D; (2) Alpha 5 Is not S; (3) Alpha 6 Is not S; (4) Alpha 3 Is not D; alpha 5 Is not S; and alpha 6 Is not S; (5) Alpha 3 Not D, and alpha 5 Is not S; (6) Alpha 3 Not D, and alpha 6 Is not S; and (7) alpha 5 Not S, and alpha 6 Is not S.
The terms "folate receptor alpha" and "folate receptor 1" are used interchangeably in the present invention. Folate receptor alpha is also synonymously called including FOLR1, folra, folate binding protein, FBP, adult folate binding protein, folbp1, FR-a, fra, KB cell FBP, and ovarian tumor associated antigen MOv18, among others. Unless otherwise indicated, the term includes any variant, subtype, and species homolog of human natural folate receptor alpha that is expressed naturally by cells or by cells transfected with the folate receptor alpha or FOLR1 gene. Folate receptor alpha proteins include, for example, human folate receptor alpha (SEQ ID NO: 1). In some embodiments, the folate receptor alpha protein comprises cynomolgus monkey folate receptor alpha (SEQ ID NO: 2). In some embodiments, the folate receptor alpha protein comprises murine (murine) folate receptor alpha (SEQ ID NO: 3).
The term "angiogenesis inhibitor" as used herein refers to a substance that inhibits neovascularization.
"VEGF" refers to vascular endothelial growth factor. "VEGF" is a signaling protein produced by many cells that stimulates angiogenesis. VEGF is known in the art (see, e.g., shibiuya, M. (2013) J Biochem 153 (1): 13-19). Normally, the role of VEGF is to promote the formation of new blood vessels during embryonic development, after injury, muscle formation after exercise, and formation of new blood vessels that bypass occluded blood vessels (collateral circulation). The VEGF family includes 5 members: VEGF-A, placental Growth Factor (PGF), VEGF-B, VEGF-C, VEGF-D, VEGF-E, and endocrine gland derived vascular endothelial growth factor (EG-VEGF). The latter members were all found after VEGF-A; before its discovery, VEGF-A was called VEGF. Thus, as used herein, the term "VEGF" is synonymous with "VEGF-A".
Bevacizumab (Bevacizumab) is Sub>A humanized monoclonal antibody that produces angiogenesis inhibition by inhibiting the activity of vascular endothelial growth factor Sub>A (VEGF-Sub>A). Bevacizumab binds to VEGF, thereby preventing VEGF from binding to VEGF receptor (VEGFR). Bevacizumab is known in the art (see, e.g., ignofo, r.j. (2004) American Journal of Health-System Pharmacy 61,Issue suppl 5:S21-S26).
The term "biologic" as used herein refers to a pharmaceutical substance prepared from or derived from a living organism or prepared by recombinant DNA or controlled gene expression methods.
The terms "biosimilar," "biomimetic," or "bioproduct subsequent product" as used herein refer to a product that has similar structure and properties to existing bioproducts. Thus, the term "bio-analog" is generally used to describe a subsequent version or product (typically from a different source) of "Innovative biopharmaceutical product" that has been previously approved and formally granted marketing authorization. Because biologics or biologics are of high molecular complexity and are generally sensitive to manufacturing process variations (e.g., if different cell lines are used in their production process), and because subsequent manufacturers of imitated drugs are generally unable to obtain molecular clones of the original drug, cell libraries, proprietary technology of the production process, nor the active drug substance itself (limited to the innovators 'commercial drugs), the "bio-analog" may not be exactly the same as the innovators' drug product. However, bio-analog must demonstrate no clinically significant differences in safety and efficacy from its reference product. Thus, the term "biosimilar" or "biosimilar" as used herein includes currently known and approved "biosimilar" as well as any "biosimilar" developed in the future, since the biosimilar is a subsequent version of a known product and it must be demonstrated that there is no clinically significant difference from its reference product.
The term "immunoglobulin" refers to a class of structurally related proteins that generally comprise two pairs of polypeptide chains: a pair of light (L) chains and a pair of heavy (H) chains. In "intact immunoglobulins" all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been characterized in detail. See, e.g., paul, fundamental Immunology th ed., ch.5 (2013) Lippincott Williams&Wilkins, philiadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (V H ) And a heavy chain constant region (C) H ). Heavy chain constant regions generally comprise three domains, abbreviated as C H1 、C H2 And C H3 . Each light chain typically comprises a light chain variable region (V L ) And a light chain constant region. The light chain constant region generally comprises a domain, abbreviated as C L 。
The term "antibody" describes an immunoglobulin molecule and is used in its broadest sense in the present invention. Antibodies include, inter alia, intact antibodies (e.g., intact immunoglobulins) and antibody fragments. The antibody comprises at least one antigen binding domain. An example of an antigen binding domain is that defined by V H -V L An antigen binding domain formed by the dimer."folate receptor alpha antibody", "antifolate receptor alpha antibody", "folate receptor alpha 0Ab", "folate receptor alpha 1 specific antibody", "antifolate receptor alpha Ab", "FOLR1 antibody", "FOLR alpha antibody", "anti-FOLR alpha antibody", "FOLR1 Ab", "FOLR alpha Ab", "FOLR1 specific antibody", "FOLR alpha specific antibody", "anti-FOLR alpha Ab", or "anti-FOLR 1 Ab" are antibodies that specifically bind to folate receptor alpha or FOLR1 according to the invention. In some embodiments, the antibody binds to the extracellular domain of folate receptor alpha (FOLR 1).
V H Region and V L The regions may be further subdivided into regions of hypervariability ("hypervariable regions (HVRs)", also known as "Complementarity Determining Regions (CDRs)") interspersed with more conserved regions. The more conserved regions are called Framework Regions (FR). Each V is H And V L Typically comprising three CDRs and four FRs (from N-terminus to C-terminus) arranged in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. CDRs are involved in antigen binding and affect the specificity of the antigen and the binding affinity of the antibody. See Kabat et al Sequences of Proteins of Immunological Interest th ed (1991) Public Health Service, national Institutes of Health, bethesda, MD, incorporated herein by reference in its entirety.
The light chain of any vertebrate species can be assigned to one of two types called kappa and lambda, depending on the sequence of the constant domain.
The heavy chain of any vertebrate species can be assigned to one of five different types (or isotypes): igA, igD, igE, igG and IgM. These types are also named α, δ, ε, γ, and μ, respectively. IgG and IgA types are further divided into subclasses according to sequence differences and functions. The human expresses the following subclasses: igG1, igG2, igG3, igG4, igA1, and IgA2.
The amino acid sequence boundaries of the CDRs can be determined by those of ordinary skill in the art using any of a number of known numbering schemes, including Kabat et al, supra ("Kabat" numbering scheme); al-Lazikani et Al, 1997, J.mol.biol.,. 273:927-948 ("Ke Xiya (Chothia)" numbering scheme); macCallum et al, 1996, J.mol. Biol.262:732-745 ("Contact" numbering scheme); lefranc et al, dev. Comp. Immunol.,2003,27:55-77 ("IMGT" numbering scheme); and Hongge and Pluckthun, J.mol.biol.,2001,309:657-70 ("AHo" numbering scheme), each of which is incorporated herein by reference in its entirety.
Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 identified by the kappa (Kabat) and Coxiya (Chothia) protocols. In the case of CDR-H1, residue numbering is provided using the two numbering schemes of Kaba and Coxia.
TABLE 1 residues in CDRs according to the sub-numbering scheme of Kaba He Kexi
CDR Carba (Kabat) Ke Xiya (Chothia)
L1 L24-L34 L24-L34
L2 L50-L56 L50-L56
L3 L89-L97 L89-L97
H1 (kappa number) H31-H35B H26-H32 or H34
H1 (Ke Xiya numbering) H31-H35 H26-H32
H2 H50-H65 H52-H56
H3 H95-H102 H95-H102
* When numbered using the kappa numbering convention, the C-terminus of CDR-H1 will differ between H32 and H34 depending on the length of the CDR.
Unless otherwise indicated, the numbering scheme used to identify specific CDRs in the present invention is the kappa (Kabat)/Ke Xiya (Chothia) numbering scheme. When the residues encompassed by both numbering schemes diverge (CDR-H1 and/or CDR-H2), the numbering scheme will be designated as either kappa or cauchy. For convenience, CDR-H3 is sometimes referred to herein as kappa (Kabat) or Caxiya (Chothia). However, this is not intended to imply that there is no difference in the sequences, and one skilled in the art can easily confirm whether the sequences are identical or different by examining the sequences.
CDRs can be assigned, for example, using antibody numbering software such as Abnum, available from www.bioinf.org.uk/abs/Abnum/and described in Abhinandan and Martin, immunology,2008,45:3832-3839, the entire disclosure of which is incorporated herein by reference.
When referring to residues in the antibody heavy chain constant region, the "EU numbering scheme" is generally used (e.g., kabat et al, supra). The EU numbering scheme is used to refer to residues in the heavy chain constant region of an antibody according to the invention, unless otherwise specified.
An "antibody fragment" comprises a portion of an intact antibody, such as the antigen-binding region of an intact antibody or may beA variable region. Antibody fragments include, for example, fv fragments, fab fragments, F (ab') 2 Fragments, fab' fragments, scFv (sFv) fragments, and scFv-Fc fragments.
An "Fv" fragment comprises a non-covalently linked dimer of one heavy chain variable domain and one light chain variable domain.
The "Fab" fragment comprises, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain of the heavy chain (C H1 ). Fab fragments can be produced, for example, by papain digestion of full length antibodies or recombinant methods.
“F(ab’) 2 "fragments contain two Fab' fragments linked by disulfide bonds near the hinge region. F (ab') 2 Fragments can be produced, for example, by pepsin digestion of intact antibodies or recombinant methods. F (ab') fragments can be dissociated, for example, by treatment with β -mercaptoethanol.
A "single chain Fv" or "sFv" or "scFv" antibody fragment comprises V in a single polypeptide chain H Domain and V L A domain. V (V) H And V L The ligation is typically performed by a peptide linker. See pluckthun a (1994). In some embodiments, the linker is SEQ ID NO:377. in some embodiments, the linker is SEQ ID NO:378.antibodies from Escherichia colli.in Rosenberg M.&Moore g.p. (eds.), the Pharmacology of Monoclonal Antibodies vol.113 (pp.269-315). Spring-Verlag, new York, incorporated herein by reference in its entirety.
The "scFv-Fc" fragment comprises an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminus of an scFv. The Fc domain may be located at V H Or V L Thereafter, depending on the directionality of the variable domains in the scFv (i.e., V H -V L Or V L -V H ). Any suitable Fc domain known in the art or described herein may be used. In certain instances, the Fc domain comprises an IgG1 Fc domain. In some embodiments, the IgG1 Fc domain comprises SEQ ID NO:370 or a portion thereof. SEQ ID NO:370 provides C of the human IgG1 constant region H1 、C H2 And C H3 Is a sequence of (a).
The term "monoclonal antibody" refers to an antibody from a substantially homogeneous population of antibodies. A substantially homogeneous population of antibodies comprises antibodies that are substantially similar and bind to the same epitope, excluding variants that normally occur during monoclonal antibody production. Such variants are typically present in only small amounts. Monoclonal antibodies are typically obtained by a process involving selection of a single antibody from a plurality of antibodies. For example, the selection process may be to select unique clones from a collection of clones such as hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibodies can be further altered, e.g., to improve affinity for the target ("affinity maturation"), to humanize the antibodies, to improve their production in cell culture, and/or to reduce their immunogenicity in the subject.
The term "chimeric antibody" refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.
A "humanized" form of a non-human antibody refers to a chimeric antibody that contains minimal sequences derived from the non-human antibody. Humanized antibodies are typically human immunoglobulins (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs from a non-human antibody (donor antibody). The donor antibody may be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken or non-human primate antibody having the desired specificity, affinity or biological effect. In some embodiments, selected framework region residues of the recipient antibody are replaced with residues of the corresponding framework region of the donor antibody. Humanized antibodies may also comprise residues that are not present in the recipient antibody or the donor antibody. Such modifications may be made to further improve antibody function. For further details see Jones et al, nature,1986,321:522-525; riechmann et al, nature,1988,332:323-329; and Presta, curr.op.struct.biol.,1992,2:593-596, each of which is incorporated herein by reference in its entirety.
A "human antibody" is an antibody having an amino acid sequence corresponding to that of an antibody produced by a human or human cell, or derived from a non-human source that utilizes a human antibody reservoir or human antibody coding sequence (e.g., obtained from a human source or redesigned). Human antibodies specifically exclude humanized antibodies.
An "isolated antibody" refers to an antibody that has been separated from and/or recovered from components in its natural environment. Components of the natural environment may include enzymes, hormones, and other proteinaceous or non-proteinaceous materials. In some embodiments, the isolated antibody is purified to an extent sufficient to obtain at least 15N-terminal or internal amino acid sequence residues, for example, by use of a rotor sequencer. In some embodiments, the isolated antibody is purified to homogeneity as detected by Coomassie blue (Coomassie blue) or silver staining under reducing or non-reducing conditions by gel electrophoresis (e.g., SDS-PAGE). The isolated antibody includes an in situ antibody within the recombinant cell because at least one component of the antibody's natural environment is absent. In some aspects, the isolated antibody is prepared by at least one purification step.
In some embodiments, the isolated antibody is purified to at least 80 wt%, 85 wt%, 90 wt%, 95 wt%, or 99 wt%. In some embodiments, the isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by volume. In some embodiments, the isolated antibody is provided as a solution comprising at least 85 wt%, 90 wt%, 95 wt%, 98 wt%, 99 wt% to 100 wt% of the antibody. In some embodiments, the isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% (by volume) of the antibody.
"affinity" refers to the total strength of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). As used herein, unless otherwise indicated, "binding affinity" refers to an inherent binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibodies and antigens). The affinity of a molecule X for its partner Y can generally be determined by the dissociation constant (K D ) And (3) representing. Affinity can be determined by conventional methods known in the art, including the present inventionThose described. Affinity may use, for example, surface Plasmon Resonance (SPR) techniques such asThe instrument performs the measurement. In some embodiments, the affinity is measured at 25 ℃.
With respect to binding of an antibody to a target molecule, the terms "specifically bind," "specifically bind to …," "pair," "specific," "selectively bind," and "pair," "selectively" a particular antigen (e.g., a polypeptide target) or epitope of a particular antigen means that there is an analytically distinct binding to non-specific or non-selective interaction. Specific binding can be determined, for example, by determining the binding of a molecule as compared to the binding of a control molecule. Specific binding can also be determined by competition with a control molecule that mimics the binding site of the antibody to the target. In this case, specific binding is indicated if the binding of the antibody to the target is competitively inhibited by the control molecule.
The term "k" as used herein d ”(sec -1 ) Refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also known as k Dissociation of Values.
The term "k" as used herein a ”(M -1 ×sec -1 ) Refers to the association rate constant for a particular antibody-antigen interaction. This value is also known as k Association with Values.
The term "K" as used herein D "(M) refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. K (K) D ＝k d /k a 。
The term "K" as used herein A ”(M -1 ) Refers to the association equilibrium constant for a particular antibody-antigen interaction. K (K) A ＝k a /k d 。
An "affinity matured" antibody refers to an antibody having one or more alterations in one or more CDRs or FRs that result in an increase in affinity of the antibody for its antigen as compared to the parent antibody without the alterations. In one embodiment, the affinity matured antibody is directed againstThe antigen of interest has nanomolar or picomolar affinity. Affinity matured antibodies can be generated using a variety of methods known in the art. For example, marks et al (Bio/Technology, 1992,10:779-783, the entire disclosure of which is incorporated herein by reference) describe a composition described by V H And V L The affinity resulting from domain replacement matures. Random mutability of CDR and/or framework residues is described, for example, in: barbes et al (proc.nat. Acad.sci.u.s.a.,1994, 91:3809-3813); schier et al, gene,1995,169:147-155; yelton et al, J.Immunol.,1995,155:1994-2004; jackson et al, J.Immunol.,1995,154:3310-33199; and Hawkins et al, J.mol.biol.,1992,226:889-896, each of which is incorporated herein by reference in its entirety.
In the present invention, the term "competition with" or "cross-competition with" when used in the context of two or more antibodies means that two or more antibodies compete for binding to an antigen (e.g., folate receptor α, or FOLR 1). In one exemplary assay, FOLR1 is coated on a plate and allowed to bind to a primary antibody, followed by the addition of a labeled secondary antibody. If the presence of the first antibody reduces the binding of the second antibody, the antibodies compete with each other. In another exemplary assay, a first antibody is coated on a plate and allowed to bind to an antigen, followed by the addition of a second antibody. The term "competition with" also includes combinations of antibodies in which one antibody reduces binding of another antibody, but competition is not observed when the antibodies are added in reverse order. However, in some embodiments, the first and second antibodies inhibit binding to each other regardless of the order of their addition. In some embodiments, one antibody reduces binding of another antibody to its antigen by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.
The term "epitope" means a portion of an antigen capable of specifically binding to an antibody. Epitopes often consist of surface accessible amino acid residues and/or sugar side chains and may have specific three-dimensional structural features as well as specific charge features. Conformational and non-conformational epitopes differ in that the binding to the former is lost in the presence of denaturing solvents, whereas the latter is not. Epitopes can include amino acid residues that are directly involved in binding and other amino acid residues that are not directly involved in binding. The epitope bound by the antibody may be determined using known epitope-determining techniques, such as, for example, testing the antibody for binding to folate receptor alpha (FOLR 1) variants with different point mutations.
The "percent identity" between a polypeptide sequence and a reference sequence is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to amino acid residues in the reference sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for the purpose of determining percent amino acid sequence identity can be accomplished in a variety of ways in the art, for example using computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA or MUSCLE software, available to the public. One skilled in the art can determine the appropriate parameters for the aligned sequences, including any algorithms needed to achieve maximum alignment of the full length of the compared sequences.
"conservative substitutions" or "conservative amino acid substitutions" refer to the substitution of an amino acid with a chemically or functionally similar amino acid. Conservative substitution tables provide similar amino acids well known in the art. Polypeptide sequences having such substitutions are known as "conservatively modified variants". Such conservatively modified variants are the complement of, and do not exclude, polymorphic variants, inter-species homologs, and alleles. For example, the amino acid groups provided in tables 2-4, in some embodiments, are considered conservative substitutions of one another.
TABLE 2 selected groups of amino acids that are considered conservative substitutions for one another in certain embodiments
Acidic residues D and E
Basic residues K. R and H
Hydrophilic uncharged residues S, T, N and Q
Aliphatic uncharged residues G. A, V, L and I
Nonpolar uncharged residues C. M and P
Aromatic residues F. Y and W
Residues containing alcohol groups S and T
Aliphatic residues I. L, V and M
Cycloalkenyl-related residues F. H, W and Y
Hydrophobic residues A. C, F, G, H, I, L, M, R, T, V, W and Y
Negatively charged residues D and E
Polar residues C. D, E, H, K, N, Q, R, S and T
Positively charged residues H. K and R
Small residues A. C, D, G, N, P, S, T and V
Very small residues A. G and S
Residues involved in turn formation A. C, D, E, G, H, K, N, Q, R, S, P and T
Flexible residues Q, T, K, S, G, P, D, E and R
TABLE 3 other selected groups of amino acids that are considered conservative substitutions for one another in certain embodiments
TABLE 4 further selected groups of amino acids that are considered conservative substitutions for one another in certain embodiments
Group A A and G
Group B D and E
Group C N and Q
Group D R, K and H
Group E I、L、M、V
Group F F. Y and W
Group G S and T
H group C and M
Other conservative substitutions are known, for example, from Cright on, proteins: structures and Molecular Properties nd ed. (1993) W.H.Freeman & Co., new York, N.Y.. Antibodies produced by one or more conservative substitutions of amino acid residues in a parent antibody are referred to as "conservatively modified variants".
The term "amino acid" refers to twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), glycine (Gly; G); histidine (His; H), isoleucine (Ile; 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 (Val; V).
Naturally encoded amino acids are proteinogenic amino acids known to those skilled in the art. They include the 20 common amino acids (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine) and the less common pyrrolysine and selenocysteine. Naturally encoded amino acids include posttranslational variants of 22 naturally occurring amino acids, such as prenylated amino acids, myristoylated amino acids, palmitoylated amino acids, N-linked glycosylated amino acids, O-linked glycosylated amino acids, phosphorylated amino acids, and acylated amino acids.
The term "unnatural amino acid" refers to an amino acid that is not a proteinogenic amino acid or a post-translationally modified variant thereof. In particular, the term refers to amino acids that are not one of the 20 common amino acids or pyrrolysine or selenocysteine or post-translationally modified variants thereof.
The term "conjugate" or "antibody conjugate" refers to an antibody that is linked to one or more payload moieties. The antibody may be any antibody described herein. The payload may be any payload according to the present invention. The antibody may be directly attached to the payload by a covalent bond, or the antibody may be indirectly attached to the payload by a linker. Typically, the linker is covalently linked to the antibody, and also to the payload. The term "antibody drug conjugate" or "ADC" refers to a conjugate in which at least one payload is a therapeutic moiety, such as a drug.
The term "payload" or "payload" refers to the portion of a molecular moiety that is conjugated to an antibody. In particular embodiments, the payload is selected from the group consisting of a therapeutic moiety and a labeling moiety.
The term "linker" refers to a moiety of a molecular group capable of forming at least two covalent bonds. Typically, the linker is capable of forming at least one covalent bond with the antibody and at least one other covalent bond with the payload. In certain embodiments, the linker may form more than one covalent bond with the antibody. In certain embodiments, the linker may form more than one covalent bond with the payload, or may form multiple covalent bonds with more than one payload. After the linker forms a bond with the antibody or the payload or both, the remaining structure, i.e., the residue of the linker after formation of one or more covalent bonds, may still be referred to as a "linker" in the present invention. The term "linker precursor" refers to a linker having one or more reactive groups capable of forming covalent bonds with an antibody or a payload or both. In some embodiments, the linker is a cleavable linker. For example, the cleavable linker may be released by a biostable function, which may or may not be engineered. In some embodiments, the linker is a non-cleavable linker. For example, the non-cleavable linker may be a linker that is released after degradation of the antibody.
The terms "pharmaceutical formulation" and "pharmaceutical composition" both refer to a formulation in a form that is capable of exerting a biological activity of the active ingredient and that does not contain additional components that have unacceptable toxicity to the individual to whom the formulation or composition is to be administered. Such formulations or compositions may be sterile.
As used herein, "adjuvant" includes pharmaceutically acceptable excipients, carriers, vehicles, or stabilizers that are non-toxic to the cells or mammals to which they are exposed at the dosages and concentrations employed. In certain embodiments, the physiologically acceptable adjuvant is an aqueous pH buffered solution.
In certain embodiments, "treating" any disease or disorder refers to ameliorating a disease or disorder present in a subject. In another embodiment, "treating" or "treatment" includes improving at least one physical parameter that may not be perceived by the subject. In yet another embodiment, "treating" or "treatment" includes modulating the disease or disorder, whether physical (e.g., stabilization of a perceptible symptom) or physiological (e.g., stabilization of a physiological parameter), or both. In another embodiment, "treating" or "treatment" includes delaying or preventing the onset of the disease or disorder.
The term "therapeutically effective amount" or "effective amount" as used herein refers to an amount of an antibody or composition that is effective to treat a disease or disorder when administered to a subject. In some embodiments, a therapeutically effective amount or effective amount refers to an amount of an antibody or composition that is effective to prevent or ameliorate a disease or disease progression or cause a symptom to be ameliorated when administered to a subject.
The term "inhibit growth" (e.g., referring to a cell, such as a tumor cell) as used herein is intended to include any measurable reduction in cell growth (e.g., tumor cell growth) when contacted with a folate receptor alpha (FOLR 1) antibody as compared to the growth of the same cell not contacted with a FOLR1 antibody. In some embodiments, growth may be inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100%. The reduction in cell growth may occur through a variety of mechanisms including, but not limited to, antibody internalization, apoptosis, necrosis, and/or effector function mediated activity.
The term "subject" or "patient" as used herein refers to a mammalian subject or patient. Exemplary subjects include, but are not limited to, humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, birds, goats, and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has a disease that can be treated or diagnosed with an antibody provided herein. In some embodiments, the subject suffers from a disease that can be treated or diagnosed with an antibody provided herein in combination with an angiogenesis inhibitor (e.g., bevacizumab or bevacizumab anti-biological analog). In some embodiments, the disease is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. In some embodiments, the disease is gastric cancer, colorectal cancer, renal cell carcinoma, cervical cancer, non-small cell lung cancer, ovarian cancer, breast cancer, triple negative breast cancer, endometrial cancer, prostate cancer, and/or cancer of epithelial origin.
In some of the chemical structures shown in the present invention, certain substituents, chemical groups and atoms are represented by curved/wavy lines (e.g.,) Depicted, the curve/wavy line intersects one or more bonds to represent an atom through which the substituent, chemical group, and atom are linked. For example, in certain constructions, such as but not limited toThe curve/wavy line represents the atoms in the backbone of the conjugate or linker-payload structure attached to the chemical entity shown. In some constructions, for example, but not limited to +.>The curve/wavy line represents the atoms in the antibody or antibody fragment attached to the chemical entity shown, and the atoms in the conjugate or linker-payload structural backbone attached to the chemical entity shown.
The term "site-specific" refers to modification of a polypeptide at a predetermined sequence position in the polypeptide. Modifications are at a single predictable residue of a polypeptide with little or no change. In certain embodiments, modified amino acids are introduced at the sequence positions, e.g., by recombination or synthesis. Similarly, a moiety may be "site-specifically" linked to a residue at a particular sequence position in a polypeptide. In certain embodiments, the polypeptide may comprise more than one site-specific modification.
1. Combination/association
The present invention provides anti-FOLRl antibody conjugates for use in combination with a second therapeutic agent that modulates angiogenesis. In certain embodiments, the combination of the anti-FOLR 1 antibody conjugate with the second therapeutic agent results in a significantly increased efficacy against solid tumors in vivo. In certain embodiments, the combination of the anti-FOLR 1 antibody conjugate with the second therapeutic agent results in a significantly increased in vivo anti-hematologic cancer efficacy. The anti-FOLR 1 antibody conjugate may be any anti-FOLR 1 antibody conjugate described herein. In certain embodiments, the second therapeutic agent is a VEGF inhibitor. The invention describes useful VEGF inhibitors.
In general, the anti-FOLR 1 antibody conjugate and the VEGF inhibitor are administered according to their respective dosages and schedules. Thus, in certain embodiments, the anti-FOLR 1 antibody conjugate is administered at dosages and schedules deemed useful by those skilled in the art. In certain embodiments, the VEGF inhibitor is administered at dosages and schedules deemed useful by those skilled in the art. In certain embodiments, the VEGF inhibitor is administered according to the instructions for labeling thereof.
The combination or association may be used to treat or prevent any disease or condition deemed appropriate by the person skilled in the art. In certain embodiments, the patient has cancer. In certain embodiments, the patient has endometrial cancer. In certain embodiments, the patient has ovarian cancer. In certain embodiments, the subject has previously received a cancer treatment. In certain embodiments, the subject has not previously received a cancer treatment. In certain embodiments, the anti-FOLR 1 antibody conjugate may enhance the treatment provided by the VEGF inhibitor. In certain embodiments, the VEGF inhibitor may enhance the treatment provided by the anti-FOLR 1 antibody conjugate. In certain embodiments, the enhancement is synergistic. In certain embodiments, the disease or disorder is any disease or disorder suitable for treatment with the anti-FOLR 1 antibody conjugate. In certain embodiments, the disease or disorder is any disease or disorder suitable for treatment with the VEGF inhibitor. In certain embodiments, the combination is for use in treating cancer. In certain embodiments, the combination is for use in treating a solid tumor. In certain embodiments, the combination is for use in treating ovarian cancer. In certain embodiments, the combination is for treating recurrent ovarian cancer. In certain embodiments, the combination is for treating refractory ovarian cancer. In certain embodiments, the combination is used to treat recurrent/refractory ovarian cancer. The present invention describes useful diseases and conditions.
In certain embodiments, the amount of the anti-FOLR 1 antibody conjugate is therapeutically effective. In certain embodiments, the amount of the VEGF inhibitor is therapeutically effective. In certain embodiments, the amount of the anti-FOLR 1 antibody conjugate is therapeutically effective and the amount of the VEGF inhibitor is therapeutically effective. In certain embodiments, the amount of the anti-FOLR 1 antibody conjugate is sub-therapeutic. In certain embodiments, the amount of the VEGF inhibitor is sub-therapeutic. In certain embodiments, the amount of the anti-FOLR 1 antibody conjugate is sub-therapeutic and the amount of the VEGF inhibitor is sub-therapeutic. In certain sub-therapeutic embodiments, the combination is therapeutic, and one or both components are provided in sub-therapeutic doses.
In some embodiments, the amount of the one or more VEGF-A inhibitors is about 15mg/kg. In some embodiments, the amount of the one or more VEGF-A inhibitors is 15mg/kg.
In some embodiments, the amount of the antibody conjugate is about 3.5mg/kg or more. In some embodiments, the amount of the antibody conjugate is 3.5mg/kg or more. In some embodiments, the amount of the antibody conjugate is about 4.3mg/kg. In some embodiments, the amount of antibody conjugate is 4.3mg/kg. In some embodiments, the amount of the antibody conjugate is about 5.2mg/kg. In some embodiments, the amount of antibody conjugate is 5.2mg/kg.
In some embodiments, the method further comprises administering the antibody conjugate to the subject at a reduced dose. In some embodiments, the reduced dose is about 4.3mg/kg or less. In some embodiments, the reduced dose is 4.3mg/kg or less. In some embodiments, the reduced dose is about 4.3mg/kg. In some embodiments, the reduced dose is 4.3mg/kg. In some embodiments, the reduced dose is about 3.5mg/kg. In some embodiments, the reduced dose is 3.5mg/kg. In some embodiments, the reduced dose is about 2.9mg/kg. In some embodiments, the reduced dose is 2.9mg/kg. In some embodiments, the initial dose of the antibody conjugate is 5.3mg/kg, then subsequently reduced to 4.3mg/kg. The dosage of the antibody conjugate can be further reduced to 3.5mg/kg. In some embodiments, the initial dose of the antibody conjugate is 4.3mg/kg, then subsequently reduced to 3.5mg/kg. The dosage of the antibody conjugate can be further reduced to 2.9mg/kg.
In some embodiments, the antibody conjugate is administered to the subject at a first dose for 1 to 5 cycles prior to the reduced dose, wherein each cycle is about 3 weeks or more. For example, the antibody conjugate may be administered for 1, 2, 3, 4, or 5 cycles. Each cycle may be 3, 4, 5 or 6 weeks. The cycle length may be 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days. The duration of each cycle may be the same or different. In some embodiments, each cycle is about 3 to 5 weeks. In some embodiments, each cycle is 3-5 weeks. In some embodiments, each cycle is about 3-4 weeks. In some embodiments, each cycle is 3-4 weeks. In some embodiments, the antibody conjugate is administered to the subject at a first dose for 1 to 5 cycles prior to the reduced dose, wherein each cycle is 3 weeks or more. In some embodiments, the antibody conjugate is administered to the subject at a first dose for 1 to 5 cycles prior to the reduced dose, wherein each cycle is 3 weeks to 5 weeks. In some embodiments, the antibody conjugate is administered to the subject in a first dose for 1 to 3 cycles prior to the reduced dose, wherein each cycle is about 3 weeks or more. In some embodiments, the antibody conjugate is administered to the subject at a first dose for 1 to 3 cycles prior to the reduced dose, wherein each cycle is 3 weeks to 4 weeks. In some embodiments, the antibody conjugate is administered to the subject at a first dose for 2 to 4 cycles prior to the reduced dose, wherein each cycle is about 3 weeks or more. In some embodiments, the antibody conjugate is administered to the subject at a first dose for 2 to 4 cycles prior to the reduced dose, wherein each cycle is 3 weeks to 4 weeks. In certain embodiments, the clinician or practitioner will adjust the cycle length. In certain embodiments, the clinician or therapist will switch from the first dose to a reduced dose as described herein. Furthermore, it is worth noting that the clinician or treating physician will know how and when to interrupt, adjust or terminate the treatment in conjunction with the subject's response. For example, a clinician or treating physician may further adjust the dosage level in conjunction with side effects from the subject being treated or the underlying disease the subject is receiving treatment.
In certain embodiments, the anti-FOLR 1 antibody conjugate and the additional therapeutic agent are administered sequentially in either order. As used herein, the terms "sequentially," "serially," and "sequentially" refer to administration of an anti-FOLR 1 antibody conjugate after administration of an additional therapeutic agent, or administration of the additional therapeutic agent after administration of the anti-FOLR 1 antibody conjugate. For example, sequential administration may include administration of the anti-FOLR 1 antibody conjugate in the absence of the additional therapeutic agent during an induction period (first treatment), followed by a post-induction treatment period comprising administration of the additional therapeutic agent. The method may further comprise a maintenance phase comprising administering the anti-FOLR 1 antibody conjugate or the additional therapeutic agent, or both the anti-FOLR 1 antibody conjugate and the additional therapeutic agent. Alternatively, sequential administration may include administration of the additional therapeutic agent in the absence of the anti-FOLR 1 antibody conjugate during an induction period (first treatment), followed by a post-induction treatment period comprising administration of the anti-FOLR 1 antibody conjugate. The method may further comprise a maintenance phase comprising administering the anti-FOLR 1 antibody conjugate or the additional therapeutic agent, or both the anti-FOLR 1 antibody conjugate and the additional therapeutic agent.
In some embodiments, the administration is by Intravenous (IV) administration. In some embodiments, the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered separately on the same day. In some embodiments, the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered simultaneously on the same day. In some embodiments, the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered about once every 3 weeks or more for the remainder of the treatment. In some embodiments, the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered about once every 3 weeks. In some embodiments, the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered about once every 4 weeks.
In certain embodiments, the anti-FOLR 1 antibody conjugate and the additional therapeutic agent are administered simultaneously. As used herein, the terms "simultaneously," "concomitantly" and "concurrently" refer to administration of an anti-FOLR 1 antibody conjugate and an additional therapeutic agent during the same doctor's visit or during the same treatment session. For example, the anti-FOLR 1 antibody conjugate and the additional therapeutic agent may be administered during one or more of the induction period, the treatment period, and the maintenance period. However, simultaneous administration does not require that the anti-FOLR 1 antibody conjugate and the additional therapeutic agent be present together in a single formulation or pharmaceutical composition, or that the anti-FOLR 1 antibody conjugate and the additional therapeutic agent be administered at exactly the same time.
In certain embodiments, the combinations provided herein can be administered directly to an individual to modulate the immune response of the individual, treat a disease or disorder (e.g., cancer and/or abnormal cell proliferation) in the individual, and/or inhibit the FOLRl activity and/or VEGF activity in the individual.
In certain embodiments, the invention provides a method of treating cancer responsive to inhibition of FOLR1 activity, the method comprising administering to an individual an effective amount of a combination provided herein to treat the cancer responsive to inhibition of FOLR1 activity. In certain embodiments, the cancer is ovarian cancer, such as one of the cancers described herein.
In certain embodiments, the invention provides a method of treating cancer that is not responsive to inhibition of FOLR1 activity alone, the method comprising administering to the subject an effective amount of a combination provided herein to treat the cancer that is not responsive to inhibition of FOLR1 activity alone. In certain embodiments, the cancer is ovarian cancer, such as one of the cancers described herein.
In certain embodiments, the invention provides a method of treating cancer responsive to inhibition of VEGF activity, the method comprising administering to an individual an effective amount of a combination provided herein to treat the cancer responsive to inhibition of VEGF activity. In certain embodiments, the cancer is ovarian cancer, such as one of the cancers described herein.
In certain embodiments, the invention provides a method of treating cancer that is not responsive to inhibition of VEGF activity alone, the method comprising administering to the individual an effective amount of a combination provided herein to treat the cancer that is not responsive to inhibition of VEGF activity alone. In certain embodiments, the cancer is ovarian cancer, such as one of the cancers described herein.
In certain embodiments, the invention provides a method of inhibiting abnormal cell proliferation (e.g., hyperplasia) comprising administering to an individual an effective amount of a combination provided herein to inhibit abnormal cell proliferation in the individual.
In certain embodiments, the invention provides a method of inhibiting FOLR1 activity, the method comprising administering to an individual an effective amount of a combination provided herein, to inhibit FOLR1 activity in the individual.
In certain embodiments, the invention provides a method of inhibiting VEGF activity, the method comprising administering to an individual an effective amount of a combination provided herein, to inhibit VEGF activity in the individual.
In certain embodiments, the invention provides a method of inhibiting FOLR1 activity and VEGF activity, the method comprising administering to an individual an effective amount of a combination provided herein, to inhibit FOLR1 activity and VEGF activity in the individual.
In certain embodiments, for example, in modulating an immune response in an individual in need thereof (e.g., an individual having a T cell dysfunction disorder), treating a disease or disorder in an individual (e.g., an individual having cancer and/or abnormal cell proliferation), and/or inhibiting FOLRl or VEGF activity in an individual, the appropriate dosage of the active agent will depend on the disorder, type of disease or condition to be treated (as defined above), the severity and course of the disorder, disease or condition, whether the drug is administered for prophylactic or therapeutic purposes, past treatment, the subject's clinical history and response to an FOLR1 antibody conjugate or VEGF inhibitor, and the discretion of the attending physician.
The anti-FOLR 1 antibody conjugate or composition thereof is suitably administered to the subject in one or a series of treatments. In certain embodiments, the treatment comprises multiple administrations of the anti-FOLR 1 antibody conjugate or composition, wherein the interval between administrations may vary. For example, the interval between the first administration and the second administration is about one month, and the interval between subsequent administrations is about three months. In certain embodiments, the anti-FOLR 1 antibody conjugate is administered in a fixed dose. In certain embodiments, the anti-FOLR 1 antibody conjugates of the invention are administered to an individual in a fixed dose based on the weight of the individual (e.g., mg/kg).
The VEGF inhibitor or a composition thereof is suitably administered to the subject in one or a series of treatments. In certain embodiments, the treatment comprises multiple administrations of the VEGF inhibitor or composition, wherein the interval between administrations can vary. For example, the interval between the first administration and the second administration is about one month, and the interval between subsequent administrations is about three months. In certain embodiments, the VEGF inhibitor is administered in a fixed dose. In certain embodiments, the VEGF inhibitor is administered to the subject in a fixed dose based on the subject's weight (e.g., mg/kg).
In certain embodiments of the invention, the cancer is a solid tumor. For example, the cancer may be ovarian cancer, ovarian carcinoma (ovarian carcinoma), ovarian cancer, endometrial cancer, endometrioid adenocarcinoma, fallopian tube cancer, or primary peritoneal cancer. In certain embodiments, the cancer is recurrent ovarian cancer. In certain embodiments, the cancer is refractory ovarian cancer. In certain embodiments, the cancer is recurrent/refractory ovarian cancer.
In certain embodiments, the effectiveness of the combination in a method of the invention (e.g., a method of modulating an immune response in an individual) can be assessed by determining the biological activity of cancer cells present in a sample isolated from the subject.
In certain embodiments, the invention provides compositions and therapeutic formulations comprising any of the antibody conjugates provided herein in combination with one or more VEGF inhibitors, as well as methods of treatment comprising administering such combinations to a subject in need thereof. In some embodiments, the one or more VEGF inhibitors comprise antibodies that inhibit VEGF activity. In some embodiments, the one or more VEGF inhibitors are selected from bevacizumabAnd bevacizumab anti-biological analogues. In some embodiments, the bevacizumab anti-biosimilar drug is selected from the group consisting of: MVASI (ABP 215, amgen), zirabev (Pfizer), bevax (BEVZ 92, mAb xi ce), lumiere (Elea), apotex (Apobiologix), equidacent (FKB 238, astraZeneca/Centus Biotherapeutics), avega (BCD-021, biocad), BP 01 (Aurobundo Pharma), BCD500 (BIOCND), krabeva (Biocon), BAT1706 (Bio-thermal Solutions), BXT-2316 (BioXpress Therapeutics), bevaro (Cadila Pharmaceuticals), 695502 (Boehringer Ingelheim), CT-P16 (Celltrion), CHS-5217 (Coheres), DRZ_BZ (Dr Reddy's Laboratories), cimab (Hetero/Lu), byvasda (IBI 305, innovent Biologics), MIL60 (Mabworks), MYL 1402 (ONOCND), ONS-1045 (Octoics/Virol 204), QHD (QX 67), and Hupex (Hupex) and (Hupex) are included in the formula (FIGS. 1, zirabev (Pfizer), 5452, flex (Flex), and Flex (Hupex) as well as pillow (UK).
2. Conjugates
In the combination, the anti-FOLR 1 antibody conjugate may be any anti-FOLR 1 antibody conjugate provided herein. The conjugate comprises an antibody directed against FOLR1 covalently linked to a payload directly or indirectly via a linker. In certain embodiments, the antibody is linked to a payload. In further embodiments, the antibody is linked to more than one payload. In certain embodiments, the antibody is linked to 2, 3, 4, 5, 6, 7, 8 or more payloads. In certain embodiments, the anti-FOLR 1 antibody conjugate is an anti-FOLR 1 antibody conjugate described in U.S. patent No. 10,596,270, the contents of which are incorporated herein by reference.
In certain embodiments, the anti-FOLR 1 antibody conjugate has a structure represented by general formula conjugate P described herein, wherein the antibody is 1848-H01 coupled via the azidomethylphenylalanine residues at heavy chain positions Y180 and F404. In certain embodiments, the antibody of the anti-FOLR 1 antibody conjugate comprises a heavy chain of SEQ ID NO:362 and three heavy and light chain CDRs of SEQ ID NO: 367. In certain embodiments, the antibody to the FOLR1 antibody conjugate comprises SEQ ID NO: 58. SEQ ID NO: 176. and SEQ ID NO:294 and the light chain SEQ ID NO: 367. In certain embodiments, the antibody to the FOLR1 antibody conjugate comprises SEQ ID NO: 117. SEQ ID NO: 235. and SEQ ID NO:294 and the light chain SEQ ID NO: 367. In certain embodiments, the antibody of the anti-FOLR 1 antibody conjugate comprises a heavy chain of SEQ ID NO: v of 362 H Region and light chain SEQ ID NO: 367V L A zone. In certain embodiments, the antibody of the anti-FOLR 1 antibody conjugate comprises a heavy chain of SEQ ID NO:362 and light chain SEQ ID NO:367. in each of these embodiments, the antibody may comprise mutations Y180 and F404 for azidomethylphenylalanine.
The payload may be any payload that the skilled person deems useful. In certain embodiments, the payload is a therapeutic moiety. In certain embodiments, the payload is a diagnostic moiety, such as a tag. Useful payloads are described in the following sections and examples.
The linker may be any linker capable of forming at least one bond with the antibody and at least one bond with the payload. Useful connectors are described in the following sections and examples.
In the conjugates provided herein, the antibody may be any antibody having binding specificity for folate receptor alpha (FOLR 1 or folra). FOLR1 may be from any species. In certain embodiments, FOLR1 is a vertebrate FOLR1. In certain embodiments, FOLR1 is mammalian FOLR1. In certain embodiments, FOLR1 is human FOLR1. In certain embodiments, FOLR1 is mouse FOLR1. In certain embodiments, FOLR1 is cynomolgus FOLR1.
In certain embodiments, antibodies directed against folate receptor alpha (FOLR 1 or folra) compete for binding with antibodies of the invention. In certain embodiments, the antibodies directed against FOLR1 bind to the same epitope as the antibodies described herein.
Antibodies are typically proteins comprising multiple polypeptide chains. In certain embodiments, the antibody is a hetero-tetramer comprising two identical light (L) chains and two identical heavy (H) chains. Each light chain may be linked to the heavy chain by a covalent disulfide bond. Each heavy chain may be linked to another heavy chain by one or more covalent disulfide bonds. Each heavy chain and each light chain may also have one or more intrachain disulfide bonds. As known to those skilled in the art, each heavy chain typically comprises a variable domain (V H ) Then a plurality of constant domains. Each light chain typically comprises a variable domain at one end (V L ) Comprising a constant domain. As known to those skilled in the art, antibodies typically have selective affinity for their target molecule, i.e., antigen.
The antibodies provided herein may have any antibody format known to those skilled in the art. They may be full length or may be fragments. Exemplary full length antibodies include IgA, igA1, igA2, igD, igE, igG, igG1, igG2, igG3, igG4, igM, and the like. Exemplary fragments include Fv, fab, fc, scFv, scFv-Fc and the like.
In certain embodiments, the antibody of the conjugate comprises 1, 2, 3, 4, 5, or 6 CDR sequences of the invention. In certain embodiments, the antibody of the conjugate comprises a heavy chain variable domain (V H ). In certain embodiments, the antibody of the conjugate comprises a light chain variable domain (V L ). In certain embodiments, the conjugate comprises an antibody packageComprising a heavy chain variable domain according to the invention (V H ) And the light chain variable domain (V L ). In certain embodiments, the antibody of the conjugate comprises a pair of heavy chain variable domain and light chain variable domain according to the invention (V H -V L For (2).
In certain embodiments, the antibody of the conjugate comprises any of the amino acid sequences of the antibodies described above. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 10 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 9 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 8 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 7 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 6 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 5 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 4 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 3 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 2 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 1 amino acid substitution. In some embodiments, the amino acid substitutions are all conservative amino acid substitutions. For example, in certain embodiments, the antibody comprises any of the above amino acid sequences having up to 10 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 9 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 8 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 7 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 6 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 5 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 4 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 3 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 2 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences having up to 1 conservative amino acid substitutions.
In certain embodiments, the antibody conjugates can be formed from antibodies comprising one or more reactive groups. In certain embodiments, the antibody conjugate may be formed from an antibody comprising all naturally encoded amino acids. Those skilled in the art will recognize that several naturally encoded amino acids include reactive groups that can be coupled to a payload or to a linker. These reactive groups include cysteine side chains, lysine side chains, and amino end groups. In these embodiments, the antibody conjugate may comprise a payload or linker attached to a residue of an antibody-reactive group. In these embodiments, the payload precursor or linker precursor comprises a reactive group capable of forming a bond with an antibody reactive group. Typical reactive groups include maleimide groups, activated carbonates (including but not limited to p-nitrophenyl esters), activated esters (including but not limited to N-hydroxysuccinimide, p-nitrophenyl esters, and aldehydes). Particularly useful reactive groups include maleimides and succinimides, such as N-hydroxysuccinimide, which are used to form bonds to cysteine and lysine side chains. Other reactive groups are described in the following sections and examples.
In a further embodiment, the antibody comprises one or more modified amino acids having reactive groups, as described herein. Typically, the modified amino acid is not a naturally encoded amino acid. These modified amino acids may comprise a reactive group for forming a covalent bond with a linker precursor or a payload precursor. The skilled artisan can use reactive groups to attach the polypeptide to any molecular entity capable of forming a covalent bond with a modified amino acid. Accordingly, the present invention provides conjugates comprising an antibody comprising a modified amino acid residue linked directly or indirectly via a linker to a payload. Exemplary modified amino acids are described in the following sections. Typically, the modified amino acid has a reactive group capable of forming a bond with a linker or payload having a complementary reactive group.
Unnatural amino acids are located at selected positions in the polypeptide chain of an antibody. These positions are identified as the optimal sites for providing unnatural amino acid substitutions. Each site can carry unnatural amino acids with optimal structure, function, and/or methods of producing antibodies.
In certain embodiments, the site-specific positions for substitution provide stable antibodies. Stability may be determined by any technique apparent to one skilled in the art.
In certain embodiments, the site-specific positions for substitution provide antibodies with optimal functional properties. For example, there is little or no loss of binding affinity of the antibody to its target antigen as compared to an antibody without the site-specific unnatural amino acid. In certain embodiments, the antibodies may exhibit enhanced binding compared to antibodies without site-specific unnatural amino acids.
In certain embodiments, the site-specific positions for substitution provide antibodies that can be advantageously made. For example, in certain embodiments, antibodies exhibit advantageous properties in their methods of synthesis, as described below. In certain embodiments, the antibodies have little or no loss in production yield as compared to antibodies without site-specific unnatural amino acids. In certain embodiments, the antibodies may exhibit improved production yields as compared to antibodies without site-specific unnatural amino acids. In certain embodiments, the antibodies can exhibit little or no loss of tRNA inhibition compared to antibodies without site-specific unnatural amino acids. In certain embodiments, the antibody may exhibit enhanced tRNA suppression in production as compared to an antibody that does not have a site-specific unnatural amino acid.
In certain embodiments, the site-specific positions for substitution provide antibodies with favorable solubility. In certain embodiments, the solubility of the antibody is little or no loss as compared to an antibody that does not have a site-specific unnatural amino acid. In certain embodiments, the antibodies may exhibit enhanced solubility as compared to antibodies without site-specific unnatural amino acids.
In certain embodiments, the site-specific positions for substitution provide antibodies with advantageous expression. In certain embodiments, the antibodies may exhibit little or no loss of expression compared to antibodies without site-specific unnatural amino acids. In certain embodiments, the antibodies may exhibit enhanced expression compared to antibodies without site-specific unnatural amino acids.
In certain embodiments, the site-specific positions for substitution provide antibodies with favorable foldability. In certain embodiments, the antibodies have little or no loss in proper folding compared to antibodies without site-specific unnatural amino acids. In certain embodiments, the antibodies may exhibit enhanced foldability as compared to antibodies without site-specific unnatural amino acids.
In certain embodiments, the site-specific positions for substitution provide antibodies that can be advantageously coupled. As described below, several unnatural amino acids have side chains or functional groups that can facilitate the coupling of antibodies to a second drug, either directly or indirectly via a linker. In certain embodiments, the antibodies may exhibit enhanced coupling efficiency as compared to antibodies that do not have the same or other unnatural amino acids at other positions. In certain embodiments, the antibodies may exhibit enhanced conjugation yields as compared to antibodies that do not have the same or other unnatural amino acids at other positions. In certain embodiments, the antibodies may exhibit enhanced coupling specificity as compared to antibodies that do not have the same or other unnatural amino acids at other positions.
One or more unnatural amino acids are located at selected site-specific positions in at least one polypeptide chain of the antibody. The polypeptide chain may be any polypeptide chain of an antibody, including, without limitation, a light chain or a heavy chain. The site-specific position may be in any domain of the antibody, including any variable domain and any constant domain.
In certain embodiments, the antibodies provided herein comprise an unnatural amino acid at a site-specific position. In certain embodiments, the antibodies provided herein comprise two unnatural amino acids at a site-specific position. In certain embodiments, the antibodies provided herein comprise three unnatural amino acids at a site-specific position. In certain embodiments, the antibodies provided herein comprise more than three unnatural amino acids at a site-specific position.
In certain embodiments, the antibodies provided herein comprise one or more unnatural amino acid, each of which is located at a position selected from the group consisting of a heavy chain residue or a light chain residue: HC-F404, HC-K121, HC-Y180, HC-F241, HC-221, LC-T22, LC-S7, LC-N152, LC-K42, LC-E161, LC-D170, HC-S136, HC-S25, HC-A40, HC-S119, HC-S190, HC-K222, HC-R19, HC-Y52, or HC-S70 according to the Kabat (Kabat) or Chothia (Chothia) or EU numbering scheme, or post-translational modified variants thereof. In these designations, HC represents heavy chain residues, and LC represents light chain residues. In certain embodiments, the antibody comprises one or more unnatural amino acid at a site selected from the group consisting of: HC-F404, HC-Y180, and LC-K42 according to the kappa (Kabat), ke Xiya (Chothia) or EU numbering schemes. In certain embodiments, the antibody comprises an unnatural amino acid at position HC-F404. In certain embodiments, the antibody comprises an unnatural amino acid at position HC-F404. In certain embodiments, the antibody comprises unnatural amino acids at positions HC-F404 and HC-Y180. In certain embodiments, the residues of the one or more unnatural amino acids are linked to the payload moiety via a hydrolytically stable linker. In certain embodiments, the residues of the one or more unnatural amino acids are linked to the payload moiety via a cleavable linker.
In certain embodiments, the one or more unnatural amino acids are selected from the group consisting of: p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, L-3- (2-naphthyl) alanine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, tri-O-acetyl-GlcNAcP-serine, L-Dopa (Dopa), fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-methyl-L-phenylalanine, compound 56, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, L-phosphoserine, phosphonoserine (phosphoserine), phosphonotyrosine (phosphotyrosine), p-iodo-phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, and p-propargyloxy-phenylalanine. In certain embodiments, the unnatural amino acid residue is a residue of compound (30) or compound (56).
In a particular embodiment, the invention provides an anti-FOLR 1 conjugate represented by any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid represented by formula (30) below. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate as shown in any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid as shown in formula (30) below, which is located at heavy chain position 404 according to the EU numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate as shown in any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid as shown in formula (30) below, which is located at heavy chain position 180 according to the EU numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate as shown in any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid as shown in formula (30) below, which is located at heavy chain position 241 according to the EU numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate as shown in any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid as shown in formula (30) below, which is located at heavy chain position 222 according to the EU numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate according to any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid according to formula (30) below, which is located at light chain position 7 according to the kappa (Kabat) or coxia (Chothia) numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate according to any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid according to formula (30) below, which is located at light chain position 42 according to the kappa (Kabat) or coxia (Chothia) numbering system. In certain embodiments, the PAY is selected from the group consisting of: maytansine (maytansine), hamiltin (hemiasterlin), amanitin (amanitin), monomethyl auristatin F (MMAF), and monomethyl auristatin E (MMAE). In certain embodiments, the PAY is maytansine (maytansine). In certain embodiments, the PAY is hamiltin (hemiasterlin). In certain embodiments, the PAY is amanitin (amanitin). In certain embodiments, the PAY is MMAF. In certain embodiments, the PAY is MMAE.
In a particular embodiment, the invention provides an anti-FOLR 1 conjugate represented by any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid represented by formula (56) below. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate as shown in any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid as shown in formula (56) below, which is located at heavy chain position 404 according to the EU numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate as shown in any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid shown in formula (56) below, which is located at heavy chain position 180 according to the EU numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate as shown in any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid as shown in formula (56) below, which is located at heavy chain position 241 according to the EU numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate as shown in any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid as shown in formula (56) below, which is located at heavy chain position 222 according to the EU numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate according to any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid according to formula (56) below, which is located at light chain position 7 according to the kappa (Kabat) or coxia (Chothia) numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate according to any one of formulas 101a to 104b, wherein COMP represents a residue of an unnatural amino acid according to formula (56) below, which is located at light chain position 42 according to the kappa (Kabat) or coxia (Chothia) numbering system. In certain embodiments, the PAY is selected from the group consisting of: maytansine (maytansine), hamiltin (hemiasterlin), amanitin (amanitin), MMAF, and MMAE. In certain embodiments, the PAY is maytansine (maytansine). In certain embodiments, the PAY is hamiltin (hemiasterlin). In certain embodiments, the PAY is amanitin (amanitin). In certain embodiments, the PAY is MMAF. In certain embodiments, the PAY is MMAE.
In a particular embodiment, the invention provides an anti-FOLR 1 conjugate according to any one of formulas 101a to 104b, wherein COMP represents an unnatural amino acid residue to azido-L-phenylalanine. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate according to any one of formulas 101a to 104b, wherein COMP represents an unnatural amino acid residue for azido-L-phenylalanine at heavy chain position 404 according to the EU numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate according to any one of formulas 101a to 104b, wherein COMP represents an unnatural amino acid residue for azido-L-phenylalanine at heavy chain position 180 according to the EU numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate according to any one of formulas 101a to 104b, wherein COMP represents an unnatural amino acid residue for azido-L-phenylalanine at heavy chain position 241 according to the EU numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate according to any one of formulas 101a to 104b, wherein COMP represents an unnatural amino acid residue for azido-L-phenylalanine at heavy chain position 222 according to the EU numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate according to any one of formulas 101a to 104b, wherein COMP represents an unnatural amino acid residue of para-azido-L-phenylalanine at light chain position 7 according to the kappa (Kabat) or coxia (Chothia) numbering system. In a particular embodiment, the invention provides an anti-FOLR 1 conjugate according to any one of formulas 101a to 104b, wherein COMP represents an unnatural amino acid residue of para-azido-L-phenylalanine at light chain position 42 according to the kappa (Kabat) or coxia (Chothia) numbering system. In certain embodiments, the PAY is selected from the group consisting of: maytansine (maytansine), hamiltin (hemiasterlin), amanitin (amanitin), MMAF, and MMAE. In certain embodiments, the PAY is maytansine (maytansine). In certain embodiments, the PAY is hamiltin (hemiasterlin). In certain embodiments, the PAY is amanitin (amanitin). In certain embodiments, the PAY is MMAF. In certain embodiments, the PAY is MMAE.
In certain embodiments, the at least one payload group moiety is selected from the group consisting of: maytansinoids (maytansines), hamiltines (hemiasterlins), amanits (amanitins), and auristatins (auristatins). In certain embodiments, the at least one payload group moiety is selected from the group consisting of: DM1, hammeterlin (hemiasterlin), amatoxins (amanitin), MMAF, and MMAE. In certain embodiments, the at least one payload moiety is a hamiltin (hemiasterlin) derivative. In certain embodiments, the at least one payload group moiety is:
wherein the method comprises the steps ofAr is optionally substituted aryl or optionally substituted heteroaryl, L is a linker, and the wavy line represents a bond to the antibody. In certain embodiments, the at least one payload group moiety is:
wherein L is a linker and the wavy line represents a bond to the antibody.
In some embodiments, the invention provides anti-FOLR 1 conjugates comprising modified hamiltin (hemiasterlin) and a linker, for example as described in PCT publication No. WO 2016/123582. For example, as described in PCT publication number WO 2016/123582, the conjugates may have a structure comprising any of formulas 1000-1000b, 1001-1001b, 1002-1002b, and I-XIXb-2, 101-111b, or 1-8 b. Examples of conjugates comprising modified hamiltin (hemiasterlin) and a linker are provided below.
In some embodiments, the invention provides anti-FOLR 1 conjugates having the structure shown by conjugate M:
wherein n is an integer from 1 to 6. In some embodiments, n is an integer from 1 to 4. In some embodiments, n is 2. For example, in some embodiments, the anti-FOLR 1 conjugate has the following structure:
in some embodiments, n is 4. For example, in some embodiments, the anti-FOLR 1 conjugate has the following structure:
in some embodiments, the invention provides anti-FOLR 1 conjugates having the structure shown by conjugate P:
wherein n is an integer from 1 to 6. In some embodiments, n is an integer from 1 to 4. In some embodiments, n is 2. For example, in some embodiments, the anti-FOLR 1 conjugate has the following structure:
in some embodiments, n is 4. For example, in some embodiments, the anti-FOLR 1 conjugate has the following structure:
in some embodiments, the invention provides anti-FOLR 1 conjugates having the structure shown by conjugate Q:
wherein n is an integer from 1 to 6. In some embodiments, n is an integer from 1 to 4. In some embodiments, n is 2. For example, in some embodiments, the anti-FOLR 1 conjugate has the following structure:
In some embodiments, n is 4. For example, in some embodiments, the anti-FOLR 1 conjugate has the following structure:
in any of the above embodiments, wherein the anti-FOLR 1 conjugate has a structure as shown in conjugate M, conjugate P, or conjugate Q, the bracketed structure is covalently linked to one or more unnatural amino acids of the antibody, wherein the one or more unnatural amino acids are located at a site selected from the group consisting of: HC-F404, HC-Y180, and LC-K42 according to the EP numbering scheme of Kabat or Kabat. In some embodiments, the bracketed structure is covalently linked to one or more unnatural amino acids located at the antibody's site HC-F404. In some embodiments, the bracketed structure is covalently linked to one or more unnatural amino acids located at the antibody's site HC-Y180. In some embodiments, the bracketed structure is covalently linked to one or more unnatural amino acids located at the site LC-K42 of the antibody. In some embodiments, the bracketed structure is covalently linked to one or more unnatural amino acids located at sites HC-F404 and HC-Y180 of the antibody. In some embodiments, at least one bracketed structure is covalently linked to an unnatural amino acid located at position HC-F404 of the antibody, and at least one bracketed structure is covalently linked to an unnatural amino acid located at position HC-Y180 of the antibody. In some embodiments, the bracketed structure is covalently linked to one or more unnatural amino acids located at sites HC-Y180 and LC-K42 of the antibody. In some embodiments, at least one bracketed structure is covalently linked to an unnatural amino acid located at position HC-Y180 of the antibody, and at least one bracketed structure is covalently linked to an unnatural amino acid located at position LC-K32 of the antibody.
5. Antibody specificity
The conjugate comprises an antibody that selectively binds human folate receptor alpha. In some aspects, the antibody selectively binds to the extracellular domain of human folate receptor alpha (human FOLR 1).
In some embodiments, the antibody binds to a homolog of human FOLR 1. In some aspects, the antibody binds to a homolog of human FOLR1 of a species selected from the group consisting of monkey, mouse, canine, feline, rat, bovine, equine, caprine, and ovine. In some aspects, the homolog is a cynomolgus monkey homolog. In some aspects, the homolog is a mouse or murine analog.
In some embodiments, the antibody comprises at least one CDR sequence defined by the consensus sequences provided herein. In some embodiments, the antibodies comprise exemplary CDRs, V provided in the invention H Or V L A sequence or variant thereof. In some aspects, the variant is a variant having a conservative amino acid substitution.
In some embodiments, the antibody has one or more CDRs of a particular length in terms of the number of amino acid residues. In some embodiments, the Ke Xiya (Chothia) CDR-H1 of the antibody is 6, 7 or 8 residues in length. In some embodiments, the antibody has a kappa (Kabat) CDR-H1 length of 4, 5, or 6 residues. In some embodiments, the Ke Xiya (Chothia) CDR-H2 of the antibody is 5, 6 or 7 residues in length. In some embodiments, the antibody has a kappa (Kabat) CDR-H2 length of 16, 17 or 18 residues. In some embodiments, the antibody has a kappa (Kabat)/Ke Xiya (Chothia) CDR-H3 length of 13, 14, 15, 16, or 17 residues.
In some aspects, the antibody has a kappa (Kabat)/Ke Xiya (Chothia) CDR-L1 length of 11, 12, 13, 14, 15, 16, 17, or 18 residues. In some aspects, the antibody has a kappa (Kabat)/Ke Xiya (Chothia) CDR-L2 length of 6, 7, or 8 residues. In some aspects, the antibody has a kappa (Kabat)/Ke Xiya (Chothia) CDR-L3 length of 8, 9, or 10 residues.
In some embodiments, the antibody comprises a light chain. In some aspects, the light chain is a kappa light chain. In some aspects, the light chain is a lambda light chain.
In some embodiments, the antibody comprises a heavy chain. In some aspects, the heavy chain is IgA. In some aspects, the heavy chain is IgD. In some aspects, the heavy chain is IgE. In some aspects, the heavy chain is IgG. In some aspects, the heavy chain is IgM. In some aspects, the heavy chain is IgG1. In some aspects, the heavy chain is IgG2. In some aspects, the heavy chain is IgG3. In some aspects, the heavy chain is IgG4. In some aspects, the heavy chain is IgA1. In some aspects, the heavy chain is IgA2.
In some embodiments, the antibody is an antibody fragment. In some aspects, the antibody fragment is an Fv fragment. In some aspects, the antibody fragment is a Fab fragment. In some aspects, the antibody fragment is F (ab') 2 Fragments. In some aspects, the antibody fragment is a Fab' fragment. In some aspects, the antibody fragment is an scFv (sFv) fragment. In some aspects, the antibody fragment is an scFv-Fc fragment.
In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody.
In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody.
In some embodiments, the antibody is an affinity matured antibody. In some aspects, the antibody is an affinity matured antibody derived from the exemplary sequences provided herein.
The antibodies provided herein are useful for treating a variety of diseases and conditions, including cancer. In some embodiments, the antibodies provided herein can be used to treat cancer of a solid tumor. For example, the antibodies provided herein can be used to treat colorectal cancer.
In certain embodiments, the antibody comprises: v provided by the invention H Region and V provided by the invention L Three heavy chain CDRs and three light chain CDRs of a region. In certain embodiments, the V H The region is selected from: SEQ ID NO:308 to SEQ ID NO:366. in certain embodiments, the V L The region is selected from: SEQ ID NO:367 to SEQ ID NO:369. in a particular embodiment, the V H The region is according to SEQ ID NO:362, and the V L Region 367 is according to SEQ ID NO. CDR sequences can be obtained by conventional techniques well known to those skilled in the artAnd (5) identification. In certain embodiments, the CDRs are identified according to a Kabat (Kabat) number. In certain embodiments, the CDRs are identified according to Ke Xiya (Chothia) numbering. In certain embodiments, the CDRs are identified according to Martin numbers. In certain embodiments, the CDRs are identified according to an AHo number. In certain embodiments, the CDRs are identified according to IMGT numbers. Tools for identifying CDR sequences are available, for example, in abysis. Org, swindells et al 2017, J.mol. Biol. 429:356-364.
5.1 CDR-H3 sequences
In some embodiments, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: exemplary antibodies or V provided herein H CDR-H3 sequence of the sequence. In some aspects, the CDR-H3 sequence is SEQ ID NO:308 to SEQ ID NO: v provided in 366 H CDR-H3 sequence of the sequence.
In some embodiments, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: selected from SEQ ID NOs: 240 to SEQ ID NO:298. In some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:240. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:241. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:242. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:243. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:244. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:245. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:246. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:247. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:248. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:249. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:250. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:251. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:252. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:253. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:254. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:255. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:256. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:257. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:258. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:259. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:260. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:261. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:262. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:263. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:264. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:265. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:266. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:267. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:268. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:269. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:270. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:271. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:272. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:273. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:274. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:275. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:276. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:277. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:278. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:279. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:280. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:281. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:282. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:283. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:284. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:285. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:286. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:287. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:288. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:289. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:290. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:291. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:292. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:293. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:294. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:295. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:296. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:297. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-H3 sequences that comprise: SEQ ID NO:298.
In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-H3 sequences provided herein. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary CDR-H3 sequences provided herein. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-H3 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
5.2V containing exemplary CDRs H Sequence(s)
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of one or more CDR-H sequences comprising: one or more exemplary CDR-H sequences provided herein, and variants thereof. In some embodiments, the CDR-H sequence comprises, consists of, or consists essentially of: in a sequence selected from the group consisting of SEQ ID NOs: 308 to SEQ ID NO: v of 366 H One or more CDR-H sequences provided in the sequence.
5.2.1. V comprising exemplary kappa (Kabat) CDRs H Sequence(s)
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of one or more kappa (Kabat) CDR-H sequences comprising: one or more exemplary kappa CDR-H sequences provided herein, and variants thereof.
5.2.1.1. Carba (Kabat) CDR-H3
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises a CDR-H3 sequence, wherein the CDR-H3 sequence comprises, consists of, or consists essentially of: exemplary antibodies or V provided herein H The kappa (Kabat) CDR-H3 sequence of the sequence. In some aspects, the kappa (Kabat) CDR-H3 sequence is SEQ ID noNO:308 to SEQ ID NO: v provided in 366 H The kappa (Kabat) CDR-H3 sequence of the sequence.
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: selected from SEQ ID NOs: 240 to SEQ ID NO: 298. In some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:240. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:241. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:242. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:243. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:244. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:245. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:246. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a kappa CDR-H3 sequence comprising the followingA column, consisting of, or consisting essentially of: SEQ ID NO:247. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:248. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:249. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:250. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:251. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:252. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:253. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:254. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:255. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:256. in some aspectsIn which the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:257. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:258. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:259. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:260. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:261. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:262. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:263. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:264. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:265. in some aspects, the antibody comprises V H A sequence of V H Sequences comprising kappa CDRs-an H3 sequence, said kappa CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:266. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:267. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:268. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:269. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:270. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:271. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:272. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:273. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:274. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising The column composition: SEQ ID NO:275. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:276. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:277. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:278. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:279. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:280. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:281. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:282. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:283. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:284. in some aspects, the antibody comprises V H Sequence(s)The V is H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:285. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:286. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:287. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:288. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:289. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:290. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:291. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:292. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:293. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a kappa CDR-H3 sequence comprising the followingA column, consisting of, or consisting essentially of: SEQ ID NO:294. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:295. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:296. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:297. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence comprising: SEQ ID NO:298.
5.2.1.2. Carba (Kabat) CDR-H2
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises a CDR-H2 sequence, wherein the CDR-H2 sequence comprises, consists of, or consists essentially of: exemplary antibodies or V provided herein H The kappa (Kabat) CDR-H2 sequence of the sequence. In some aspects, the kappa (Kabat) CDR-H2 sequence is SEQ ID NO:308 to SEQ ID NO: v provided in 366 H The kappa (Kabat) CDR-H2 sequence of the sequence.
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: selected from SEQ ID NOs: 181 to SEQ ID NO: 239. In some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:181. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:182. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:183. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:184. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:185. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:186. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:187. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:188. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:189. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:190. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a kappa CDR-H2 sequence comprising, consisting ofThe following composition, or consisting essentially of: SEQ ID NO:191. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:192. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:193. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:194. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:195. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:196. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:197. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:198. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:199. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:200. in some aspects, a subject is The antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:201. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:202. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:203. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:204. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:205. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:206. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:207. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:208. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:209. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a kappa CDR-H2 sequenceThe kappa CDR-H2 sequence comprises, consists of, or consists essentially of: SEQ ID NO:210. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:211. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:212. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:213. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:214. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:215. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:216. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:217. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:218. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:219. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:220. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:221. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:222. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:223. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:224. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:225. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:226. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:227. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:228. in some aspects, the antibody comprises V H A sequence of, saidV H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:229. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:230. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:231. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:232. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:233. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:234. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:235. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:236. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:237. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a kappa CDR-H2 sequence comprising, consisting ofThe following composition, or consisting essentially of: SEQ ID NO:238. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H2 sequence comprising: SEQ ID NO:239.
5.2.1.3. carba (Kabat) CDR-H1
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises a CDR-H1 sequence, wherein the CDR-H1 sequence comprises, consists of, or consists essentially of: exemplary antibodies or V provided herein H The kappa (Kabat) CDR-H1 sequence of the sequence. In some aspects, the kappa (Kabat) CDR-H1 sequence is SEQ ID NO:308 to SEQ ID NO: v provided in 366 H The kappa (Kabat) CDR-H1 sequence of the sequence.
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: selected from SEQ ID NOs: 63 to SEQ ID NO: 121. In some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:63. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:64. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:65. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:66. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:67. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:68. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:69. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:70. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:71. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:72. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:73. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:74. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:75. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a kappa CDR-H1 sequence comprising, consisting of, or consisting essentially ofThe upper part is composed of the following components: SEQ ID NO:76. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:77. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:78. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:79. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:80. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:81. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:82. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:83. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:84. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:85. in some aspects, the antibody comprises V H Sequence(s)The V is H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:86. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:87. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:88. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:89. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:90. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:91. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:92. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:93. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:94. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a kappa CDR-H1 sequence comprising, consisting ofThe following composition, or consisting essentially of: SEQ ID NO:95. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:96. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:97. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:98. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:99. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:100. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:101. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:102. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:103. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:104. in some aspects, the anti-cancer agentThe body contains V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:105. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:106. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:107. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:108. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:109. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:110. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:111. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:112. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:113. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a kappa CDR-H1 sequence, anThe kappa CDR-H1 sequence comprises, consists of, or consists essentially of: SEQ ID NO:114. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:115. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:116. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:117. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:118. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:119. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:120. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence comprising: SEQ ID NO:121.
5.2.1.4. Kaba (Kabat) CDR-H3+ Kabat (Kabat) CDR-H2
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence and a kappa CDR-H2 sequence, the kappa CDR-H3 sequence comprising: selected from SEQ ID NOs: 240 to SEQ ID NO:298, said kappa CDR-H2 sequence comprisingThe following, consisting of, or consisting essentially of: selected from SEQ ID NOs: 181 to SEQ ID NO: 239. In some aspects, the kappa CDR-H3 sequence and the kappa CDR-H2 sequence are both from a single exemplary V provided herein H Sequence. For example, in some aspects, the kappa CDR-H3 and kappa CDR-H2 are both from a sequence selected from the group consisting of SEQ ID NOs: 308 to SEQ ID NO: single exemplary V of 366 H Sequence.
5.2.1.5. Kaba (Kabat) CDR-H3+ Kabat (Kabat) CDR-H1
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H3 sequence and a kappa CDR-H1 sequence, the kappa CDR-H3 sequence comprising: selected from SEQ ID NOs: 240 to SEQ ID NO:298, said kappa CDR-H1 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 63 to SEQ ID NO: 121. In some aspects, the kappa CDR-H3 sequence and the kappa CDR-H1 sequence are both from a single exemplary V provided herein H Sequence. For example, in some aspects, both the kappa CDR-H3 and kappa CDR-H1 are from a polypeptide selected from the group consisting of SEQ ID NOs: 308 to SEQ ID NO: single exemplary V of 366 H Sequence.
5.2.1.6. Kaba (Kabat) CDR-H1+ Kabat (Kabat) CDR-H2
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises a kappa CDR-H1 sequence and a kappa CDR-H2 sequence, said kappa CDR-H1 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 63 to SEQ ID NO:121, said kappa CDR-H2 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 181 to SEQ ID NO: 239. In some aspects, the kappa CDR-H1 sequence and the kappa CDR-H2 sequence are both from a single exemplary V provided herein H Sequence. For example, in some aspects, the kappa CDR-H1 and kappa CDR-H2 are both from a sequence selected from the group consisting of SEQ ID NOs: 308 to SEQ ID NO: single exemplary V of 366 H Sequence.
5.2.1.7. Kaba (Kabat) CDR-H1+ Kabat (Kabat) CDR-H2+ Kabat (Kabat) CDR-H3
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of a kappa CDR-H1 sequence, a kappa CDR-H2 sequence, and a kappa CDR-H3 sequence, the kappa CDR-H1 sequence comprising, consisting of, or consisting of: selected from SEQ ID NOs: 63 to SEQ ID NO:121, said kappa CDR-H2 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 181 to SEQ ID NO:239 comprising, consisting of, or consisting essentially of the following: selected from SEQ ID NOs: 240 to SEQ ID NO: 298. In some aspects, the kappa CDR-H1 sequence, the kappa CDR-H2 sequence and the kappa CDR-H3 sequence are all from a single exemplary V provided herein H Sequence. For example, in some aspects, the kappa CDR-H1, kappa CDR-H2, and kappa CDR-H3 are all from a sequence selected from the group consisting of SEQ ID NOs: 308 to SEQ ID NO: single exemplary V of 366 H Sequence.
5.2.1.8. V comprising exemplary kappa (Kabat) CDRs H Variants of the sequence
In some embodiments, the invention provides V H Sequences comprise variants of exemplary kappa (Kabat) CDR-H3, CDR-H2, and/or CDR-H1 sequences provided herein.
In some aspects, the kappa CDR-H3 sequence comprises, consists of, or consists essentially of: variants of the exemplary kappa CDR-H3 sequences provided by the present invention. In some aspects, the kappa CDR-H3 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90%, or 95% identity to any of the exemplary kappa CDR-H3 sequences provided herein. In some aspects, the kappa CDR-H3 sequence comprises, consists of, or consists essentially of: any of the exemplary kappa CDR-H3 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the kappa CDR-H2 sequence comprises, consists of, or consists essentially of: variants of the exemplary kappa CDR-H2 sequences provided by the present invention. In some aspects, the kappa CDR-H2 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90%, or 95% identity to any of the exemplary kappa CDR-H2 sequences provided herein. In some aspects, the kappa CDR-H2 sequence comprises, consists of, or consists essentially of: any of the exemplary kappa CDR-H2 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the kappa CDR-H1 sequence comprises, consists of, or consists essentially of: variants of the exemplary kappa CDR-H1 sequences provided herein. In some aspects, the kappa CDR-H1 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90%, or 95% identity to any of the exemplary kappa CDR-H1 sequences provided herein. In some aspects, the kappa CDR-H1 sequence comprises, consists of, or consists essentially of: any of the exemplary kappa CDR-H1 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
5.2.2. V comprising exemplary Ke Xiya (Chothia) CDRs H Sequence(s)
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of one or more cauchy (Chothia) CDR-H sequences comprising: one or more exemplary Ke Xiya (Chothia) CDR-H sequences, and variants thereof, provided herein.
5.2.2.1. Ke Xiya (Chothia) CDR-H3
In some embodiments, the antibody packageContaining V H A sequence of V H The sequence comprises a CDR-H3 sequence, wherein the CDR-H3 sequence comprises, consists of, or consists essentially of: exemplary antibodies or V provided herein H Ke Xiya (Chothia) CDR-H3 sequences of the sequence. In some aspects, the Ke Xiya (Chothia) CDR-H3 sequence is SEQ ID NO:308 to SEQ ID NO: v provided in 366 H Ke Xiya (Chothia) CDR-H3 sequences of the sequence.
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 240 to SEQ ID NO: 298. In some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:240. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:241. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:242. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:243. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:244. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises Ke Xiya (Chothia) CDR-H3, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:245. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:246. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:247. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:248. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:249. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:250. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:251. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:252. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ (SEQ)ID NO:253. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:254. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:255. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:256. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:257. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:258. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:259. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:260. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:261. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises cauchyA sub (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:262. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:263. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:264. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:265. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:266. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:267. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:268. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:269. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially ofThe column composition: SEQ ID NO:270. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:271. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:272. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:273. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:274. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:275. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:276. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:277. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:278. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:279. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:280. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:281. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:282. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:283. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:284. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:285. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:286. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of,Or consist essentially of: SEQ ID NO:287. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:288. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:289. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:290. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:291. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:292. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:293. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:294. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:295. in some aspects, the antibody comprises V H Sequence of, aThe V is H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:296. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:297. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:298.
5.2.2.2. ke Xiya (Chothia) CDR-H2
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises a CDR-H2 sequence, wherein the CDR-H2 sequence comprises, consists of, or consists essentially of: exemplary antibodies or V provided herein H Ke Xiya (Chothia) CDR-H2 sequences of the sequence. In some aspects, the Ke Xiya (Chothia) CDR-H2 sequence is SEQ ID NO:308 to SEQ ID NO: v provided in 366 H Ke Xiya (Chothia) CDR-H2 sequences of the sequence.
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 122 to SEQ ID NO: 180. In some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:122. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:123. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:124. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:125. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:126. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:127. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:128. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:129. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:130. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:131. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises the Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDRThe H2 sequence comprises, consists of, or consists essentially of: SEQ ID NO:132. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:133. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:134. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:135. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:136. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:137. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:138. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:139. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:140. in some aspects, a subject isThe antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:141. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:142. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:143. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:144. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:145. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:146. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:147. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:148. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises the Ke Xiya (Chothia) CDR-H2 sequence, the cauchy sequenceThe sub (Chothia) CDR-H2 sequence comprises, consists of, or consists essentially of: SEQ ID NO:149. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:150. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:151. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:152. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:153. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:154. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:155. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:156. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:157. in some casesIn one aspect, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:158. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:159. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:160. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:161. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:162. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:163. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:164. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:165. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises the Ke Xiya (Chothia) CDR-H2 sequenceThe Ke Xiya (Chothia) CDR-H2 sequence comprises, consists of, or consists essentially of: SEQ ID NO:166. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:167. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:168. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:169. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:170. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:171. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:172. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:173. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO: 174. In some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:175. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:176. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:177. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:178. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:179. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:180.
5.2.2.3. ke Xiya (Chothia) CDR-H1
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises a CDR-H1 sequence, wherein the CDR-H1 sequence comprises, consists of, or consists essentially of: exemplary antibodies or V provided herein H Ke Xiya (Chothia) CDR-H1 sequence of the sequence. In some aspects, the Ke Xiya (Chothia) CDR-H1 sequence is SEQ ID NO:308 to SEQ ID NO: v provided in 366 H Ke Xiya (Chothia) CDR-H1 sequence of the sequence.
In one placeIn some embodiments, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 4 to SEQ ID NO: 62. In some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:4. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:5. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:6. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:7. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:8. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:9. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:10. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises cauchyA sub (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:11. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:12. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:13. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:14. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:15. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:16. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:17. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:18. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of The method comprises the following steps: SEQ ID NO:19. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:20. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:21. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:22. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:23. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:24. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:25. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:26. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:27. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises cauchyA sub (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:28. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:29. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:30. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:31. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:32. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:33. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:34. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:35. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially ofThe method comprises the following steps: SEQ ID NO:36. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:37. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:38. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:39. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:40. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:41. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:42. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:43. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:44. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises cauchyA sub (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:45. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:46. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:47. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:48. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:49. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:50. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:51. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:52. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially ofThe method comprises the following steps: SEQ ID NO:53. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:54. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:55. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:56. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:57. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:58. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:59. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:60. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:61. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises cauchyA sub (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:62.
5.2.2.4. ke Xiya (Chothia) CDR-H3+ Ke Xiya (Chothia) CDR-H2
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence and a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 240 to SEQ ID NO:298, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 122 to SEQ ID NO: 180. In some aspects, the Ke Xiya (Chothia) CDR-H3 sequence and the Ke Xiya (Chothia) CDR-H2 sequence are both from a single exemplary V provided herein H Sequence. For example, in some aspects, both the Ke Xiya (Chothia) CDR-H3 and Ke Xiya (Chothia) CDR-H2 are from a sequence selected from SEQ ID NOs: 308 to SEQ ID NO: single exemplary V of 366 H Sequence.
5.2.2.5. Ke Xiya (Chothia) CDR-H3+ Ke Xiya (Chothia) CDR-H1
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H3 sequence and a Ke Xiya (Chothia) CDR-H1 sequence, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 240 to SEQ ID NO:298, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 4 to SEQ ID NO: 62. In some aspects, the Ke Xiya (Chothia) CDR-H3 sequence and the Ke Xiya (Chothia) CDR-H1 sequence are both from a single exemplary V provided herein H Sequence. For example, in some aspects, both the Ke Xiya (Chothia) CDR-H3 and Ke Xiya (Chothia) CDR-H1 are from a sequence selected from SEQ ID NOs: 308 to SEQ ID NO: single exemplary V of 366 H Sequence.
5.2.2.6. Ke Xiya (Chothia) CDR-H1+ Ke Xiya (Chothia) CDR-H2
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises a Ke Xiya (Chothia) CDR-H1 sequence and a Ke Xiya (Chothia) CDR-H2 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 4 to SEQ ID NO:62, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 122 to SEQ ID NO: 180. In some aspects, the Ke Xiya (Chothia) CDR-H1 sequence and the Ke Xiya (Chothia) CDR-H2 sequence are both from a single exemplary V provided herein H Sequence. For example, in some aspects, both the Ke Xiya (Chothia) CDR-H1 and Ke Xiya (Chothia) CDR-H2 are from a sequence selected from SEQ ID NOs: 308 to SEQ ID NO: single exemplary V of 366 H Sequence.
5.2.2.7. Ke Xiya (Chothia) CDR-H1+ Ke Xiya (Chothia) CDR-H2+ Ke Xiya (Chothia) CDR-H3
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises Ke Xiya (Chothia) CDR-H1 sequence, ke Xiya (Chothia) CDR-H2 sequence and Ke Xiya (Chothia) CDR-H3 sequence, said Ke Xiya (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 4 to SEQ ID NO:62, said Ke Xiya (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 122 to SEQ ID NO:180, said Ke Xiya (Chothia) CDR-H3 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 240 to SEQ ID NO: 298. In some aspects, the Ke Xiya (Chothia) CDR-H1 sequence, ke Xiya (Chothia) CDR-H2 sequence and Ke Xiya (Chothia) CDR-H3 sequence are all from a single exemplary V provided by the present invention H Sequence. For example, in some aspects, the Ke Xiya (Chothia) CDR-H1, ke Xiya (Chothia) CDR-H2, and Ke Xiya (Chothia) CDR-H3 are all from a sequence selected from SEQ ID NOs: 308 to SEQ ID NO:366 single unitExemplary V H Sequence.
5.2.2.8. V comprising exemplary Ke Xiya (Chothia) CDRs H Variants of the sequence
In some embodiments, the invention provides V H The sequences comprise variants of the exemplary Ke Xiya (Chothia) CDR-H3, CDR-H2, and/or CDR-H1 sequences provided herein.
In some aspects, the Ke Xiya (Chothia) CDR-H3 sequence comprises, consists of, or consists essentially of: the present invention provides variants of the exemplary Ke Xiya (Chothia) CDR-H3 sequences. In some aspects, the Ke Xiya (Chothia) CDR-H3 sequence comprises, consists of, or consists essentially of: a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity to any of the exemplary Ke Xiya (Chothia) CDR-H3 sequences provided herein. In some aspects, the Ke Xiya (Chothia) CDR-H3 sequence comprises, consists of, or consists essentially of: any of the exemplary Ke Xiya (Chothia) CDR-H3 sequences provided herein have 1, 2 or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the Ke Xiya (Chothia) CDR-H2 sequence comprises, consists of, or consists essentially of: the present invention provides variants of the exemplary Ke Xiya (Chothia) CDR-H2 sequences. In some aspects, the Ke Xiya (Chothia) CDR-H2 sequence comprises, consists of, or consists essentially of: a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity to any of the exemplary Ke Xiya (Chothia) CDR-H2 sequences provided herein. In some aspects, the Ke Xiya (Chothia) CDR-H2 sequence comprises, consists of, or consists essentially of: any of the exemplary Ke Xiya (Chothia) CDR-H2 sequences provided herein have 1, 2 or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the Ke Xiya (Chothia) CDR-H1 sequence comprises, consists of, or consists essentially of: the present invention provides variants of the exemplary Ke Xiya (Chothia) CDR-H1 sequences. In some aspects, the Ke Xiya (Chothia) CDR-H1 sequence comprises, consists of, or consists essentially of: a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity to any exemplary Ke Xiya (Chothia) CDR-H1 sequence provided herein. In some aspects, the Ke Xiya (Chothia) CDR-H1 sequence comprises, consists of, or consists essentially of: any of the exemplary Ke Xiya (Chothia) CDR-H1 sequences provided herein have 1, 2 or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
5.3.V H Sequence(s)
In some embodiments, the antibody comprises, consists of, or consists essentially of: SEQ ID NO:308 to SEQ ID NO: v provided in 366 H Sequence.
In some embodiments, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: selected from SEQ ID NOs: 308 to SEQ ID NO:366, a sequence of seq id no. In some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:308. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:309. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:310. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:311. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:312. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:313. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:314. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:315. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:316. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:317. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:318. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:319. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:320. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:321. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:322. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:323. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:324. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises the following groupsAnd consists essentially of: SEQ ID NO:325. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:326. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:327. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:328. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:329. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:330. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:331. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:332. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:333. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:334. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:335. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:336. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:337. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:338. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:339. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:340. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:341. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:342. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:343. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:344. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:345. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:346. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:347. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:348. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:349. in some aspects, the antibody packageContaining V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:350. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:351. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:352. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:353. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:354. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:355. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:356. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:357. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:358. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:359. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:360. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:361. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:362. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:363. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:364. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:365. in some aspects, the antibody comprises V H A sequence of V H The sequence comprises, consists of, or consists essentially of: SEQ ID NO:366.
5.3.1.V H variants of the sequence
In some embodiments, the invention provides V H The sequence comprises, consists of, or consists essentially of: exemplary V provided by the invention H Variants of the sequences.
In some aspects, the V H The sequence comprises, consists of, or consists essentially of: exemplary V provided by the invention H Variants of the sequences. In some aspects, the V H The sequence comprises, consists of, or consists essentially of: any of the exemplary V provided with the present invention H Sequences have at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5% identity.
In some embodiments, the V H The sequence comprises, consists of, or consists essentially of: any of the exemplary V provided herein with 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions H Sequence. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
CDR-L3 sequences
In some embodiments, the antibody comprises, consists of, or consists essentially of CDR-L3 sequences that comprise: exemplary antibodies or V provided herein L CDR-L3 sequence of the sequence. In some aspects, the CDR-L3 sequence is SEQ ID NO:367 to SEQ ID NO: 369V provided in L CDR-L3 sequence of the sequence.
In some embodiments, the antibody comprises, consists of, or consists essentially of CDR-L3 sequences that comprise: selected from SEQ ID NOs: 305 to SEQ ID NO:307. In some aspects, the antibody comprises, consists of, or consists essentially of CDR-L3 sequences that comprise: SEQ ID NO:305. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-L3 sequences that comprise: SEQ ID NO:306. in some aspects, the antibody comprises, consists of, or consists essentially of CDR-L3 sequences that comprise: SEQ ID NO:307.
In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-L3 sequences provided herein. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary CDR-L3 sequences provided herein. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-L3 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
5.5. VL sequences comprising exemplary CDRs
In some embodiments, the antibody comprises V L A sequence of V L The sequence comprises, consists of, or consists essentially of one or more CDR-L sequences comprising: one or more exemplary CDR-L sequences provided herein, and variants thereof.
5.5.1.CDR-L3
In some embodiments, the antibody comprises V L A sequence of V L The sequence comprises a CDR-L3 sequence, wherein the CDR-L3 sequence comprises, consists of, or consists essentially of: exemplary antibodies or V provided herein L CDR-L3 sequence of the sequence. In some aspects, the CDR-L3 sequence is SEQ ID NO:367 to SEQ ID NO: 369V provided in L CDR-L3 sequence of the sequence.
In some embodiments, the antibody comprises V L A sequence of V L A sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence comprising: selected from SEQ ID NOs: 305 to SEQ ID NO:307. In some aspects, the antibody comprises V L A sequence of V L A sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence comprising: SEQ ID NO:305. in some aspects, the antibody comprises V L A sequence of V L A sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence comprising: SEQ ID NO:306. in some aspects, the antibody comprises V L A sequence of V L A sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence comprising: SEQ ID NO:307.
5.5.2.CDR-L2
in some embodiments, the antibody comprises V L A sequence of V L The sequence comprises a CDR-L2 sequence, wherein the CDR-L2 sequence comprises, consists of, or consists essentially of: exemplary antibodies or V provided herein L CDR-L2 sequences of the sequences. In some aspects, the CDR-L2 sequence is SEQ ID NO:367 to SEQ ID NO: 369V provided in L CDR-L2 sequences of sequencesColumns.
In some embodiments, the antibody comprises V L A sequence of V L The sequence comprises, consists of, or consists essentially of a CDR-L2 sequence comprising: selected from SEQ ID NOs: 302 to SEQ ID NO:304. In some aspects, the antibody comprises V L A sequence of V L The sequence comprises, consists of, or consists essentially of a CDR-L2 sequence comprising: SEQ ID NO:302. in some aspects, the antibody comprises V L A sequence of V L The sequence comprises, consists of, or consists essentially of a CDR-L2 sequence comprising: SEQ ID NO:303. in some aspects, the antibody comprises V L A sequence of V L The sequence comprises, consists of, or consists essentially of a CDR-L2 sequence comprising: SEQ ID NO:304.
5.5.3.CDR-L1
in some embodiments, the antibody comprises V L A sequence of V L The sequence comprises a CDR-L1 sequence, wherein the CDR-L1 sequence comprises, consists of, or consists essentially of: exemplary antibodies or V provided herein L CDR-L1 sequences of the sequences. In some aspects, the CDR-L1 sequence is SEQ ID NO:367 to SEQ ID NO: 369V provided in L CDR-L1 sequences of the sequences.
In some embodiments, the antibody comprises V L A sequence of V L A sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence comprising: selected from SEQ ID NOs: 299 to SEQ ID NO:301. In some aspects, the antibody comprises V L A sequence of V L A sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence comprising: SEQ ID NO:299. in some aspects, the antibody comprises V L A sequence of V L A sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence comprising:SEQ ID NO:300. in some aspects, the antibody comprises V L A sequence of V L A sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence comprising: SEQ ID NO:301.
5.5.4.CDR-L3+CDR-L2
in some embodiments, the antibody comprises V L A sequence of V L The sequences comprise, consist of, or consist essentially of a CDR-L3 sequence and a CDR-L2 sequence, the CDR-L3 sequence comprising: selected from SEQ ID NOs: 305 to SEQ ID NO:307, said CDR-L2 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 302 to SEQ ID NO: 304. In some aspects, the CDR-L3 sequences and the CDR-L2 sequences are both from a single exemplary V provided herein L Sequence. For example, in some aspects, both the CDR-L3 and CDR-L2 are from a sequence selected from SEQ ID NOs: 367 to SEQ ID NO:369 single exemplary V L Sequence.
5.5.5.CDR-L3+CDR-L1
In some embodiments, the antibody comprises V L A sequence of V L The sequences comprise, consist of, or consist essentially of a CDR-L3 sequence and a CDR-L1 sequence, the CDR-L3 sequence comprising: selected from SEQ ID NOs: 305 to SEQ ID NO:307, said CDR-L1 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 299 to SEQ ID NO: 301. In some aspects, the CDR-L3 sequences and the CDR-L1 sequences are both from a single exemplary V provided herein L Sequence. For example, in some aspects, both the CDR-L3 and CDR-L1 are from a sequence selected from SEQ ID NOs: 367 to SEQ ID NO:369 single exemplary V L Sequence.
5.5.6.CDR-L1+CDR-L2
In some embodiments, the antibody comprises V L A sequence of V L The sequence comprises, consists of, or consists essentially of a CDR-L1 sequence and a CDR-L2 sequence, the CDR-L1 sequence comprising: selected from SEQ ID NOs: 299 to SEQ ID NO:301, said CDR-L2 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 302 to SEQ ID NO: 304. In some aspects, the CDR-L1 sequences and the CDR-L2 sequences are both from a single exemplary V provided herein L Sequence. For example, in some aspects, both the CDR-L1 and CDR-L2 are from a sequence selected from SEQ ID NOs: 367 to SEQ ID NO:369 single exemplary V L Sequence.
5.5.7.CDR-L1+CDR-L2+CDR-L3
In some embodiments, the antibody comprises V L A sequence of V L The sequences comprise, consist, or consist essentially of a CDR-L1 sequence, a CDR-L2 sequence, and a CDR-L3 sequence, the CDR-L1 sequence comprising, consisting of, or consisting of: selected from SEQ ID NOs: 299 to SEQ ID NO:301, said CDR-L2 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 302 to SEQ ID NO:304, said CDR-L3 sequence comprising, consisting of, or consisting essentially of: selected from SEQ ID NOs: 305 to SEQ ID NO: 307. In some aspects, the CDR-L1, CDR-L2 and CDR-L3 sequences are all from a single exemplary V provided by the present invention L Sequence. For example, in some aspects, the CDR-L1, CDR-L2 and CDR-L3 are all from a polypeptide selected from the group consisting of SEQ ID NOs: 367 to SEQ ID NO:369 single exemplary V L Sequence.
5.5.8. V comprising exemplary CDR-L L Variants of the sequence
In some embodiments, the invention provides V L Sequences include variants of the exemplary CDR-L3, CDR-L2, and/or CDR-L1 sequences provided herein.
In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-L3 sequences provided herein. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90%, or 95% identity to any of the exemplary CDR-L3 sequences provided herein. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-L3 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-L2 sequences provided herein. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90%, or 95% identity to any of the exemplary CDR-L2 sequences provided herein. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-L2 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-L1 sequences provided herein. In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90%, or 95% identity to any of the exemplary CDR-L1 sequences provided herein. In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-L1 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
5.6.V L Sequence(s)
In some embodiments, the antibody comprises, consists of, or consists essentially of: SEQ ID NO:367 to SEQ ID NO: 369V provided in L Sequence.
In some embodiments, the antibody comprises V L A sequence of V L The sequence comprises, consists of, or consists essentially of: selected from SEQ ID NOs: 367 to SEQ ID NO: 369. In some aspects, the antibody comprises V L A sequence of V L The sequence comprises, consists of, or consists essentially of: SEQ ID NO:367. in some aspects, the antibody comprises V L A sequence of V L The sequence comprises, consists of, or consists essentially of: SEQ ID NO:368. in some aspects, the antibody comprises V L A sequence of V L The sequence comprises, consists of, or consists essentially of: SEQ ID NO:369.
5.6.1.V L variants of the sequence
In some embodiments, the invention provides V L The sequence comprises, consists of, or consists essentially of: exemplary V provided by the invention L Variants of the sequences.
In some aspects, the V L The sequence comprises, consists of, or consists essentially of: exemplary V provided by the invention L Variants of the sequences. In some aspects, the V L The sequence comprises, consists of, or consists essentially of: any of the exemplary V provided with the present invention L Sequences have at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5% identity.
In some embodiments, the V L The sequence comprises, consists of, or consists essentially of: any of the exemplary V provided herein with 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions L Sequence. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
5.7. Paired pairs of
CDR-H3-CDR-L3 pairs
In some embodiments, the antibody comprises a CDR-H3 sequence and a CDR-L3 sequence. In some aspects, the CDR-H3 sequence is V H And the CDR-L3 sequence is V L Is a part of the same.
In some aspects, the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:240 to SEQ ID NO:298, and said CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:305 to SEQ ID NO:307.
in some aspects, the CDR-H3-CDR-L3 pair is selected from the group consisting of: SEQ ID NO:305 and SEQ ID NO:240, a step of; SEQ ID NO:305 and SEQ ID NO:241, a base; SEQ ID NO:305 and SEQ ID NO:242; SEQ ID NO:305 and SEQ ID NO:243; SEQ ID NO:305 and SEQ ID NO:244; SEQ ID NO:305 and SEQ ID NO:245; SEQ ID NO:305 and SEQ ID NO: 246. SEQ ID NO:305 and SEQ ID NO:247, respectively; SEQ ID NO:305 and SEQ ID NO:248; SEQ ID NO:305 and SEQ ID NO:249; SEQ ID NO:305 and SEQ ID NO:250; SEQ ID NO:305 and SEQ ID NO:251; SEQ ID NO:305 and SEQ ID NO: 252. SEQ ID NO:305 and SEQ ID NO:253; SEQ ID NO:305 and SEQ ID NO:254, a base plate; SEQ ID NO:305 and SEQ ID NO:255, respectively; SEQ ID NO:305 and SEQ ID NO:256; SEQ ID NO:305 and SEQ ID NO:257; SEQ ID NO:305 and SEQ ID NO:258; SEQ ID NO:305 and SEQ ID NO:259; SEQ ID NO:305 and SEQ ID NO:260; SEQ ID NO:305 and SEQ ID NO:261; SEQ ID NO:305 and SEQ ID NO:262; SEQ ID NO:305 and SEQ ID NO:263; SEQ ID NO:305 and SEQ ID NO:264; SEQ ID NO:305 and SEQ ID NO:265; SEQ ID NO:305 and SEQ ID NO:266; SEQ ID NO:305 and SEQ ID NO:267; SEQ ID NO:305 and SEQ ID NO:268, a step of; SEQ ID NO:305 and SEQ ID NO:269; SEQ ID NO:305 and SEQ ID NO:270; SEQ ID NO:305 and SEQ ID NO: 271(s); SEQ ID NO:305 and SEQ ID NO:272; SEQ ID NO:305 and SEQ ID NO:273; SEQ ID NO:305 and SEQ ID NO:274; SEQ ID NO:305 and SEQ ID NO:275; SEQ ID NO:305 and SEQ ID NO:276, respectively; SEQ ID NO:305 and SEQ ID NO:277; SEQ ID NO:305 and SEQ ID NO:278; SEQ ID NO:305 and SEQ ID NO:279; SEQ ID NO:305 and SEQ ID NO:280; SEQ ID NO:305 and SEQ ID NO: 281. SEQ ID NO:305 and SEQ ID NO:282; SEQ ID NO:305 and SEQ ID NO:283; SEQ ID NO:305 and SEQ ID NO:284; SEQ ID NO:305 and SEQ ID NO:285; SEQ ID NO:305 and SEQ ID NO:286; SEQ ID NO:305 and SEQ ID NO:287; SEQ ID NO:305 and SEQ ID NO:288; SEQ ID NO:305 and SEQ ID NO:289; SEQ ID NO:305 and SEQ ID NO:290; SEQ ID NO:305 and SEQ ID NO:291 of a metal strip; SEQ ID NO:305 and SEQ ID NO:292; SEQ ID NO:305 and SEQ ID NO:293; SEQ ID NO:305 and SEQ ID NO:294; SEQ ID NO:305 and SEQ ID NO:295; SEQ ID NO:305 and SEQ ID NO:296; SEQ ID NO:305 and SEQ ID NO:297; and SEQ ID NO:305 and SEQ ID NO:298.
In some aspects, the CDR-H3-CDR-L3 pair is selected from the group consisting of: SEQ ID NO:306 and SEQ ID NO:240, a step of; SEQ ID NO:306 and SEQ ID NO:241, a base; SEQ ID NO:306 and SEQ ID NO:242; SEQ ID NO:306 and SEQ ID NO:243; SEQ ID NO:306 and SEQ ID NO:244; SEQ ID NO:306 and SEQ ID NO:245; SEQ ID NO:306 and SEQ ID NO: 246. SEQ ID NO:306 and SEQ ID NO:247, respectively; SEQ ID NO:306 and SEQ ID NO:248; SEQ ID NO:306 and SEQ ID NO:249; SEQ ID NO:306 and SEQ ID NO:250; SEQ ID NO:306 and SEQ ID NO:251; SEQ ID NO:306 and SEQ ID NO: 252. SEQ ID NO:306 and SEQ ID NO:253; SEQ ID NO:306 and SEQ ID NO:254, a base plate; SEQ ID NO:306 and SEQ ID NO:255, respectively; SEQ ID NO:306 and SEQ ID NO:256; SEQ ID NO:306 and SEQ ID NO:257; SEQ ID NO:306 and SEQ ID NO:258; SEQ ID NO:306 and SEQ ID NO:259; SEQ ID NO:306 and SEQ ID NO:260; SEQ ID NO:306 and SEQ ID NO:261; SEQ ID NO:306 and SEQ ID NO:262; SEQ ID NO:306 and SEQ ID NO:263; SEQ ID NO:306 and SEQ ID NO:264; SEQ ID NO:306 and SEQ ID NO:265; SEQ ID NO:306 and SEQ ID NO:266; SEQ ID NO:306 and SEQ ID NO:267; SEQ ID NO:306 and SEQ ID NO:268, a step of; SEQ ID NO:306 and SEQ ID NO:269; SEQ ID NO:306 and SEQ ID NO:270; SEQ ID NO:306 and SEQ ID NO: 271(s); SEQ ID NO:306 and SEQ ID NO:272; SEQ ID NO:306 and SEQ ID NO:273; SEQ ID NO:306 and SEQ ID NO:274; SEQ ID NO:306 and SEQ ID NO:275; SEQ ID NO:306 and SEQ ID NO:276, respectively; SEQ ID NO:306 and SEQ ID NO:277; SEQ ID NO:306 and SEQ ID NO:278; SEQ ID NO:306 and SEQ ID NO:279; SEQ ID NO:306 and SEQ ID NO:280; SEQ ID NO:306 and SEQ ID NO: 281. SEQ ID NO:306 and SEQ ID NO:282; SEQ ID NO:306 and SEQ ID NO:283; SEQ ID NO:306 and SEQ ID NO:284; SEQ ID NO:306 and SEQ ID NO:285; SEQ ID NO:306 and SEQ ID NO:286; SEQ ID NO:306 and SEQ ID NO:287; SEQ ID NO:306 and SEQ ID NO:288; SEQ ID NO:306 and SEQ ID NO:289; SEQ ID NO:306 and SEQ ID NO:290; SEQ ID NO:306 and SEQ ID NO:291 of a metal strip; SEQ ID NO:306 and SEQ ID NO:292; SEQ ID NO:306 and SEQ ID NO:293; SEQ ID NO:306 and SEQ ID NO:294; SEQ ID NO:306 and SEQ ID NO:295; SEQ ID NO:306 and SEQ ID NO:296; SEQ ID NO:306 and SEQ ID NO:297; and SEQ ID NO:306 and SEQ ID NO:298.
In some aspects, the CDR-H3-CDR-L3 pair is selected from the group consisting of: SEQ ID NO:307 and SEQ ID NO:240, a step of; SEQ ID NO:307 and SEQ ID NO:241, a base; SEQ ID NO:307 and SEQ ID NO:242; SEQ ID NO:307 and SEQ ID NO:243; SEQ ID NO:307 and SEQ ID NO:244; SEQ ID NO:307 and SEQ ID NO:245; SEQ ID NO:307 and SEQ ID NO: 246. SEQ ID NO:307 and SEQ ID NO:247, respectively; SEQ ID NO:307 and SEQ ID NO:248; SEQ ID NO:307 and SEQ ID NO:249; SEQ ID NO:307 and SEQ ID NO:250; SEQ ID NO:307 and SEQ ID NO:251; SEQ ID NO:307 and SEQ ID NO: 252. SEQ ID NO:307 and SEQ ID NO:253; SEQ ID NO:307 and SEQ ID NO:254, a base plate; SEQ ID NO:307 and SEQ ID NO:255, respectively; SEQ ID NO:307 and SEQ ID NO:256; SEQ ID NO:307 and SEQ ID NO:257; SEQ ID NO:307 and SEQ ID NO:258; SEQ ID NO:307 and SEQ ID NO:259; SEQ ID NO:307 and SEQ ID NO:260; SEQ ID NO:307 and SEQ ID NO:261; SEQ ID NO:307 and SEQ ID NO:262; SEQ ID NO:307 and SEQ ID NO:263; SEQ ID NO:307 and SEQ ID NO:264; SEQ ID NO:307 and SEQ ID NO:265; SEQ ID NO:307 and SEQ ID NO:266; SEQ ID NO:307 and SEQ ID NO:267; SEQ ID NO:307 and SEQ ID NO:268, a step of; SEQ ID NO:307 and SEQ ID NO:269; SEQ ID NO:307 and SEQ ID NO:270; SEQ ID NO:307 and SEQ ID NO: 271(s); SEQ ID NO:307 and SEQ ID NO:272; SEQ ID NO:307 and SEQ ID NO:273; SEQ ID NO:307 and SEQ ID NO:274; SEQ ID NO:307 and SEQ ID NO:275; SEQ ID NO:307 and SEQ ID NO:276, respectively; SEQ ID NO:307 and SEQ ID NO:277; SEQ ID NO:307 and SEQ ID NO:278; SEQ ID NO:307 and SEQ ID NO:279; SEQ ID NO:307 and SEQ ID NO:280; SEQ ID NO:307 and SEQ ID NO: 281. SEQ ID NO:307 and SEQ ID NO:282; SEQ ID NO:307 and SEQ ID NO:283; SEQ ID NO:307 and SEQ ID NO:284; SEQ ID NO:307 and SEQ ID NO:285; SEQ ID NO:307 and SEQ ID NO:286; SEQ ID NO:307 and SEQ ID NO:287; SEQ ID NO:307 and SEQ ID NO:288; SEQ ID NO:307 and SEQ ID NO:289; SEQ ID NO:307 and SEQ ID NO:290; SEQ ID NO:307 and SEQ ID NO:291 of a metal strip; SEQ ID NO:307 and SEQ ID NO:292; SEQ ID NO:307 and SEQ ID NO:293; SEQ ID NO:307 and SEQ ID NO:294; SEQ ID NO:307 and SEQ ID NO:295; SEQ ID NO:307 and SEQ ID NO:296; SEQ ID NO:307 and SEQ ID NO:297; and SEQ ID NO:307 and SEQ ID NO:298.
Variants of the CDR-H3-CDR-L3 pair
In some embodiments, the CDR-H3-CDR-L3 pairs provided herein comprise variants of exemplary CDR-H3 and/or CDR-L1 sequences provided herein.
In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-H3 sequences provided herein. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary CDR-H3 sequences provided herein. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-H3 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-L3 sequences provided herein. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary CDR-L3 sequences provided herein. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-L3 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
CDR-H1-CDR-L1 pairs
In some embodiments, the antibody comprises a CDR-H1 sequence and a CDR-L1 sequence. In some aspects, the CDR-H1 sequence is V H And the CDR-L1 sequence is V L Is a part of the same.
In some aspects, the CDR-H1 sequence is a cauchy (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:4 to SEQ ID NO:62, and said CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:299 to SEQ ID NO:301.
in some aspects, the CDR-H1 sequence is a Kabat (Kabat) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:63 to SEQ ID NO:121, and said CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:299 to SEQ ID NO:301.
variants of CDR-H1-CDR-L1 pairs
In some embodiments, the CDR-H1-CDR-L1 pairs provided herein comprise variants of exemplary CDR-H1 and/or CDR-L1 sequences provided herein.
In some aspects, the CDR-H1 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-H1 sequences provided herein. In some aspects, the CDR-H1 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary CDR-H1 sequences provided herein. In some aspects, the CDR-H1 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-H1 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-L1 sequences provided herein. In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary CDR-L1 sequences provided herein. In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-L1 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
CDR-H2-CDR-L2 pairs
In some embodiments, the antibody comprises a CDR-H2 sequence and a CDR-L2 sequence. In some aspects, the CDR-H2 sequence is V H And the CDR-L2 sequence is V L Is a part of the same.
In some aspects, the CDR-H2 sequence is a cauchy (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:122 to SEQ ID NO:180, and said CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:302 to SEQ ID NO:304.
In some aspects, the CDR-H2 sequence is a Kabat (Kabat) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:181 to SEQ ID NO:239, and said CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:302 to SEQ ID NO:304.
variants of CDR-H2-CDR-L2 pairs
In some embodiments, the CDR-H2-CDR-L2 pairs provided herein comprise variants of exemplary CDR-H2 and/or CDR-L2 sequences provided herein.
In some aspects, the CDR-H2 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-H2 sequences provided by the present invention. In some aspects, the CDR-H2 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary CDR-H2 sequences provided herein. In some aspects, the CDR-H2 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-H2 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-L2 sequences provided herein. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary CDR-L2 sequences provided herein. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-L2 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
5.7.4.V H –V L For a pair of
In some embodiments, the antibody comprises V H Sequence and V L Sequence.
In some aspects, the V H The sequence is V comprising, consisting of, or consisting essentially of H Sequence: SEQ ID NO:308 to SEQ ID NO:366, and said V L The sequence is composed ofOr essentially consists of L Sequence: SEQ ID NO:367 to SEQ ID NO:369.
in some aspects, the V H -V L The pairs are selected from: SEQ ID NO:367 and SEQ ID NO: 308. SEQ ID NO:367 and SEQ ID NO:309, and (c) a third party; SEQ ID NO:367 and SEQ ID NO:310; SEQ ID NO:367 and SEQ ID NO:311; SEQ ID NO:367 and SEQ ID NO:312; SEQ ID NO:367 and SEQ ID NO:313; SEQ ID NO:367 and SEQ ID NO:314, a step of; SEQ ID NO:367 and SEQ ID NO:315; SEQ ID NO:367 and SEQ ID NO:316, a step of; SEQ ID NO:367 and SEQ ID NO: 317. SEQ ID NO:367 and SEQ ID NO:318; SEQ ID NO:367 and SEQ ID NO:319; SEQ ID NO:367 and SEQ ID NO: 320. SEQ ID NO:367 and SEQ ID NO:321, a base; SEQ ID NO:367 and SEQ ID NO:322; SEQ ID NO:367 and SEQ ID NO:323 (323); SEQ ID NO:367 and SEQ ID NO:324, a base; SEQ ID NO:367 and SEQ ID NO:325, a step of; SEQ ID NO:367 and SEQ ID NO:326, a step of; SEQ ID NO:367 and SEQ ID NO:327, respectively; SEQ ID NO:367 and SEQ ID NO: 328. SEQ ID NO:367 and SEQ ID NO:329; SEQ ID NO:367 and SEQ ID NO:330; SEQ ID NO:367 and SEQ ID NO:331; SEQ ID NO:367 and SEQ ID NO:332; SEQ ID NO:367 and SEQ ID NO:333; SEQ ID NO:367 and SEQ ID NO:334; SEQ ID NO:367 and SEQ ID NO:335; SEQ ID NO:367 and SEQ ID NO:336, a base; SEQ ID NO:367 and SEQ ID NO:337, respectively; SEQ ID NO:367 and SEQ ID NO:338; SEQ ID NO:367 and SEQ ID NO:339; SEQ ID NO:367 and SEQ ID NO:340 (340); SEQ ID NO:367 and SEQ ID NO:341; SEQ ID NO:367 and SEQ ID NO:342; SEQ ID NO:367 and SEQ ID NO:343; SEQ ID NO:367 and SEQ ID NO:344; SEQ ID NO:367 and SEQ ID NO:345, a frame structure; SEQ ID NO:367 and SEQ ID NO:346; SEQ ID NO:367 and SEQ ID NO:347; SEQ ID NO:367 and SEQ ID NO:348; SEQ ID NO:367 and SEQ ID NO:349; SEQ ID NO:367 and SEQ ID NO:350; SEQ ID NO:367 and SEQ ID NO:351; SEQ ID NO:367 and SEQ ID NO:352; SEQ ID NO:367 and SEQ ID NO:353; SEQ ID NO:367 and SEQ ID NO:354; SEQ ID NO:367 and SEQ ID NO:355; SEQ ID NO:367 and SEQ ID NO:356, respectively; SEQ ID NO:367 and SEQ ID NO:357, in the middle of the frame; SEQ ID NO:367 and SEQ ID NO:358, respectively; SEQ ID NO:367 and S EQ ID NO:359; SEQ ID NO:367 and SEQ ID NO: 360. SEQ ID NO:367 and SEQ ID NO:361, respectively; SEQ ID NO:367 and SEQ ID NO:362; SEQ ID NO:367 and SEQ ID NO:363; SEQ ID NO:367 and SEQ ID NO:364, respectively; SEQ ID NO:367 and SEQ ID NO:365; and SEQ ID NO:367 and SEQ ID NO:366.
in some aspects, the V H -V L The pairs are selected from: SEQ ID NO:368 and SEQ ID NO: 308. SEQ ID NO:368 and SEQ ID NO:309, and (c) a third party; SEQ ID NO:368 and SEQ ID NO:310; SEQ ID NO:368 and SEQ ID NO:311; SEQ ID NO:368 and SEQ ID NO:312; SEQ ID NO:368 and SEQ ID NO:313; SEQ ID NO:368 and SEQ ID NO:314, a step of; SEQ ID NO:368 and SEQ ID NO:315; SEQ ID NO:368 and SEQ ID NO:316, a step of; SEQ ID NO:368 and SEQ ID NO: 317. SEQ ID NO:368 and SEQ ID NO:318; SEQ ID NO:368 and SEQ ID NO:319; SEQ ID NO:368 and SEQ ID NO: 320. SEQ ID NO:368 and SEQ ID NO:321, a base; SEQ ID NO:368 and SEQ ID NO:322; SEQ ID NO:368 and SEQ ID NO:323 (323); SEQ ID NO:368 and SEQ ID NO:324, a base; SEQ ID NO:368 and SEQ ID NO:325, a step of; SEQ ID NO:368 and SEQ ID NO:326, a step of; SEQ ID NO:368 and SEQ ID NO:327, respectively; SEQ ID NO:368 and SEQ ID NO: 328. SEQ ID NO:368 and SEQ ID NO:329; SEQ ID NO:368 and SEQ ID NO:330; SEQ ID NO:368 and SEQ ID NO:331; SEQ ID NO:368 and SEQ ID NO:332; SEQ ID NO:368 and SEQ ID NO:333; SEQ ID NO:368 and SEQ ID NO:334; SEQ ID NO:368 and SEQ ID NO:335; SEQ ID NO:368 and SEQ ID NO:336, a base; SEQ ID NO:368 and SEQ ID NO:337, respectively; SEQ ID NO:368 and SEQ ID NO:338; SEQ ID NO:368 and SEQ ID NO:339; SEQ ID NO:368 and SEQ ID NO:340 (340); SEQ ID NO:368 and SEQ ID NO:341; SEQ ID NO:368 and SEQ ID NO:342; SEQ ID NO:368 and SEQ ID NO:343; SEQ ID NO:368 and SEQ ID NO:344; SEQ ID NO:368 and SEQ ID NO:345, a frame structure; SEQ ID NO:368 and SEQ ID NO:346; SEQ ID NO:368 and SEQ ID NO:347; SEQ ID NO:368 and SEQ ID NO:348; SEQ ID NO:368 and SEQ ID NO:349; SEQ ID NO:368 and SEQ ID NO:350; SEQ ID NO:368 and SEQ ID NO:351; SEQ ID NO:368 and SEQ ID NO:352; SEQ ID NO:368 and SEQ ID NO:353; SEQ ID NO:368 and 368 SEQ ID NO:354; SEQ ID NO:368 and SEQ ID NO:355; SEQ ID NO:368 and SEQ ID NO:356, respectively; SEQ ID NO:368 and SEQ ID NO:357, in the middle of the frame; SEQ ID NO:368 and SEQ ID NO:358, respectively; SEQ ID NO:368 and SEQ ID NO:359; SEQ ID NO:368 and SEQ ID NO: 360. SEQ ID NO:368 and SEQ ID NO:361, respectively; SEQ ID NO:368 and SEQ ID NO:362; SEQ ID NO:368 and SEQ ID NO:363; SEQ ID NO:368 and SEQ ID NO:364, respectively; SEQ ID NO:368 and SEQ ID NO:365; and SEQ ID NO:368 and SEQ ID NO:366.
in some aspects, the V H -V L The pairs are selected from: SEQ ID NO:369 and SEQ ID NO: 308. SEQ ID NO:369 and SEQ ID NO:309, and (c) a third party; SEQ ID NO:369 and SEQ ID NO:310; SEQ ID NO:369 and SEQ ID NO:311; SEQ ID NO:369 and SEQ ID NO:312; SEQ ID NO:369 and SEQ ID NO:313; SEQ ID NO:369 and SEQ ID NO:314, a step of; SEQ ID NO:369 and SEQ ID NO:315; SEQ ID NO:369 and SEQ ID NO:316, a step of; SEQ ID NO:369 and SEQ ID NO: 317. SEQ ID NO:369 and SEQ ID NO:318; SEQ ID NO:369 and SEQ ID NO:319; SEQ ID NO:369 and SEQ ID NO: 320. SEQ ID NO:369 and SEQ ID NO:321, a base; SEQ ID NO:369 and SEQ ID NO:322; SEQ ID NO:369 and SEQ ID NO:323 (323); SEQ ID NO:369 and SEQ ID NO:324, a base; SEQ ID NO:369 and SEQ ID NO:325, a step of; SEQ ID NO:369 and SEQ ID NO:326, a step of; SEQ ID NO:369 and SEQ ID NO:327, respectively; SEQ ID NO:369 and SEQ ID NO: 328. SEQ ID NO:369 and SEQ ID NO:329; SEQ ID NO:369 and SEQ ID NO:330; SEQ ID NO:369 and SEQ ID NO:331; SEQ ID NO:369 and SEQ ID NO:332; SEQ ID NO:369 and SEQ ID NO:333; SEQ ID NO:369 and SEQ ID NO:334; SEQ ID NO:369 and SEQ ID NO:335; SEQ ID NO:369 and SEQ ID NO:336, a base; SEQ ID NO:369 and SEQ ID NO:337, respectively; SEQ ID NO:369 and SEQ ID NO:338; SEQ ID NO:369 and SEQ ID NO:339; SEQ ID NO:369 and SEQ ID NO:340 (340); SEQ ID NO:369 and SEQ ID NO:341; SEQ ID NO:369 and SEQ ID NO:342; SEQ ID NO:369 and SEQ ID NO:343; SEQ ID NO:369 and SEQ ID NO:344; SEQ ID NO:369 and SEQ ID NO:345, a frame structure; SEQ ID NO:369 and SEQ ID NO:346; SEQ ID NO:369 and SEQ ID NO:347; SEQ ID NO:369 and SEQ ID NO:348; SEQ ID NO:369 and method for producing the same SEQ ID NO:349; SEQ ID NO:369 and SEQ ID NO:350; SEQ ID NO:369 and SEQ ID NO:351; SEQ ID NO:369 and SEQ ID NO:352; SEQ ID NO:369 and SEQ ID NO:353; SEQ ID NO:369 and SEQ ID NO:354; SEQ ID NO:369 and SEQ ID NO:355; SEQ ID NO:369 and SEQ ID NO:356, respectively; SEQ ID NO:369 and SEQ ID NO:357, in the middle of the frame; SEQ ID NO:369 and SEQ ID NO:358, respectively; SEQ ID NO:369 and SEQ ID NO:359; SEQ ID NO:369 and SEQ ID NO: 360. SEQ ID NO:369 and SEQ ID NO:361, respectively; SEQ ID NO:369 and SEQ ID NO:362; SEQ ID NO:369 and SEQ ID NO:363; SEQ ID NO:369 and SEQ ID NO:364, respectively; SEQ ID NO:369 and SEQ ID NO:365; and SEQ ID NO:369 and SEQ ID NO:366.
5.7.4.1.V H –V L variants of pairs
In some embodiments, the invention provides V H -V L For the exemplary V provided by the invention H And/or V L Variants of the sequences.
In some aspects, the V H The sequence comprises, consists of, or consists essentially of: exemplary V provided by the invention H Variants of the sequences. In some aspects, the V H The sequence comprises, consists of, or consists essentially of: any of the exemplary V provided with the present invention H Sequences have at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 99.1% identity.
In some embodiments, the V H The sequence comprises, consists of, or consists essentially of: any of the exemplary V provided herein with 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions H Sequence. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some statesIn the sample, the V L The sequence comprises, consists of, or consists essentially of: exemplary V provided by the invention L Variants of the sequences. In some aspects, the V L The sequence comprises, consists of, or consists essentially of: any of the exemplary V provided with the present invention L Sequences have at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5% identity.
In some embodiments, the V L The sequence comprises, consists of, or consists essentially of: any of the exemplary V provided herein with 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions L Sequence. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
5.8. Antibodies comprising all six CDRs
In some embodiments, the antibody comprises a CDR-H1 sequence, a CDR-H2 sequence, a CDR-H3 sequence, a CDR-L1 sequence, and a CDR-L3 sequence. In some aspects, the CDR sequence is V H (for CDR-H) or V L (for CDR-L).
In some aspects, the CDR-H1 sequence is a cauchy (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:4 to SEQ ID NO:62; the CDR-H2 sequence is a cauchy (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:122 to SEQ ID NO:180; the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:240 to SEQ ID NO:298; the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:299 to SEQ ID NO:301; the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:302 to SEQ ID NO:304; and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:305 to SEQ ID NO:307.
In some aspects, the CDR-H1 sequence is a cauchy (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:19; the CDR-H2 sequence is a cauchy (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:137, respectively; the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:255, respectively; the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:299 to SEQ ID NO:301; the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:302 to SEQ ID NO:304; and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:305 to SEQ ID NO:307.
in some aspects, the CDR-H1 sequence is a cauchy (Chothia) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:58; the CDR-H2 sequence is a cauchy (Chothia) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:176; the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:294; the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:299 to SEQ ID NO:301; the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:302 to SEQ ID NO:304; and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:305 to SEQ ID NO:307.
In some aspects, the CDR-H1 sequence is a Kabat (Kabat) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:63 to SEQ ID NO:121; the CDR-H2 sequence is a Kabat (Kabat) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:181 to SEQ ID NO:239; the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:240 to SEQ ID NO:289; the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:299 to SEQ ID NO:301; the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:302 to SEQ ID NO:304; and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:305 to SEQ ID NO:307.
in some aspects, the CDR-H1 sequence is a Kabat (Kabat) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:78; the CDR-H2 sequence is a Kabat (Kabat) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:196; the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:255, respectively; the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:299 to SEQ ID NO:301; the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:302 to SEQ ID NO:304; and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:305 to SEQ ID NO:307.
In some aspects, the CDR-H1 sequence is a Kabat (Kabat) CDR-H1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:117; the CDR-H2 sequence is a Kabat (Kabat) CDR-H2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:235; the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:294; the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:299 to SEQ ID NO:301; the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:302 to SEQ ID NO:304; and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of: SEQ ID NO:305 to SEQ ID NO:307.
5.8.1. antibody variants comprising all six CDRs
In some embodiments, the present invention provides CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 comprising exemplary CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and/or variants of the CDR-L3 sequences provided herein.
In some aspects, the CDR-H1 sequence comprises, consists of, or consists essentially of: exemplary Ke Xiya (Chothia) or kappa (Kabat) CDR-H1 sequences variants are provided. In some aspects, the CDR-H1 sequence comprises, consists of, or consists essentially of: a sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary Ke Xiya (Chothia) or Kabat (Kabat) CDR-H1 sequences provided herein. In some aspects, the CDR-H1 sequence comprises, consists of, or consists essentially of: any of the exemplary Ke Xiya (Chothia) or Kabat (Kabat) CDR-H1 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the CDR-H2 sequence comprises, consists of, or consists essentially of: exemplary Ke Xiya (Chothia) or kappa (Kabat) CDR-H2 sequences variants are provided. In some aspects, the CDR-H2 sequence comprises, consists of, or consists essentially of: a sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary Ke Xiya (Chothia) or Kabat (Kabat) CDR-H2 sequences provided herein. In some aspects, the CDR-H2 sequence comprises, consists of, or consists essentially of: any of the exemplary Ke Xiya (Chothia) or Kabat (Kabat) CDR-H2 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-H3 sequences provided herein. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary CDR-H3 sequences provided herein. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-H3 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-L1 sequences provided herein. In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary CDR-L1 sequences provided herein. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-L1 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-L2 sequences provided herein. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary CDR-L2 sequences provided herein. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-L2 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of: variants of the exemplary CDR-L3 sequences provided herein. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of: sequences having at least 70%, 75%, 80%, 85%, 90% or 95% identity to any of the exemplary CDR-L3 sequences provided herein. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of: any of the exemplary CDR-L3 sequences provided herein have 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are all conservative amino acid substitutions.
7. Affinity for
In some embodiments, the affinity of the antibody for folate receptor alpha is determined by K D Expressed as less than about 10 -5 M is less than about 10 - 6 M is less than about 10 -7 M is less than about 10 -8 M is less than about 10 -9 M is less than about 10 -10 M is less than about 10 -11 M, or less than about 10 -12 M. In some embodiments, the affinity of the antibody is about 10 -7 M and 10 -11 M. In some embodiments, the affinity of the antibody is about 10 -7 M and 10 -10 M. In some embodiments, the affinity of the antibody is about 10 -7 M and 10 -9 M. In some embodiments, the affinity of the antibody is about 10 -7 M and 10 -8 M. In some embodiments, the affinity of the antibody is about 10 -8 M and 10 -11 M. In some embodiments, the affinity of the antibody is about 10 -8 M and 10 -10 M. In some embodiments, the affinity of the antibody is about 10 -9 M and 10 -11 M. In some embodiments, the affinity of the antibody is about 10 -9 M and 10 -10 M.
In some embodiments, at 25 ℃ by surface plasmon resonance technology determination and by K D The affinity of the antibody for human folate receptor alpha was shown to be about 0.36X 10 -9 M to about 2.21×10 -9 M. In some embodiments, at 25 ℃ by surface plasmon resonance technology determination and by K D The affinity of the antibody for human folate receptor alpha was shown to be about 8.55X10 -10 M to about 1.70X10 -8 M. In some embodiments, at 25 ℃ by surface plasmon resonance technology determination and by K D The affinity of the antibody for human folate receptor alpha was about 5.71X 10 -10 M to about 2.58X10 -8 M. In some embodiments, the affinity of the antibody for human folate receptor alpha is about any K for human folate receptor alpha reported in the examples below D Values.
In some embodiments, k of the antibody a At least about 10 4 M -1 ×sec -1 . In some embodiments, k of the antibody a At least about 10 5 M -1 ×sec -1 . In some embodiments, k of the antibody a At least about 10 6 M -1 ×sec -1 . In some embodiments, k of the antibody a At least about 10 7 M -1 ×sec -1 . In some embodiments, k of the antibody a At least about 10 8 M -1 ×sec -1 . In some embodiments, k of the antibody a At least about 10 9 M -1 ×sec -1 . In some embodiments, k of the antibody a Is about 10 4 M -1 ×sec -1 About 10 10 M -1 ×sec -1 Between them. In some embodiments, k of the antibody a Is about 10 5 M -1 ×sec -1 About 10 10 M -1 ×sec -1 Between them. In some embodiments, k of the antibody a Is about 10 6 M -1 ×sec -1 About 10 10 M -1 ×sec -1 Between them. In some embodiments, k of the antibody a Is about 10 7 M -1 ×sec -1 About 10 10 M -1 ×sec -1 Between them.
In some embodiments, the antibody k, when associated with human folate receptor alpha, is determined by surface plasmon resonance at 25 ℃ a Is about 4.44×10 5 M -1 ×sec -1 To about 1.61X 10 5 M -1 ×sec -1 . In some embodiments, the antibody k, when associated with human folate receptor alpha, is determined by surface plasmon resonance at 25 ℃ a Is about 2.90 multiplied by 10 5 M -1 ×sec -1 To about 9.64×10 9 M -1 ×sec -1 . In some embodiments, the antibody k when associated with human folate receptor alpha a Any k to human folate receptor alpha as reported in the examples below a Values.
In some embodiments, k of the antibody d Is about 10 -5 sec -1 Or less. In some embodiments, k of the antibody d Is about 10 -4 sec -1 Or less. In some embodiments, k of the antibody d Is about 10 -3 sec -1 Or less. In some embodiments, k of the antibody d At about 10 -2 sec -1 About 10 -5 sec -1 Between them. In some embodiments, k of the antibody d At about 10 -2 sec -1 About 10 -4 sec -1 Between them. In some embodiments, k of the antibody d At about 10 -3 sec -1 About 10 -5 sec -1 Between them.
In some embodiments, the antibody k when dissociated from human folate receptor alpha is determined by surface plasmon resonance at 25℃ d Is about 8.66×10 -4 sec -1 To about 1.08X10 -2 sec -1 . In some embodiments, the antibody k when dissociated from human folate receptor alpha is determined by surface plasmon resonance at 25℃ d Is about 2.28X10 -4 sec -1 To about 4.82×10 1 sec -1 . In some embodiments, the antibody k when dissociated from human folate receptor alpha d Is about belowAny k to human folate receptor alpha reported in the examples d Values.
In some embodiments, at 25 ℃ by surface plasmon resonance technology determination and by K D The affinity of the antibody for the cynomolgus monkey folate receptor alpha was shown to be about 0.19X10 -9 M to about 2.84X10 -9 M. In some embodiments, the affinity of the antibody for cynomolgus monkey folate receptor alpha is any K to cynomolgus monkey folate receptor alpha as reported about in the examples below D Values.
In some embodiments, at 25 ℃ by surface plasmon resonance technology determination and by K D The affinity of the antibody for the mouse folate receptor alpha was shown to be about 0.5X10 -9 M to about 9.07×10 -8 M. In some embodiments, the affinity of the antibody for mouse folate receptor alpha is any K for mouse folate receptor alpha reported approximately in the examples below D Values.
In some aspects, the K D 、k a And k d All measurements were carried out at 25 ℃. In some embodiments, the K D 、k a And k d All measured by surface plasmon resonance techniques. In some embodiments, the K D 、k a And k d The assays were all performed according to the methods described in the examples provided herein.
8. EPITOPE bin (EPITOPE BINS)
In some embodiments, the antibody hybridizes to a polypeptide comprising SEQ ID NO:308 to SEQ ID NO:366 binds to the same epitope. In some embodiments, the antibody and the antibody comprising any of V described above H -V L The antibodies of the pair bind the same epitope. In some embodiments, the antibody hybridizes to a polypeptide comprising SEQ ID NO:308 to SEQ ID NO:366 competes for epitope binding. In some embodiments, the antibody and the antibody comprising any of V described above H -V L The antibodies of the pair compete for epitope binding.
9. Glycosylation variants
In certain embodiments, antibodies may be altered to increase, decrease, or eliminate the extent of their glycosylation. Glycosylation of polypeptides is typically either "N-linked" or "O-linked".
"N-linked" glycosylation refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine are both recognition sequences for the enzymatic attachment of a carbohydrate moiety to an asparagine side chain, where X is any amino acid except proline. Thus, the presence of any such tripeptide sequences in a polypeptide results in a possible glycosylation site.
"O-linked" glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxy amino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.
The addition or deletion of an N-linked glycosylation site in an antibody can be accomplished by altering the amino acid sequence to create or remove one or more of the above tripeptide sequences. The addition or deletion of an O-linked glycosylation site can be accomplished by adding, deleting or replacing one or more serine or threonine residues (as the case may be) in the antibody sequence.
FC variants
In certain embodiments, amino acid modifications may be introduced into the Fc region of an antibody provided herein to generate an Fc region variant. In certain embodiments, the Fc region variant possesses some, but not all, effector functions. Such antibodies may be used, for example, in applications where the in vivo half-life of the antibody is important, but where some effector function is not necessary or detrimental. Examples of effector functions include Complement Dependent Cytotoxicity (CDC) and antibody directed complement mediated cytotoxicity (ADCC). Many substitutions or deletions with altered effector functions are known in the art.
In some embodiments, the Fc is at least one C H 3 comprising one or more modifications. In some embodiments, the Fc is at least one C H 2 comprising one or more modifications. For example, the Fc may include one or more modifications selected from the group consisting of: V262E, V262D, V262K, V262R, V262S, V264S, V R, and V305R. In some implementations In embodiments, the Fc is a single polypeptide. In some embodiments, the Fc is a plurality of peptides, e.g., two polypeptides. Exemplary modifications of the Fc region are described in international patent application number PCT/US2017/037545 filed on, for example, 14, 6, 2017.
The alteration of CDC and/or ADCC activity may be confirmed using in vitro and/or in vivo assays. For example, an Fc receptor (FcR) binding assay may be performed to determine fcγr binding. The primary cells mediating ADCC, NK cells, express fcyriii only, whereas monocytes express fcyri, fcyrii and fcyriii. FcR expression on hematopoietic cells is summarized in Ravetch and Kinet, ann.Rev.Immunol.,1991,9:457-492, the entire disclosure of which is incorporated herein by reference.
Non-limiting examples of in vitro assays for assessing ADCC activity of a molecule of interest are provided in U.S. Pat. nos. 5,500,362 and 5,821,337; hellstrom et al, proc.Natl.Acad.Sci.U.S.A.,1986,83:7059-7063; hellstrom et al, proc.Natl. Acad.Sci.U.S.A.,1985,82:1499-1502; and Bruggemann et al, J.Exp.Med.,1987, 166:1351-1361; each of which is incorporated by reference in its entirety. Effector cells useful in such assay assays include Peripheral Blood Mononuclear Cells (PBMC) and Natural Killer (NK) cells. Alternatively or additionally, ADCC activity of a molecule of interest can be assessed in vivo using an animal model, such as the animal model disclosed in Clynes et al Proc. Natl. Acad. Sci. U.S. A.,1998,95:652-656, which is incorporated herein by reference in its entirety.
A C1q binding assay may also be performed to confirm that the antibody is unable to bind to C1q and thus lacks CDC activity. Examples of C1q binding assays include those described in WO 2006/029879 and WO 2005/100402, each of which is incorporated herein by reference in its entirety.
Complement activation assays include, for example, those described in the following documents: gazzano-Santoro et al, J.Immunol. Methods,1996,202:163-171; cragg et al, blood,2003,101:1045-1052; and Cragg and Glennie, blood,2004,103:2738-2743; each of which is incorporated by reference in its entirety.
FcRn binding and in vivo clearance (half-life assays) can also be determined using, for example, the methods described in Petkova et al, intl.immunol.,2006,18:1759-1769, which is incorporated herein by reference in its entirety.
12. Preparation of antibody conjugates
12.1. Antigen preparation
The FOLR1 protein used to isolate the antibody may be intact FOLR1 or a fragment of FOLR 1. The intact FOLR1 protein or FOLR1 fragment may be in the form of an isolated protein or a protein expressed by a cell. Other forms of FOLR1 that can be used to generate antibodies will be apparent to those skilled in the art.
12.2. Monoclonal antibodies
Monoclonal antibodies can be obtained, for example, using the hybridoma method described first by Kohler et al, nature,1975,256:495-497 (incorporated herein by reference in its entirety), and/or by recombinant DNA methods (see, e.g., U.S. patent No. 4,816,567, incorporated herein by reference in its entirety). Monoclonal antibodies can also be obtained, for example, using phage or yeast-based libraries. See, for example, U.S. patent nos. 8,258,082 and 8,691,730, each of which is incorporated by reference in its entirety.
In the hybridoma method, a mouse or other suitable host animal is immunized to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization. Alternatively, lymphocytes may be immunized in vitro. The lymphocytes are then fused with myeloma cells using a suitable fusion agent, such as polyethylene glycol, to form hybridoma cells. See Goding J.W., monoclonal Antibodies: principles and Practice 3 rd ed. (1986) Academic Press, san Diego, calif., which is incorporated herein by reference in its entirety.
Hybridoma cells are inoculated and grown in a suitable medium containing one or more substances that inhibit the growth or survival of the unfused, parent myeloma cells. For example, if the parent myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which substances prevent the growth of HGPRT-deficient cells.
Useful myeloma cells are those that fuse efficiently, support stable production of antibodies in large quantities by selected antibody-producing cells, and are sensitive to conditions of culture medium such as the presence or absence of HAT medium. Among the preferred myeloma cell lines are murine myeloma cell lines such as those derived from MOP-21 and MC-11 mouse tumors (available from Salk Institute Cell Distribution Center, san Diego, calif.), and SP-2 or X63-Ag8-653 cells (available from American type culture Collection (American Type Culture Collection), rockville, md.). Human myeloma and mouse-human heterologous myeloma cells have also been described for use in the production of human monoclonal antibodies. See, e.g., kozbor, j.immunol.,1984,133:3001, which is incorporated herein by reference in its entirety.
After identifying hybridoma cells that produce antibodies of the desired specificity, affinity and/or biological activity, the selected clones can be subcloned by limiting dilution procedures and grown by standard methods. See Goding, supra. Suitable media for this purpose include, for example, D-MEM or RPMI-1640 medium. In addition, hybridoma cells can be grown in vivo in the form of ascites tumors in animals.
DNA encoding a monoclonal antibody can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that specifically bind to genes encoding the heavy and light chains of the monoclonal antibody). Thus, hybridoma cells can serve as a useful source of DNA encoding antibodies having the desired properties. Once isolated, the DNA may be placed into an expression vector, which is then transfected into a host cell such as a bacterium (e.g., escherichia coli (e.coli)), yeast (e.g., saccharomyces (Saccharomyces) or Pichia (Pichia sp.)), COS cells, chinese Hamster Ovary (CHO) cells, or myeloma cells that do not otherwise produce antibodies, to produce monoclonal antibodies.
12.3. Humanized antibodies
Humanized antibodies can be generated by replacing most or all of the structural parts of a non-human monoclonal antibody with the corresponding human antibody sequences. Thus, hybrid molecules are generated in which only the antigen-specific variable groups or CDRs are composed of non-human sequences. Methods for obtaining humanized antibodies include, for example, those described in the following: winter and Milstein, nature,1991,349:293-299; rader et al, proc.nat.acad.sci.u.s.a.,1998,95:8910-8915; steinberger et al, J.biol.chem.,2000,275:36073-36078; queen et al, proc.Natl. Acad.Sci.U.S.A.,1989,86:10029-10033; and U.S. Pat. nos. 5,585,089, 5,693,761, 5,693,762 and 6,180,370; each of which is incorporated by reference in its entirety.
12.4. Human antibodies
Human antibodies can be generated by a variety of techniques known in the art, for example, using transgenic animals (e.g., humanized mice). See, e.g., jakobovits et al, proc.Natl. Acad.Sci.U.S.A.,1993,90:2551; jakobovits et al, nature,1993,362:255-258; bruggermann et al, year in Immuno, 1993,7:33; and U.S. patent nos. 5,591,669, 5,589,369 and 5,545,807; each of which is incorporated by reference in its entirety. Human antibodies can also be derived from phage display libraries (see, e.g., hoogenboom et al, J.Mol. Biol.,1991,227:381-388; marks et al, J.Mol. Biol.,1991,222:581-597; and U.S. Pat. Nos. 5,565,332 and 5,573,905; each of which is incorporated herein by reference in its entirety). Human antibodies may also be produced by activated B cells in vitro (see, e.g., U.S. Pat. nos. 5,567,610 and 5,229,275, each of which is incorporated herein by reference in its entirety). Human antibodies can also be derived from yeast-based libraries (see, e.g., U.S. patent No. 8,691,730, which is incorporated herein by reference in its entirety).
12.5. Conjugates
The antibody conjugates can be prepared by standard techniques. In certain embodiments, the antibody is contacted with the payload precursor under conditions suitable for formation of a bond by the antibody and the payload to form an antibody-payload conjugate. In certain embodiments, the antibody is contacted with the linker precursor under conditions suitable for the formation of a bond from the antibody and the linker. Contacting the resulting antibody-linker with a payload precursor under conditions suitable for formation of a bond from the antibody-linker and the payload to form an antibody-linker-payload conjugate. In certain embodiments, the payload precursor is contacted with the linker precursor under conditions suitable for bonding the payload to the linker. Contacting the resulting payload-linker with an antibody under conditions suitable for formation of a bond by the payload-linker and the antibody to form an antibody-linker-payload conjugate. Suitable linkers for preparing antibody conjugates are disclosed, and exemplary conditions for conjugation are described in the examples below.
In some embodiments, an anti-FOLR 1 conjugate is prepared by contacting an anti-FOLR 1 antibody as disclosed herein with a linker precursor having a structure as shown in any one of (a) - (L):
in some embodiments, as shown in the following formulas (A1) - (L1) and (A2) - (L2), from left to right, the stereochemistry of the linker precursor identified as (a) - (L) is identified with R and S symbols for each chiral center:
13. vectors, host cells and recombinant methods
Embodiments also relate to providing isolated nucleic acids encoding anti-FOLR 1 antibodies, vectors and host cells comprising the nucleic acids, and recombinant techniques for producing the antibodies.
For recombinant production of antibodies, the nucleic acid encoding the antibody may be isolated and inserted into a replicable vector for further cloning (i.e., amplifying the DNA) or expression. In some aspects, the nucleic acids can be generated by homologous recombination, such as described in U.S. patent No. 5,204,244, which is incorporated herein by reference in its entirety.
Many different vectors are known in the art. The carrier component typically includes, but is not limited to, one or more of the following: signal sequences, origins of replication, one or more marker genes, enhancer elements, promoters, and transcription termination sequences, such as described in U.S. Pat. No. 5,534,615, which is incorporated herein by reference in its entirety.
Illustrative examples of suitable host cells are provided below. These host cells are not intended to be limiting.
Suitable host cells include any prokaryotic (e.g., bacterial), lower eukaryotic (e.g., yeast), or higher eukaryotic (e.g., mammalian) cells. Suitable prokaryotic cells include eubacteria (eubacteria), such as gram-negative or gram-positive organisms, for example Enterobacteriaceae (Enterobacteriaceae) such as Escherichia (E.coli), enterobacter (Enterobacter), erwinia (Erwinia), klebsiella (Klebsiella), proteus (Proteus), salmonella (Salmonella typhimurium), serratia (Serratia) mucilaginous Serratia (S.marcescens), shigella (Shigella), bacillus (B.subsumei) and Bacillus licheniformis), pseudomonas (Pseudomonas), pseudomonas (P.aeruginosa) and Streptomyces (Streptomyces). One useful E.coli cloning host is E.coli 294, although other strains such as E.coli B, E.coli X1776 and E.coli W3110 are also suitable.
In addition to prokaryotic cells, eukaryotic microorganisms such as filamentous fungi or yeast are also suitable cloning or expression hosts for vectors encoding anti-FOLR 1 antibodies. Saccharomyces cerevisiae (Saccharomyces cerevisiae), or commonly known as Saccharomyces cerevisiae, is a commonly used lower eukaryotic host microorganism. However, several other genera, species and strains are available and available, such as spodoptera frugiperda (Spodoptera frugiperda (e.g., SF 9)), schizosaccharomyces pombe (Schizosaccharomyces pombe), kluyveromyces (Kluyveromyces lactis) (k.lactis), kluyveromyces fragilis (k.fragilis), kluyveromyces bulgaricus (k.bulgaricus), kluyveromyces welfare (k.winamii), kluyveromyces watt (k.walti), drosophila (k.drosophila), kluyveromyces thermotolerans (k.thermalis), kluyveromyces (k.marxianus)), yarrowia (Yarrowia), pichia pastoris (Candida), candida (c.album), trichoderma (sche), aspergillus (schedularium) (62), aspergillus (e.g., aspergillus niger), aspergillus and Aspergillus (Candida) (Aspergillus oryzae), and Aspergillus (Candida), such as Aspergillus (Candida), aspergillus (toruloparius) and Aspergillus (torulopsis).
Useful mammalian host cells include COS-7 cells, HEK293 cells; baby Hamster Kidney (BHK) cells; chinese Hamster Ovary (CHO); mouse sertoli (sertoli) cells; african green monkey kidney cells (VERO-76), and the like.
Host cells for producing the anti-FOLR 1 antibodies of the invention may be cultured in a variety of media. Commercially available media such as, for example, ham's F, minimal Essential Medium (MEM), RPMI-1640 and Darby's Modified Eagle's Medium (DMEM) are suitable for culturing the host cells. Furthermore, ham et al, meth.enz.,1979,58:44; barnes et al, anal. Biochem.,1980,102:255; and any of the media described in U.S. Pat. Nos. 4,767,704, 4,657,866, 4,927,762, 4,560,655 and 5,122,469 or WO 90/03430 and WO 87/00195. Each of which is incorporated by reference in its entirety.
Any of these media may be supplemented, if necessary, with hormones and/or other growth factors (such as insulin, transferrin or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics, trace elements (defined as inorganic compounds typically present in final concentrations in the micromolar range), and glucose or equivalent energy sources. Any other necessary supplements may also be included at appropriate concentrations as known to those skilled in the art.
The culture conditions, such as temperature, pH, etc., are those previously used for the expression host cell and will be apparent to those of ordinary skill in the art.
When recombinant techniques are used, antibodies may be produced in the cell, in the periplasmic space (periplasmic space), or directly secreted into the culture medium. If the antibody is produced intracellularly, the first step is to remove the particle fragments (whether host cells or lysed fragments) by, for example, centrifugation or ultrafiltration. For example, carter et al (Bio/Technology, 1992, 10:163-167) describe procedures for isolating antibodies secreted into the periplasmic space of E.coli cells. Briefly, the cell paste was thawed in the presence of sodium acetate (pH 3.5), EDTA and phenylmethylsulfonyl fluoride (PMSF) for about 30 minutes. Cell debris can be removed by centrifugation.
In some embodiments, the antibody is produced in a cell-free system. In some aspects, cell-free systems such as the in vitro transcription and translation systems described in Yin et al, mAbs,2012,4:217-225, are incorporated herein by reference. In some aspects, the cell-free system utilizes cell-free extracts from eukaryotic cells or from prokaryotic cells. In some aspects, the prokaryotic cell is E.coli (E.coli). Cell-free expression of antibodies may be useful, for example, where antibodies accumulate in cells in insoluble aggregates or where the yield of periplasmic expression is low. Antibodies generated in cell-free systems may be non-glycosylated, depending on the source of the cell.
When the antibody is secreted into the culture medium, it is first concentrated using a commercial protein concentration filter such asOr (b)Ultrafiltration means to substantially concentrate the supernatant from the expression system. Any of the above steps may include protease inhibitors such as PMSF to inhibit proteolysis, and antibiotics to prevent opportunistic contaminant growth. />
Antibody compositions prepared from cells can be purified using, for example, hydroxyapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being a particularly useful purification technique. The suitability of protein a as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain present in the antibody. Protein A can be used to purify antibodies based on the human gamma 1, gamma 2 or gamma 4 heavy chain (Lindmark et al, J.Immunol. Meth.,1983,62:1-13, the disclosure of which is incorporated herein by reference in its entirety). Protein G is useful for all mouse isoforms and human gamma 3 (Guss et al, EMBO J.,1986, 5:1567-1575), the entire disclosure of which is incorporated herein by reference).
The most commonly used groups for attaching such affinity ligandsAgarose in nature, but other matrices may be used. The use of mechanically stable substrates such as controlled pore glass or poly (styrene divinyl) benzene can achieve faster flow rates and shorter processing times than agarose. When the antibody comprises C H3 In the case of domains, baker bond may be usedThe resin was purified.
Other protein purification techniques such as ion exchange column fractionation, ethanol precipitation, reverse phase HPLC, silica gel chromatography, heparin may also be usedChromatography, chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation, and these techniques may be applied by one of skill in the art.
After any preliminary purification steps, the mixture comprising the antibody of interest and contaminants may be treated by low pH hydrophobic interaction chromatography using an elution buffer having a pH of about 2.5 to about 4.5, typically at a low salt concentration (e.g., about 0 to about 0.25M salt).
14. Pharmaceutical compositions and methods of administration
The antibodies and antibody conjugates provided herein can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the antibody conjugates provided herein may be provided in a suitable pharmaceutical composition and administered by a suitable route of administration.
Typically, the VEGF inhibitors are formulated, administered, and administered according to commercially available instructions.
The methods provided herein comprise administering a pharmaceutical composition comprising at least one antibody conjugate provided herein and one or more compatible and pharmaceutically acceptable carriers. In this context, the term "pharmaceutically acceptable" refers to those approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" includes diluents, adjuvants (e.g., freund's) adjuvants (complete and incomplete), adjuvants or vehicles for administration with therapeutic agents. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. When the pharmaceutical composition is administered intravenously, water may be used as a carrier. Saline solutions as well as aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutically acceptable carriers are described in Martin, e.w., remington's Pharmaceutical Sciences.
In clinical practice, the pharmaceutical compositions or antibody conjugates provided herein may be administered by any route known in the art. Exemplary routes of administration include, but are not limited to, inhalation, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes. In some embodiments, the pharmaceutical compositions or antibody conjugates provided herein are administered/dosed parenterally.
Compositions for parenteral administration may be in the form of emulsions or sterile solutions. Parenteral compositions may include, for example, propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters (e.g., ethyl oleate). The compositions may also contain wetting agents, isotonic agents, emulsifying agents, dispersing agents, and stabilizing agents. Sterilization can be performed in several ways, for example using a bacterial filter, by irradiation or by heating. Parenteral compositions can also be prepared in the form of sterile solid compositions which are intended to be dissolved in sterile water or any other injectable sterile medium at the time of use.
In some embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic antibody conjugates.
The pharmaceutical composition may comprise one or more pharmaceutical excipients. Any suitable pharmaceutical excipients may be used and one of ordinary skill in the art will be able to select a suitable pharmaceutical excipient. Non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular adjuvant is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form is administered to a subject and the specific antibody in the dosage form. The composition or single unit dosage form may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. Accordingly, the pharmaceutical excipients provided below are exemplary only and not intended to be limiting. Other pharmaceutical excipients include, for example, those described in Handbook of Pharmaceutical Excipients, rowe et al (eds.) 6th Ed (2009), which is incorporated herein by reference in its entirety.
In some embodiments, the pharmaceutical composition comprises an antifoaming agent. Any suitable defoamer may be used. In some aspects, the defoamer is selected from the group consisting of alcohols, ethers, oils, waxes, polysiloxanes, surfactants, and combinations thereof. In some aspects, the defoamer is selected from the group consisting of mineral oil, vegetable oil, vinyl bis-stearamide, paraffin wax, ester wax, fatty alcohol wax, long chain fatty alcohols, fatty acid soaps, fatty acid esters, silicone glycols, fluorosilicones, polyethylene glycol-polypropylene glycol copolymers, polydimethylsiloxane-silica, ethers, octanol, decanoyl alcohol, sorbitan trioleate, ethanol, 2-ethyl-hexanol, dimethicone (dimethicone), oleyl alcohol, dimethicone (simethicone), and combinations thereof.
In some embodiments, the pharmaceutical composition comprises a co-solvent. Illustrative examples of the co-solvent include ethanol, polyethylene glycol (poly (ethylene) glycol), butylene glycol, dimethylacetamide, glycerol, and propylene glycol.
In some embodiments, the pharmaceutical composition comprises a buffer. Illustrative examples of buffers include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate.
In some embodiments, the pharmaceutical composition comprises a carrier or filler. Illustrative examples of carriers or fillers include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.
In some embodiments, the pharmaceutical composition comprises a surfactant. Illustrative examples of the surfactant include d-alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glyceryl monooleate, lauric acid, polyethylene glycol 15hydroxystearate (macrogol 15 hydroxystearate), myristyl alcohol, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxyglycerols, sodium lauryl sulfate, sorbitan esters, and vitamin E polyethylene (ethylene glycol) succinate.
In some embodiments, the pharmaceutical composition comprises an anti-caking agent. Illustrative examples of the anticaking agent include calcium phosphate (trivalent), hydroxymethyl cellulose, hydroxypropyl cellulose, and magnesium oxide.
Other excipients that may be used with the pharmaceutical composition include, for example, albumin, antioxidants, antibacterial, antifungal, bioabsorbable polymers, chelating agents, controlled release agents, diluents, dispersing agents, dissolution enhancers, emulsifiers, gelling agents, ointment bases, permeation enhancers, preservatives, solubilizers, solvents, stabilizers, and sugars. Specific examples of each of these agents are described, for example, in Handbook of Pharmaceutical Excipients, rowe et al (eds.) 6th Ed (2009), the Pharmaceutical Press, the disclosure of which is incorporated by reference in its entirety.
In some embodiments, the pharmaceutical composition comprises a solvent. In some aspects, the solvent is a saline solution, such as a sterile isotonic saline solution or dextrose solution. In some aspects, the solvent is water for injection.
In some embodiments, the pharmaceutical composition is in the form of particles, such as microparticles or nanoparticles. The microparticles and nanoparticles may be formed of any suitable material, such as polymers or lipids. In some aspects, the microparticles or nanoparticles are micelles, liposomes, or polymer vesicles.
The invention further provides anhydrous pharmaceutical compositions and dosage forms comprising antibody conjugates, as in some embodiments, water may promote the degradation of certain antibodies.
The anhydrous pharmaceutical compositions and dosage forms provided by the present invention can be prepared using anhydrous or low moisture content ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine may be anhydrous if significant exposure to moisture and/or humidity during manufacture, packaging and/or storage is contemplated.
Anhydrous pharmaceutical compositions can be prepared and stored in a manner that maintains their anhydrous nature. Thus, anhydrous compositions can be packaged with materials known to prevent exposure to water so that they can be included in a kit of appropriate prescription. Examples of suitable packages include, but are not limited to, seal foils, plastics, unit dose containers (e.g., vials), blister packs, and tape packs.
Lactose-free compositions provided herein may comprise excipients well known in the art and include, for example, those listed in the United States Pharmacopeia (USP) SP (XXI)/NF (XVI). Typically, lactose-free compositions comprise pharmaceutically compatible and pharmaceutically acceptable amounts of active ingredients, binders/fillers, and lubricants. Exemplary lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.
The invention also provides pharmaceutical compositions and dosage forms comprising one or more excipients that reduce the rate of decomposition of an antibody or antibody conjugate. Such excipients are referred to herein as "stabilizers," including but not limited to antioxidants, such as ascorbic acid, pH buffers, or salt buffers.
14.1. Parenteral dosage forms
In certain embodiments, the invention provides parenteral dosage forms. Parenteral dosage forms can be administered to a subject by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Parenteral dosage forms are typically sterile or may be sterilized prior to administration to a subject, as their administration typically bypasses the subject's natural defenses against contaminants. Examples of parenteral dosage forms include, but are not limited to, ready-to-use injectable solutions, dried products that can be immediately dissolved or suspended in a pharmaceutically acceptable injectable vehicle, ready-to-use injectable suspensions, and emulsions.
Suitable vehicles that may be used to provide parenteral dosage forms are known to those skilled in the art. Examples include, but are not limited to: water for injection USP; aqueous vehicles such as, but not limited to, sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
Adjuvants that increase the solubility of one or more of the antibodies disclosed herein may also be incorporated into the parenteral dosage forms.
14.2. Dosage and unit dosage forms
In the treatment of humans, a physician will determine what he deems most appropriate dosing based on prophylactic or therapeutic therapy and on the age, weight, condition and other specific factors of the subject to be treated.
In certain embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic antibodies.
The amount of antibody conjugate or composition effective to prevent or treat a disorder or one or more symptoms of the disorder will vary with the nature and severity of the disease or condition, as well as the route of administration of the antibody. The frequency and dosage will also vary depending on the particular factors of each subject, which depend on the particular therapy (e.g., therapeutic or prophylactic agent) being administered, the severity of the disorder, disease or condition, the route of administration, and the age, body, weight, response, and prior medical history of the subject. The effective dose can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
In certain embodiments, exemplary dosages of the composition include milligrams or microgram amounts of antibody per kilogram of subject or sample body weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 micrograms per kilogram to about 10 milligrams per kilogram). In certain embodiments, the dosage (by weight of antibody) of an antibody conjugate provided by the invention administered to prevent, treat, or ameliorate a disorder or one or more symptoms of the disorder in a subject is 0.1mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 10mg/kg, or 15mg/kg of the subject's body weight or more. In certain embodiments, the dosage (by weight of antibody) of an antibody conjugate provided herein administered to prevent, treat, or ameliorate a disorder or one or more symptoms of the disorder in a subject is about 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5mg/kg body weight of the subject or more. In certain embodiments, the dosage (by weight of antibody) of VEGF-Sub>A (e.g., bevacizumab) provided herein administered to prevent, treat, manage, or ameliorate Sub>A disorder or one or more symptoms of the disorder in Sub>A subject is 10, 11, 12, 13, 14, or 15mg/kg body weight of the subject or more. In another embodiment, the composition or the composition provided herein administered to prevent, treat, or ameliorate a disorder or one or more symptoms of the disorder in a subject is at a dose of 0.1mg to 200mg, 0.1mg to 100mg, 0.1mg to 50mg, 0.1mg to 25mg, 0.1mg to 20mg, 0.1mg to 15mg, 0.1mg to 10mg, 0.1mg to 7.5mg, 0.1mg to 5mg, 0.1 to 2.5mg, 0.25mg to 20mg, 0.25 to 15mg, 0.25 to 12mg, 0.25 to 10mg, 0.25mg to 7.5mg, 0.25mg to 5mg, 0.25mg to 2.5mg, 0.5mg to 20mg, 0.5 to 15mg, 0.5 to 12mg, 0.5mg to 10mg, 0.5mg to 7.5mg, 0.5mg to 5mg, 0.5mg to 2.5mg, 0.25mg to 20mg, 0.25mg to 15mg, 0.25mg to 1 to 12mg, 1 to 1, 1 to 2.5mg or 1 to 2.5mg.
The dose may be administered according to a suitable schedule, for example once, twice, three times or four times per week. Certain circumstances may necessitate the use of dosages of antibody conjugates outside the scope of the present disclosure, as will be apparent to those of ordinary skill in the art. In addition, it should be noted that the clinician or attending physician will know how and when the treatment should be discontinued, adjusted or terminated in connection with the subject's response.
Different therapeutically effective amounts may be suitable for different diseases and conditions, as will be apparent to those of ordinary skill in the art. Similarly, amounts sufficient to prevent, treat, or ameliorate such conditions, but insufficient to cause or reduce adverse effects associated with the antibodies provided herein, are also encompassed by the dosages and dose frequency schedules described herein. In addition, when multiple doses of the compositions provided herein are administered to a subject, not all doses need be the same. For example, the dose administered to a subject may be increased to improve the prophylactic or therapeutic effect of the composition, or it may be decreased to reduce one or more adverse effects experienced by a particular subject.
In certain embodiments, treatment or prophylaxis may be initiated with one or more loading doses of the antibody conjugates or compositions provided herein, and then maintained with one or more maintenance doses.
In certain embodiments, the doses of the antibody conjugates or compositions provided herein can be administered to achieve steady state concentrations of the antibodies in the blood or serum of a subject. The steady state concentration may be determined by assay techniques available to the skilled artisan, or may be determined based on physical characteristics of the subject, such as height, weight and age.
In certain embodiments, the same composition may be repeatedly administered, and the administration may be at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months apart. In certain embodiments, the same composition may be repeatedly administered, and the administrations may be separated by at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days. In other embodiments, the same prophylactic or therapeutic agent may be repeatedly administered, and the administration may be at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months apart. In other embodiments, the same prophylactic or therapeutic agent may be repeatedly administered, and the administrations may be separated by at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days.
15. Therapeutic applications
For therapeutic use, the combinations provided herein are administered to a mammal (typically a human) in a pharmaceutically acceptable dosage form, such as those known in the art and discussed above. For example, the antibody conjugates of the invention may be administered to a human intravenously or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerebroventricular, subcutaneous, intra-articular, intrasynovial, intrathecal, or intratumoral routes. The antibody conjugates may also be administered by a peri-tumor, intra-focal, or peri-focal route as appropriate to exert local as well as systemic therapeutic effects. The intravenous route may be particularly useful, for example, in the treatment of ovarian tumors.
The antibody conjugates provided herein are useful for treating any disease or disorder involving folate receptor alpha (FOLR 1). In some embodiments, the disease or disorder is a disease or disorder that can be diagnosed by overexpression of folate receptor alpha. In some embodiments, the disease or disorder is a disease or disorder that may benefit from treatment with an anti-folate receptor alpha antibody. In some embodiments, the disease or disorder is cancer.
Any suitable cancer can be treated with the antibody conjugates provided herein. Exemplary suitable cancers include, for example: acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), adrenocortical carcinoma, anal carcinoma, appendiceal carcinoma, astrocytoma, basal cell carcinoma, brain tumor, cholangiocarcinoma, bladder carcinoma, bone carcinoma, breast carcinoma (including triple negative breast carcinoma, or TNBC), bronchial tumors, primary foci of unknown origin, cardiac tumors, cervical cancer, chordoma, colon cancer, colorectal cancer, craniopharyngeal tumors, ductal cancers, embryonal tumors, endometrial cancers, ependymoma, esophageal cancer, olfactory neuroblastoma, fallopian tube cancer, fibroblastic histiocytoma, ewing's (Ewing) sarcoma, ocular cancer, germ cell tumors, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, glioma, head and neck cancer, hepatocellular carcinoma, histiocytoma, hodgkin's lymphoma, hypopharynx cancer, intraocular melanoma, islet cell tumor, kaposi's (Kaposi) sarcoma, renal cancer langerhan's (Langerhans) cell histiocytosis, laryngeal, lip and oral cancer, liver cancer, lobular carcinoma in situ, lung cancer, macroglobulinemia, malignant fibrous histiocytoma, melanoma, merkel's (Merkel) cell carcinoma, mesothelioma, primary unknown metastatic neck squamous cell carcinoma, NUT gene-related midline carcinoma, oral cancer, multiple endocrine tumor syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-small cell lung cancer (NSCLC), oropharyngeal carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleural-pulmonary blastoma, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, cerclary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, spinal cord tumor, stomach cancer, T cell lymphoma, teratoid tumor, testicular cancer, laryngeal cancer, thymoma and thymus cancer, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer, and Wilms' tumor.
In some embodiments, the disease treated with the antibody conjugates provided herein is gastric cancer, colorectal cancer, renal cell carcinoma, cervical cancer, non-small cell lung cancer, ovarian cancer, uterine cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, prostate cancer, breast cancer, head and neck cancer, brain cancer, liver cancer, pancreatic cancer, mesothelioma, and/or cancer originating from the epithelium. In a particular embodiment, the disease is colorectal cancer. In some embodiments, the disease is ovarian cancer. In some embodiments, the disease is breast cancer. In some embodiments, the disease is Triple Negative Breast Cancer (TNBC). In some embodiments, the disease is lung cancer. In some embodiments, the disease is non-small cell lung cancer (NSCLC). In some embodiments, the disease is head and neck cancer. In some embodiments, the disease is renal cell carcinoma. In some embodiments, the disease is brain cancer. In some embodiments, the disease is endometrial cancer.
16. Kit for detecting a substance in a sample
In some embodiments, the combinations provided herein are provided in the form of a kit, i.e., a packaged combination of predetermined amounts of reagents and instructions for performing a procedure. In other embodiments, the procedure is a therapeutic procedure.
In some embodiments, the kit further comprises a solvent for reconstitution of the anti-FOLR 1 antibody conjugate. In some embodiments, the anti-FOLR 1 antibody conjugate is provided in the form of a pharmaceutical composition.
In some embodiments, the kit further comprises a VEGF inhibitor (e.g., bevacizumab or bevacizumab anti-biological analog) and instructions for use.
In certain embodiments, the pharmaceutical package or pharmaceutical kit comprises a container, a folate receptor alpha (FOLRl) antibody conjugate; VEGF-A inhibitors; and Sub>A package insert comprising instructions for administering the FOLR1 antibody conjugate and the VEGF-Sub>A inhibitor according to the methods of the invention.
Examples
Example 1
anti-FOLR 1 antibody drug conjugates for use in combination with VEGF TRAP
This example provides the results of a study of the combination of an anti-FOLR 1 antibody conjugate according to the invention with bevacizumab in a mouse OV-90 tumor model.
On the day of treatment, mice bearing OV-90 tumors were administered one of the following therapies: 2.5mg/kg of conjugate A, 5.0mg/kg of bevacizumab, or 2.5mg/kg of conjugate A+5.0mg/kg of bevacizumab. A certain difference was observed in OV-90 tumor growth and response to treatment. Single agent conjugate a had little activity (fig. 1, first panel). The single dose solubilized mouse VEGF receptor also showed little to no activity (FIG. 1, first panel, VEGF Trap). Co-administration of conjugate A and bevacizumab inhibited OV-90 tumor growth (55% TGI). The second graph in fig. 1 provides the weight change.
In a further experiment, mice bearing OV-90 tumors were administered one of the following therapies on the day of treatment: 5.0mg/kg of conjugate A, 5.0mg/kg of bevacizumab, or 5.0mg/kg of conjugate A+5.0mg/kg of bevacizumab. The combination of 5mg/kg of conjugate a+5mg/kg bevacizumab per single dose increased TGI significantly to 96% compared to either single dose of conjugate a (29% TGI, p < 0.0001) or single dose of bevacizumab (68% TGI, p < 0.0054) (fig. 2A). The percentage of body weight change calculated relative to the body weight of the animals at the beginning of the study indicated that all treatments were well tolerated (fig. 2B).
Example 2
Treatment of patients with advanced epithelial ovarian cancer with anti-FOLR 1 and bevacizumab
In this study, the pharmacokinetics, safety and efficacy of conjugate a in combination with bevacizumab (15 mg/kg) administered Intravenously (IV) for the treatment of advanced epithelial ovarian cancer, including fallopian tube cancer or primary peritoneal cancer, was evaluated.
Patients include individuals with recurrent platinum-resistant ovarian cancer or other high grade serous epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
A patient will be excluded if the patient has a disorder of any of several conditions, including: low grade ovarian cancer (grade 1); clear cell carcinoma, mucinous carcinoma, endometrioid carcinoma, sarcoidosis, mixed histological ovarian carcinoma and sarcomatous ovarian carcinoma; previous treatments using FolRα -targeted ADCs or ADCs containing tubulin inhibitors; previous anti-cancer treatments (prior to the first administration of study drugs): including chemotherapy within 3 weeks, PARP inhibitors within 2 weeks, other therapeutic anti-cancer antibodies within 3 weeks, radioimmunoconjugates or toxin immunoconjugates (e.g., ADC) within 10 weeks, or radiation treatment/major surgery within 4 weeks after the first study drug administration; preexisting eye diseases of clinical significance; past history of solid organ transplantation; ileus and/or signs/symptoms of ileus occurring within the last 3 months; there is a history of gastrointestinal perforation; CTCAE not less than grade 2 toxicity of previous anticancer treatment residue; a history of CHF; nephrotic syndrome; sensory or motor neuropathy grade >1; potentially fatal concurrent or recent malignancy; chronic or persistent active infectious diseases requiring systemic treatment; sustained immunosuppressive therapy, including systemic corticosteroids; heart disease of clinical significance; serious concurrent, uncontrolled medical conditions including, but not limited to, diseases of the kidney, liver, blood, gastrointestinal tract, endocrine, pulmonary, neurological, brain or mental; a history or clinical sign of a meningeal or active central nervous system involvement; known severe chronic obstructive pulmonary disease or asthma (defined as FEV1< 40% of expected value) or active pneumonia within 6 months after the first study drug administration; a history of significant cerebrovascular disease, such as stroke or TIA, within 6 months; human immunodeficiency virus is known to be seropositive; pregnancy or lactation; serological hepatitis b detection is positive, defined as HBsAg detection positive; while participating in a therapeutic trial of another therapeutic agent; pelvic examination has evidence of involvement of the rectocele colon, or CT scan has evidence of involvement of the intestine; a history of hemoptysis within 6 months; venous or arterial thromboembolic events occurred within 3 months.
The study was a modified 3x3 dose escalation trial in which treatment was performed for 3 patients in each group. The initial dose of conjugate A was between 3.5mg/kg and 5.2mg/kg, while the bevacizumab dose remained constant. Dosing regimen will include administration of bevacizumab at a dose of 15mg/kg together with conjugate a at a starting dose of 3.5 mg/kg. The administration was once every three weeks for 7 months. For a given patient group, ADC molecule 4 was used with increasing doses until Dose Limiting Toxicity (DLT) occurred to determine the recommended phase 2 dose (RP 2D) for the combination.
Patients were serologically screened for hepatitis b and c and tested for serum or urine pregnancy (within 7 days after initiation of study treatment) and proteinuria was monitored by dipstick urine analysis to observe development or deterioration of proteinuria.
During cycles 1-4, patients were screened weekly, and every 3 weeks at the beginning of cycle 5 and EOT, patients were screened for hematology (Hgb, hematocrit, PT/PTT/fibrinogen, WBC, ANC, platelets), and serum chemistry (protein, albumin, creatinine, BUN, total bile, ALP, AST, glucose, sodium, potassium, chlorine, calcium, LDH, uric acid, phosphorus). Patients were CPK screened on day 1 of each cycle.
Patients are monitored to assess adverse events and to determine Overall Response Rate (ORR), duration of response (DOR), overall Survival (OS), and Progression Free Survival (PFS). The patient is monitored for potential drug-drug interactions.
Example 3
Table 5 provides the sequences mentioned in the present invention.
TABLE 5 sequence
Equivalents (Eq.)
The invention as set forth above may include a plurality of different inventions having independent utility. Although each of these inventions has been disclosed in its preferred form, the specific embodiments thereof as disclosed and illustrated herein are not to be considered in a limiting sense as numerous variations are possible. The subject matter of the inventions includes all novel and non-obvious combinations and subcombinations of the various elements, features, functions and/or properties disclosed herein. The following claims particularly point out certain combinations and subcombinations regarded as novel and nonobvious. Inventions embodied in other combinations and subcombinations of features, functions, elements, and/or properties may be claimed in this or a priority application or related applications. Such claims, whether related to different inventions or related to the same invention and whether broader, narrower, equal, or different in scope to the original claims, also are regarded as included within the subject matter of the inventions of the present disclosure.
One or more features of any embodiment described in the present invention or in the accompanying drawings may be combined with one or more features of any other embodiment described in the present invention or in the accompanying drawings without departing from the scope of the invention.
All publications, patents, and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes/variations and modifications/modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims (68)

1. A method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject:
(a) An effective amount of an antibody conjugate comprising an antibody that specifically binds folate receptor alpha (FOLR 1), said antibody being site-specifically linked to at least one payload group moiety, wherein said antibody comprises one or more unnatural amino acids at a site selected from the group consisting of: HC F404, HC-K121, HC-Y180, HC-F241, HC-221, LC-T22, LC-S7, LC-N152, LC-K42, LC-E161, LC-D170, HC-S136, HC S25, HC-A40, HC-S119, HC-S190, HC-K222, HC-R19, HC-Y52, or HC-S70 according to the kappa (Kabat), ke Xiya (Chothia), or EU numbering scheme; and
(b) An effective amount of one or more VEGF-Sub>A inhibitors.
2. The method of claim 1, wherein the administration is by Intravenous (IV) administration.
3. The method of claim 1 or 2, wherein the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered separately on the same day.
4. The method of claim 1 or 2, wherein the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered simultaneously on the same day.
5. The method of any one of the preceding claims, wherein the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered about once every 3 weeks or more for the remainder of the treatment.
6. The method of any one of the preceding claims, wherein the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered about once every 3 weeks.
7. The method of any one of the preceding claims, wherein the antibody conjugate and the one or more VEGF-Sub>A inhibitors are administered about once every 4 weeks.
8. The method of any one of the preceding claims, wherein the amount of antibody conjugate is about 3.5mg/kg or more.
9. The method of any one of the preceding claims, wherein the amount of antibody conjugate is about 4.3mg/kg.
10. The method of any one of the preceding claims, wherein the amount of antibody conjugate is about 5.2mg/kg.
11. The method of any one of the preceding claims, further comprising administering the antibody conjugate to the subject at a reduced dose.
12. The method of claim 11, wherein the reduced dose is about 4.3mg/kg or less.
13. The method of claim 11 or 12, wherein the reduced dose is about 4.3mg/kg.
14. The method of claim 11 or 12, wherein the reduced dose is about 3.5mg/kg.
15. The method of claim 11 or 12, wherein the reduced dose is about 2.9mg/kg.
16. The method of any one of claims 11-15, wherein the antibody conjugate is administered to the subject in a first dose for 1 to 5 cycles, wherein each cycle is about 3 weeks or more, prior to the reduced dose.
17. The method of claim 16, wherein the antibody conjugate is administered to the subject in a first dose for 1 to 3 cycles, wherein each cycle is about 3 weeks or more, prior to the reduced dose.
18. The method of claim 16, wherein the antibody conjugate is administered to the subject in a first dose for 2 to 4 cycles, wherein each cycle is about 3 weeks or more, prior to the reduced dose.
19. The method of any one of the preceding claims, wherein the one or more VEGF-Sub>A inhibitors comprises bevacizumab or Sub>A bevacizumab anti-biological analogue.
20. The method of claim 19, wherein the bevacizumab anti-biological analogue is selected from the group consisting of: MVASI, zirabev, bevax, lumiere, apotex, equidacent, avegra, BP 01, BCD500, krabeva, BAT1706, BXT-2316, bevaro, BI 695502, CT-P16, CHS-5217, DRZ_ BZ, cizumab, byvasda, MIL60, MYL 1402O, ONS-1045, HD204, ankeda, bevacirel, aybintio, onbevzi, HLX04, TX16, MB02, BI 695502, and Oyavas.
21. The method of claim 19, wherein the one or more VEGF-Sub>A inhibitors is bevacizumab.
22. The method of any one of the preceding claims, wherein the amount of the one or more VEGF-Sub>A inhibitors is about 15mg/kg.
23. The method of any one of the preceding claims, wherein the one or more unnatural amino acids are selected from the group consisting of: p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, L-3- (2-naphthyl) alanine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, tri-O-acetyl-GlcNAcP-serine, L-Dopa (Dopa), fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-methyl-L-phenylalanine, compound 56, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, L-phosphoserine, phosphonoserine (phosphoserine), phosphonotyrosine (phosphotyrosine), p-iodo-phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, and p-propargyloxy-phenylalanine.
24. The method of any of the preceding claims, wherein the one or more unnatural amino acids is compound (30) or compound (56).
25. The method of any one of the preceding claims, wherein the residues of the one or more unnatural amino acids are linked to the payload moiety via a hydrolytically stable linker.
26. The method of any one of the preceding claims, wherein the residues of the one or more unnatural amino acids are linked to the payload moiety via a cleavable linker.
27. The method of any preceding claim, wherein the payload moiety is selected from the group consisting of: maytansinoids (maytansines), hamiltines (hemiasterlins), amanits (amanitins), and auristatins (auristatins).
28. The method of any preceding claim, wherein the payload moiety is selected from the group consisting of: DM1, hammeterlin (hemiasterlin), amatoxins (amanitin), MMAF, and MMAE.
29. The method of any one of the preceding claims, wherein the payload moiety is a hamiltin (hemiasterlin) derivative.
30. A method according to any preceding claim, wherein the payload group moiety is
Wherein Ar is optionally substituted aryl or optionally substituted heteroaryl, L is a linker, and the wavy line represents a bond to the antibody.
31. The method of any one of the preceding claims, wherein the antibody comprises:
(i) The V is H Region SEQ ID NO:362 and the V L Region SEQ ID NO:367 three heavy chainsCDRs and three light chain CDRs;
(ii) The V is H Region SEQ ID NO:323 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs;
(iii) The V is H Region SEQ ID NO:308 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (iv) The V is H Region SEQ ID NO:309 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (v) The V is H Region SEQ ID NO:310 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (vi) The V is H Region SEQ ID NO:311 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (vii) The V is H Region SEQ ID NO:312 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (viii) The V is H Region SEQ ID NO:313 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (ix) The V is H Region SEQ ID NO:314 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (x) The V is H Region SEQ ID NO:315 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xi) The V is H Region SEQ ID NO:316 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xii) The V is H Region SEQ ID NO:317 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xiii) The V is H Region SEQ ID NO:318 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xiv) The V is H Region SEQ ID NO:319 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xv) The V is H Region SEQ ID NO:320 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xvi) The V is H Region SEQ ID NO:321 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xvii) The V is H Region SEQ ID NO:322 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xviii) The V is H Region SEQ ID NO:324 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xix) The V is H Region SEQ ID NO:325 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xx) The V is H Region SEQ ID NO:326 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxi) The V is H Region SEQ ID NO:327 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxii) The V is H Region SEQ ID NO:328 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxiii) The V is H Region SEQ ID NO:329 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxiv) The V is H Region SEQ ID NO:330 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxv) The V is H Region SEQ ID NO:331 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxvi) The V is H Region SEQ ID NO:332 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxvii) The V is H Region SEQ ID NO:333 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxviii) The V is H Region SEQ ID NO:334 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxix) The V is H Region SEQ ID NO:335 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxx) The V is H Region SEQ ID NO:336 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxxi) The V is H Region SEQ ID NO:337 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxxii) The V is H Region SEQ ID NO:338 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxxiii) The V is H Region SEQ ID NO:339 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxxiv) The V is H Region SEQ ID NO:340 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs;(xxxv) The V is H Region SEQ ID NO:341 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxxvi) The V is H Region SEQ ID NO:342 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxxvii) The V is H Region SEQ ID NO:343 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxxviii) The V is H Region SEQ ID NO:344 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xxxix) The V is H Region SEQ ID NO:345 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xl) The V is H Region SEQ ID NO:346 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xli) The V is H Region SEQ ID NO:347 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xlii) The V is H Region SEQ ID NO:348 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xliii) The V is H Region SEQ ID NO:349 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xliv) The V is H Region SEQ ID NO:350 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xlv) The V is H Region SEQ ID NO:351 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xlvi) The V is H Region SEQ ID NO:352 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xlvii) The V is H Region SEQ ID NO:353 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xlviii) The V is H Region SEQ ID NO:354 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (xlix) The V is H Region SEQ ID NO:355 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (l) The V is H Region SEQ ID NO:356 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (li) the V H Region SEQ ID NO:357 and the V L Region SEQ ID NO:367 three weightsChain CDRs and three light chain CDRs; (lii) the V H Region SEQ ID NO:358 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (liii) the V H Region SEQ ID NO:359 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (liv) the V H Region SEQ ID NO:360 and the V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (lv) the V H Region SEQ ID NO:361 and said V L Region SEQ ID NO:367 three heavy chain CDRs and three light chain CDRs; (lvi) the V H Region SEQ ID NO:363 and said V L Region SEQ ID NO:368 and three light chain CDRs; (lvii) the V H Region SEQ ID NO:364 and the V L Region SEQ ID NO:368 and three light chain CDRs; (lviii) the V H Region SEQ ID NO:365 and said V L Region SEQ ID NO:369 three heavy chain CDRs and three light chain CDRs; or (b)
(lix) the V H Region SEQ ID NO:366 and said V L Region SEQ ID NO:369 three heavy chain CDRs and three light chain CDRs.
32. The method of any one of the preceding claims, wherein the antibody comprises:
(i)V H comprising: comprising SEQ ID NO:58 and SEQ ID NO:117 one of CDR-H1; comprising SEQ ID NO:176 and SEQ ID NO: CDR-H2 of one of 235; and a polypeptide comprising SEQ ID NO:294 CDR-H3;
(ii)V H comprising: comprising SEQ ID NO:19 and SEQ ID NO:78, CDR-H1 of one of them; comprising SEQ ID NO:137 and SEQ ID NO: one of 196 CDR-H2; and a polypeptide comprising SEQ ID NO:255 CDR-H3;
(iii)V H Comprising: comprising SEQ ID NO:4 and SEQ ID NO: CDR-H1 of one of 63; comprising SEQ ID NO:122 and SEQ ID NO:181 one of CDR-H2; and a polypeptide comprising SEQ ID NO:240 CDR-H3;
(iv)V H comprising: comprising SEQ ID NO:5 and SEQ ID NO:64, CDR-H1 of one of the; comprising SEQ ID NO:123 and SEQ ID NO:182 one of CDR-H2; and a polypeptide comprising SEQ ID NO:241CDR-H3 of (b);
(v)V H comprising: comprising SEQ ID NO:6 and SEQ ID NO:65, CDR-H1 of one of the; comprising SEQ ID NO:124 and SEQ ID NO:183 one of CDR-H2; and a polypeptide comprising SEQ ID NO:242 CDR-H3;
(vi)V H comprising: comprising SEQ ID NO:7 and SEQ ID NO: CDR-H1 of one of 66; comprising SEQ ID NO:125 and SEQ ID NO: one of 184 CDR-H2; and a polypeptide comprising SEQ ID NO:243 CDR-H3;
(vii)V H comprising: comprising SEQ ID NO:8 and SEQ ID NO: CDR-H1 of one of 67; comprising SEQ ID NO:126 and SEQ ID NO:185 one of CDR-H2; and a polypeptide comprising SEQ ID NO:244 CDR-H3;
(viii)V H comprising: comprising SEQ ID NO:9 and SEQ ID NO: CDR-H1 of one of 68; comprising SEQ ID NO:127 and SEQ ID NO: one of 186 CDR-H2; and a polypeptide comprising SEQ ID NO:245 CDR-H3;
(ix)V H comprising: comprising SEQ ID NO:10 and SEQ ID NO: CDR-H1 of one of 69; comprising SEQ ID NO:128 and SEQ ID NO: one of 187 CDR-H2; and a polypeptide comprising SEQ ID NO:246 CDR-H3;
(x)V H Comprising: comprising SEQ ID NO:11 and SEQ ID NO:70, CDR-H1 of one of the; comprising SEQ ID NO:129 and SEQ ID NO: CDR-H2 of one of 188; and a polypeptide comprising SEQ ID NO:247 CDR-H3;
(xi)V H comprising: comprising SEQ ID NO:12 and SEQ ID NO:71 one of CDR-H1; comprising SEQ ID NO:130 and SEQ ID NO: one of 189 CDR-H2; and a polypeptide comprising SEQ ID NO:248 CDR-H3;
(xii)V H comprising: comprising SEQ ID NO:13 and SEQ ID NO:72, CDR-H1 of one of the; comprising SEQ ID NO:131 and SEQ ID NO: 190; and a polypeptide comprising SEQ ID NO: CDR-H3 of 249;
(xiii)V H comprising: comprising SEQ ID NO:14 and SEQ ID NO:73 one of CDR-H1; comprising SEQ ID NO:132 and SEQ ID NO:191 one of CDR-H2; and a polypeptide comprising SEQ ID NO:250 CDR-H3;
(xiv)V H comprising: comprising SEQ ID NO:15 and SEQ ID NO:74, one of themCDR-H1 of (b); comprising SEQ ID NO:133 and SEQ ID NO:192, CDR-H2 of one of the polypeptides; and a polypeptide comprising SEQ ID NO:251 CDR-H3;
(xv)V H comprising: comprising SEQ ID NO:16 and SEQ ID NO:75, one of CDR-H1; comprising SEQ ID NO:134 and SEQ ID NO:193 one of CDR-H2; and a polypeptide comprising SEQ ID NO:252 CDR-H3;
(xvi)V H comprising: comprising SEQ ID NO:17 and SEQ ID NO:76, CDR-H1 of one of the; comprising SEQ ID NO:135 and SEQ ID NO:194, one of CDR-H2; and a polypeptide comprising SEQ ID NO:253 CDR-H3;
(xvii)V H Comprising: comprising SEQ ID NO:18 and SEQ ID NO:77, CDR-H1 of one of the peptides; comprising SEQ ID NO:136 and SEQ ID NO: 195-H2; and a polypeptide comprising SEQ ID NO:254 CDR-H3;
(xviii)V H comprising: comprising SEQ ID NO:20 and SEQ ID NO: CDR-H1 of one of 79; comprising SEQ ID NO:138 and SEQ ID NO:197 one of CDR-H2; and a polypeptide comprising SEQ ID NO:256 CDR-H3;
(xix)V H comprising: comprising SEQ ID NO:21 and SEQ ID NO: CDR-H1 of one of 80; comprising SEQ ID NO:139 and SEQ ID NO:198, CDR-H2 of one of the polypeptides; and a polypeptide comprising SEQ ID NO:257 CDR-H3;
(xx)V H comprising: comprising SEQ ID NO:22 and SEQ ID NO:81 one of CDR-H1; comprising SEQ ID NO:140 and SEQ ID NO:199, CDR-H2 of one of the; and a polypeptide comprising SEQ ID NO:258 CDR-H3;
(xxi)V H comprising: comprising SEQ ID NO:23 and SEQ ID NO:82, CDR-H1 of one of the; comprising SEQ ID NO:141 and SEQ ID NO: CDR-H2 of one of 200; and a polypeptide comprising SEQ ID NO:259 CDR-H3;
(xxii)V H comprising: comprising SEQ ID NO:24 and SEQ ID NO:83, CDR-H1 of one of the; comprising SEQ ID NO:142 and SEQ ID NO: CDR-H2 of one of 201; and a polypeptide comprising SEQ ID NO:260 CDR-H3;
(xxiii)V H comprising: comprising SEQ ID NO:25 and SEQ ID NO: CDR-H1 of one of 84; comprising SEQ ID NO:143 and SEQ ID NO:202 one of CDR-H2; and a polypeptide comprising SEQ ID NO:261 CDR-H3;
(xxiv)V H Comprising: comprising SEQ ID NO:26 and SEQ ID NO: CDR-H1 of one of 85; comprising SEQ ID NO:144 and SEQ ID NO:203 one of CDR-H2; and a polypeptide comprising SEQ ID NO:262 CDR-H3;
(xxv)V H comprising: comprising SEQ ID NO:27 and SEQ ID NO:86 one of CDR-H1; comprising SEQ ID NO:145 and SEQ ID NO:204 one of CDR-H2; and a polypeptide comprising SEQ ID NO:263 CDR-H3;
(xxvi)V H comprising: comprising SEQ ID NO:28 and SEQ ID NO:87, CDR-H1 of one of the; comprising SEQ ID NO:146 and SEQ ID NO:205, CDR-H2 of one of the; and a polypeptide comprising SEQ ID NO:264 CDR-H3;
(xxvii)V H comprising: comprising SEQ ID NO:29 and SEQ ID NO:88, CDR-H1 of one of the; comprising SEQ ID NO:147 and SEQ ID NO:206 one of CDR-H2; and a polypeptide comprising SEQ ID NO:265 CDR-H3;
(xxviii)V H comprising: comprising SEQ ID NO:30 and SEQ ID NO: CDR-H1 of one of 89; comprising SEQ ID NO:148 and SEQ ID NO:207, CDR-H2 of one of the; and a polypeptide comprising SEQ ID NO:266 CDR-H3;
(xxix)V H comprising: comprising SEQ ID NO:31 and SEQ ID NO: CDR-H1 of one of 90; comprising SEQ ID NO:149 and SEQ ID NO:208, a CDR-H2 of one of the; and a polypeptide comprising SEQ ID NO:267 CDR-H3;
(xxx)V H comprising: comprising SEQ ID NO:32 and SEQ ID NO: CDR-H1 of one of 91; comprising SEQ ID NO:150 and SEQ ID NO:209 one of CDR-H2; and a polypeptide comprising SEQ ID NO: CDR-H3 of 268;
(xxxi)V H Comprising: comprising SEQ ID NO:33 and SEQ ID NO: CDR-H1 of one of 92; comprising SEQ ID NO:151 and SEQ ID NO:210, one of the CDRs-H2; and a polypeptide comprising SEQ ID NO:269 CDR-H3;
(xxxii)V H comprising: comprising SEQ ID NO:34 and SEQ ID NO: CDR-H1 of one of 93; comprising SEQ ID NO:152 and SEQ ID NO: one of 211 CDR-H2; and a polypeptide comprising SEQ ID NO:270 CDR-H3;
(xxxiii)V H comprising: comprising SEQ ID NO:35 and SEQ ID NO:94, CDR-H1 of one of them; comprising SEQ ID NO:153 and SEQ ID NO:212, CDR-H2 of one of the; and a polypeptide comprising SEQ ID NO:271 CDR-H3;
(xxxiv)V H comprising: comprising SEQ ID NO:36 and SEQ ID NO:95 one of CDR-H1; comprising SEQ ID NO:154 and SEQ ID NO:213 one of CDR-H2; and a polypeptide comprising SEQ ID NO:272 CDR-H3;
(xxxv)V H comprising: comprising SEQ ID NO:37 and SEQ ID NO: CDR-H1 of one of 96; comprising SEQ ID NO:155 and SEQ ID NO:214, CDR-H2 of one of the polypeptides; and a polypeptide comprising SEQ ID NO:273 CDR-H3;
(xxxvi)V H comprising: comprising SEQ ID NO:38 and SEQ ID NO: CDR-H1 of one of 97; comprising SEQ ID NO:156 and SEQ ID NO: one of 215 CDR-H2; and a polypeptide comprising SEQ ID NO:274 CDR-H3;
(xxxvii)V H comprising: comprising SEQ ID NO:39 and SEQ ID NO: CDR-H1 of one of 98; comprising SEQ ID NO:157 and SEQ ID NO:216, a CDR-H2 of one of the polypeptides; and a polypeptide comprising SEQ ID NO:275 CDR-H3;
(xxxviii)V H Comprising: comprising SEQ ID NO:40 and SEQ ID NO: CDR-H1 of one of 99; comprising SEQ ID NO:158 and SEQ ID NO: 217; and a polypeptide comprising SEQ ID NO:276 CDR-H3;
(xxxix)V H comprising: comprising SEQ ID NO:41 and SEQ ID NO: CDR-H1 of one of 100; comprising SEQ ID NO:159 and SEQ ID NO:218, a CDR-H2 of one of the peptides; and a polypeptide comprising SEQ ID NO:277 CDR-H3;
(xl)V H comprising: comprising SEQ ID NO:42 and SEQ ID NO: CDR-H1 of one of 101; comprising SEQ ID NO:160 and SEQ ID NO:219 one of CDR-H2; and a polypeptide comprising SEQ ID NO:278 CDR-H3;
(xli)V H comprising: comprising SEQ ID NO:43 and SEQ ID NO:102 to CDR-H1 of one of the; comprising SEQ ID NO:161 and SEQ ID NO:220, a CDR-H2 of one of 220; and a polypeptide comprising SEQ ID NO: CDR-H3 of 279;
(xlii)V H comprising: comprising SEQ ID NO:44 and SEQ ID NO:103, CDR-H1 of one of the; comprising SEQ ID NO:162 and SEQ ID NO:221 one of CDR-H2; and comprises SEQ ID NO:280 CDR-H3;
(xliii)V H comprising: comprising SEQ ID NO:45 and SEQ ID NO:104 to one of CDR-H1; comprising SEQ ID NO:163 and SEQ ID NO:222 one of CDR-H2; and a polypeptide comprising SEQ ID NO:281 CDR-H3;
(xliv)V H comprising: comprising SEQ ID NO:46 and SEQ ID NO:105 one of CDR-H1; comprising SEQ ID NO:164 and SEQ ID NO:223 one of CDR-H2; and a polypeptide comprising SEQ ID NO:282 CDR-H3;
(xlv)V H Comprising: comprising SEQ ID NO:47 and SEQ ID NO:106, CDR-H1 of one of the; comprising SEQ ID NO:165 and SEQ ID NO:224, a CDR-H2 of one of the polypeptides; and a polypeptide comprising SEQ ID NO:283 CDR-H3;
(xlvi)V H comprising: comprising SEQ ID NO:48 and SEQ ID NO: CDR-H1 of one of 107; comprising SEQ ID NO:166 and SEQ ID NO:225, CDR-H2 of one of the polypeptides; and a polypeptide comprising SEQ ID NO:284 CDR-H3;
(xlvii)V H comprising: comprising SEQ ID NO:49 and SEQ ID NO: CDR-H1 of one of 108; comprising SEQ ID NO:167 and SEQ ID NO:226 one of CDR-H2; and a polypeptide comprising SEQ ID NO:285 CDR-H3;
(xlviii)V H comprising: comprising SEQ ID NO:50 and SEQ ID NO:109, one of CDR-H1; comprising SEQ ID NO:168 and SEQ ID NO:227, CDR-H2 of one of the following; and a polypeptide comprising SEQ ID NO:286 CDR-H3;
(xlix)V H comprising: comprising SEQ ID NO:51 and SEQ ID NO:110, CDR-H1 of one of the; comprising SEQ ID NO:169 and SEQ ID NO:228, one of the CDRs-H2; and a polypeptide comprising SEQ ID NO:287 CDR-H3;
(l)V H comprising: comprising SEQ ID NO:52 and SEQ ID NO: CDR-H1 of one of 111; comprising SEQ ID NO:170 and SEQ ID NO: CDR-H2 of one of 229; and a polypeptide comprising SEQ ID NO:288 CDR-H3;
(li)V H comprising: comprising SEQ ID NO:53 and SEQ ID NO:112, CDR-H1 of one of the; comprising SEQ ID NO:171 and SEQ ID NO:230 one of CDR-H2; and a polypeptide comprising SEQ ID NO:289 CDR-H3;
(lii)V H Comprising: comprising SEQ IDNO:54 and SEQ ID NO:113, CDR-H1 of one of the; comprising SEQ ID NO:172 and SEQ ID NO:231, CDR-H2 of one of the; and a polypeptide comprising SEQ ID NO:290 CDR-H3;
(liii)V H comprising: comprising SEQ ID NO:55 and SEQ ID NO: CDR-H1 of one of 114; comprising SEQ ID NO:173 and SEQ ID NO: one of 232 CDR-H2; and a polypeptide comprising SEQ ID NO:291 CDR-H3;
(liv)V H comprising: comprising SEQ ID NO:56 and SEQ ID NO:115, CDR-H1 of one of the; comprising SEQ ID NO:174 and SEQ ID NO:233, one of CDR-H2; and a polypeptide comprising SEQ ID NO:292 CDR-H3;
(lv)V H comprising: comprising SEQ ID NO:57 and SEQ ID NO:116, CDR-H1 of one of the; comprising SEQ ID NO:175 and SEQ ID NO:234, CDR-H2 of one of the; and a polypeptide comprising SEQ ID NO:293 CDR-H3;
(lvi)V H comprising: comprising SEQ ID NO:59 and SEQ ID NO:118, CDR-H1 of one of the; comprising SEQ ID NO:177 and SEQ ID NO:236, CDR-H2 of one of the polypeptides; and a polypeptide comprising SEQ ID NO:295 CDR-H3;
(lvii)V H comprising: comprising SEQ ID NO:60 and SEQ ID NO:119, CDR-H1 of one of; comprising SEQ ID NO:178 and SEQ ID NO:237 one of CDR-H2; and a polypeptide comprising SEQ ID NO:296 CDR-H3;
(lviii)V H comprising: comprising SEQ ID NO:61 and SEQ ID NO: CDR-H1 of one of 120; comprising SEQ ID NO:179 and SEQ ID NO:238, one of CDR-H2; and a polypeptide comprising SEQ ID NO:297 CDR-H3; or (b)
(lix)V H Comprising: comprising SEQ ID NO:62 and SEQ ID NO:121, CDR-H1 of one of the; comprising SEQ ID NO:180 and SEQ ID NO: CDR-H2 of one of 239; and a polypeptide comprising SEQ ID NO:298 CDR-H3.
33. The method of any one of the preceding claims, wherein the antibody comprises:
(a)V L comprising: comprising SEQ ID NO:300 CDR-L1; comprising SEQ ID NO: CDR-L2 of 303; and a polypeptide comprising SEQ ID NO: CDR-L3 of 306; or (b)
(b)V L Comprising: comprising SEQ ID NO: CDR-L1 of 301; comprising SEQ ID NO:304 CDR-L2; and a polypeptide comprising SEQ ID NO:307 CDR-L3.
34. The method of any one of the preceding claims, wherein the antibody comprises:
(i) The V is H The region is SEQ ID NO: 362. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(ii) The V is H The region is SEQ ID NO: 323. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(iii) The V is H The region is SEQ ID NO: 308. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(iv) The V is H The region is SEQ ID NO: 309. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(v) The V is H The region is SEQ ID NO: 310. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(vi) The V is H The region is SEQ ID NO: 311. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(vii) The V is H The region is SEQ ID NO: 312. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(viii) The V is H The region is SEQ ID NO: 313. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(ix) The V is H The region is SEQ ID NO: 314. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(x) The V is H The region is SEQ ID NO: 315. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xi) The V is H The region is SEQ ID NO: 316. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xii) The V is H The region is SEQ ID NO: 317. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xiii) The V is H The region is SEQ ID NO: 318. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xiv) The V is H The region is SEQ ID NO: 319. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xv) The V is H The region is SEQ ID NO: 320. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xvi) The V is H The region is SEQ ID NO: 321. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xvii) The V is H The region is SEQ ID NO: 322. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xviii) The V is H The region is SEQ ID NO: 324. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xix) The V is H The region is SEQ ID NO: 325. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xx) The V is H The region is SEQ ID NO: 326. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxi) The V is H The region is SEQ ID NO: 327. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxii) The V is H The region is SEQ ID NO: 328. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxiii) The V is H The region is SEQ ID NO: 329. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxiv) The V is H The region is SEQ ID NO: 330. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxv) The V is H The region is SEQ ID NO: 331. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxvi) The V is H The region is SEQ ID NO: 332. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxvii) The V is H The region is SEQ ID NO: 333. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxviii) The V is H The region is SEQ ID NO: 334. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxix) The V is H The region is SEQ ID NO: 335. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxx) The V is H The region is SEQ ID NO: 336. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxxi) The V is H The region is SEQ ID NO: 337. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxxii) The V is H The region is SEQ ID NO: 338. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxxiii) The V is H The region is SEQ ID NO: 339. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxxiv) The V is H The region is SEQ ID NO: 340. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxxv) The V is H The region is SEQ ID NO: 341. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxxvi) The V is H The region is SEQ ID NO: 342. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxxvii) The V is H The region is SEQ ID NO: 343. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof；
(xxxviii) The V is H The region is SEQ ID NO: 344. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xxxix) The V is H The region is SEQ ID NO: 345. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xl) The V is H The region is SEQ ID NO: 346. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xli) The V is H The region is SEQ ID NO: 347. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xlii) The V is H The region is SEQ ID NO: 348. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xliii) The V is H The region is SEQ ID NO: 349. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xliv) The V is H The region is SEQ ID NO: 350. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xlv) The V is H The region is SEQ ID NO: 351. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xlvi) The V is H The region is SEQ ID NO: 352. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xlvii) The V is H The region is SEQ ID NO: 353. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xlviii) The V is H The region is SEQ ID NO: 354. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(xlix) The V is H The region is SEQ ID NO: 355. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(l) The V is H The region is SEQ ID NO: 356. or a variant thereof, and the V L The region is SEQ ID NO:367. or a variant thereof;
(li) the V H The region is SEQ ID NO: 357. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(lii) the V H The region is SEQ ID NO: 358. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(liii) the V H The region is SEQ ID NO: 359. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(liv) the V H The region is SEQ ID NO: 360. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(lv) the V H The region is SEQ ID NO: 361. or a variant thereof, and the V L The region is SEQ ID NO: 367. or a variant thereof;
(lvi) the V H The region is SEQ ID NO: 363. or a variant thereof, and the V L The region is SEQ ID NO: 368. or a variant thereof;
(lvii) the V H The region is SEQ ID NO: 364. or a variant thereof, and the V L The region is SEQ ID NO: 368. or a variant thereof;
(lviii) the V H The region is SEQ ID NO: 365. or a variant thereof, and the V L The region is SEQ ID NO: 369. or a variant thereof; or (b)
(lix) the V H The region is SEQ ID NO: 366. or a variant thereof, and the V L The region is SEQ ID NO: 369. or a variant thereof.
35. The method of any one of the preceding claims, wherein the antibody comprises one or more unnatural amino acids at a site selected from the group consisting of: HC-F404, HC-Y180, and LC-K42 according to the EU numbering scheme of Kabat (Kabat) or Kabat (Kabat).
36. The method of any one of the preceding claims, wherein the antibody comprises an unnatural amino acid at position HC-F404.
37. The method of any one of the preceding claims, wherein the antibody comprises unnatural amino acids at positions HC-F404 and HC-Y180.
38. The method of any one of the preceding claims, wherein the antibody comprises unnatural amino acids at positions HC-F404 and LC-K42.
39. The method of any one of the preceding claims, wherein the antibody comprises unnatural amino acids at positions HC-Y180 and LC-K42.
40. The method of any one of claims 36-39, wherein one or both unnatural amino acids are selected from the group consisting of: para-azidomethylphenylalanine and para-azidomethyl-L-phenylalanine.
41. The method of any one of the preceding claims, wherein the antibody conjugate has the structure shown by conjugate P:
wherein n is an integer from 1 to 6.
42. The method of any one of claims 1-40, wherein the antibody conjugate has a structure as shown in conjugate M:
wherein n is an integer from 1 to 6.
43. The method of any one of claims 1-40, wherein the antibody conjugate has a structure shown in conjugate Q:
wherein n is an integer from 1 to 6.
44. The method of any one of the preceding claims, wherein the antibody comprises: SEQ ID NO: v of 362 H A region or variant thereof having 7 or fewer amino acid substitutions, and SEQ ID NO: 367V L A region or variant thereof having 7 or fewer amino acid substitutions.
45. The method of any one of the preceding claims, wherein the antibody comprises: SEQ ID NO: 323V H A region or variant thereof having 7 or fewer amino acid substitutions, and SEQ ID NO: 367V L A region or variant thereof having 7 or fewer amino acid substitutions.
46. The method of claim 44 or 45, wherein the amino acid substitutions are conservative amino acid substitutions.
47. The method of any one of the preceding claims, wherein the antibody further comprises at least one constant region domain.
48. The method of claim 47, wherein the constant region comprises a sequence selected from the group consisting of SEQ ID NOs: 370. SEQ ID NO:371 and SEQ ID NO: 372.
49. The method of any one of the preceding claims, wherein the antibody is a monoclonal antibody.
50. The method of any one of the preceding claims, wherein the antibody is IgA, igD, igE, igG, or IgM.
51. The method of any one of the preceding claims, wherein the antibody is humanized or human.
52. The method of any one of the preceding claims, wherein the antibody is non-glycosylated.
53. The method of any one of the preceding claims, wherein the antibody is an antibody fragment.
54. The method of claim 53, wherein the antibody fragment is selected from the group consisting of Fv fragments, fab fragments, F (ab') 2 Fragments, fab' fragments, scFv (sFv) fragments, and scFv-Fc fragments.
55. The method of claim 54, wherein the antibody fragment is an scFv fragment.
56. The method of claim 55, wherein the antibody fragment is an scFv-Fc fragment.
57. The method of any one of the preceding claims, wherein the subject has previously received a cancer treatment.
58. The method of any one of the preceding claims, wherein the subject has not previously received a cancer treatment.
59. The method of any of the preceding claims, wherein the subject is diagnosed with cancer.
60. The method of any one of the preceding claims, wherein the cancer is ovarian cancer.
61. The method of claim 35, wherein the cancer is epithelial ovarian cancer.
62. The method of any one of the preceding claims, wherein the cancer is endometrial cancer.
63. The method of any one of the preceding claims, wherein the VEGF inhibitor is bevacizumab and the antibody conjugate has the structure shown by conjugate P:
Wherein,
n is 4;
the antibody is an IgG antibody comprising an amino acid sequence according to SEQ ID NO: v of 362 H Region and according to SEQ ID NO: 367V L A zone;
the antibody further comprises replacing each V H Para-azidomethylphenylalanine residues of Y180 and F404 of the region; and
each bond in the antibody structure is attached to a side chain of one of the azidomethylphenylalanine residues.
64. The method of claim 63, wherein the antibody constant region is according to SEQ ID NO:370.
65. the method of claim 63, wherein the antibody constant region is according to SEQ ID NO:371.
66. the method of claim 63, wherein the antibody constant region is according to SEQ ID NO:372.
67. a kit comprising:
(a) An effective amount of the antibody conjugate of any of the preceding claims;
(b) An effective amount of one or more VEGF-Sub>A inhibitors; and
(c) Instructions for use of the antibody conjugate and the VEGF-Sub>A inhibitor.
68. A pharmaceutical package or pharmaceutical kit comprising:
a container;
folate receptor alpha (FOLR 1) antibody conjugates;
VEGF-A inhibitors; and
Sub>A package insert comprising instructions for administering the FOLR1 antibody conjugate and the VEGF-Sub>A inhibitor according to the method of any one of the preceding claims.
CN202280050428.XA 2021-05-19 2022-05-18 Combination therapy with antifolate receptor conjugates and bevacizumab Pending CN117651565A (en)

Applications Claiming Priority (4)

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US63/190743 2021-05-19
US202163291297P 2021-12-17 2021-12-17
US63/291297 2021-12-17
PCT/US2022/029880 WO2022245978A1 (en) 2021-05-19 2022-05-18 Anti-folate receptor conjugate combination therapy with bevacizumab

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