WO2025232811A1 - Antibody targeting fibroblast growth factor receptor 2iiib and use thereof - Google Patents

Abstract

Provided are an antibody targeting fibroblast growth factor receptor 2IIIb and the use thereof. Further provided are a pharmaceutical composition containing the antibody and the use thereof. The antibody can be used in the treatment of tumors.

Description

Antibodies targeting fibroblast growth factor receptor 2IIIb and their applications

This disclosure claims priority to Chinese Patent Application No. 202410572979.3, filed on May 9, 2024, entitled "Antibody Targeting Fibroblast Growth Factor Receptor 2IIIb and Its Application", the entire contents of which are incorporated herein by reference.

Technical Field

This disclosure belongs to the field of biomedical technology, specifically relating to antibodies or antigen-binding fragments thereof targeting FGFR2IIIb, and also to the application of said antibodies or antigen-binding fragments thereof.

Background Technology

The fibroblast growth factor receptor (FGFR) family is a member of the receptor tyrosine kinase (RTK) superfamily, including FGFR1, FGFR2, FGFR3, and FGFR4, which share high sequence homology. FGFRs bind to their natural ligand, fibroblast growth factor (FGF), undergoing dimerization and autophosphorylation, thereby activating downstream signal transduction pathways. FGFRs consist of three parts: an extracellular region containing the ligand binding site, a single-transmembrane hydrophobic α-helix region, and an intracellular region containing kinase domains. The extracellular region contains three immunoglobulin-like domains, D1, D2, and D3. D2 and D3, and the connecting region between them, regulate ligand binding specificity. Between D1 and D2 lies an acidic amino acid sequence called the acid box, which inhibits ligand binding. Due to alternative splicing of RNA, there are two different variants of FGFR2, FGFR2IIIb and FGFR2IIIc (or simply FGFR2b and FGFR2c). FGFR2IIIb is a high-affinity receptor for FGF1 and members of the keratinocyte growth factor (KGF) family (including FGF7, FGF10, and FGF22).

FGFR2IIIb has been found to be aberrantly expressed, such as overexpressed or amplified, in various tumors. FGF7 and FGFR2IIIb are overexpressed in many pancreatic cancers, and their co-expression is associated with poor prognosis (Cho et al., Am.J. Pathol. 170:1964, 2007). Amplification and overexpression of FGFR2 are associated with undifferentiated diffuse gastric cancer, which has a particularly poor prognosis. Furthermore, somatic mutations of the FGFR2 gene, specifically S252W substitution, have been found in 12% of endometrial cancers. Several antibodies targeting FGFR2IIIb have been developed as potential therapeutic targets, but the pool remains limited, and more options are needed.

Invention Summary

This disclosure provides an anti-FGFR2IIIb antibody and its antigen-binding fragment, as well as related nucleic acids, vectors, cells, pharmaceutical compositions, preparation methods, and uses encoding the provided antibody and its antigen-binding fragment.

In one aspect, this disclosure provides an anti-FGFR2IIIb antibody or its antigen-binding fragment, comprising:

(1) HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6;

(2) HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14;

(3) HCDR1 containing the amino acid sequence shown in SEQ ID NO:17, HCDR2 containing the amino acid sequence shown in SEQ ID NO:18, HCDR3 containing the amino acid sequence shown in SEQ ID NO:19, LCDR1 containing the amino acid sequence shown in SEQ ID NO:20, LCDR2 containing the amino acid sequence shown in SEQ ID NO:21, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:22;

(4) HCDR1 containing the amino acid sequence shown in SEQ ID NO:25, HCDR2 containing the amino acid sequence shown in SEQ ID NO:26, HCDR3 containing the amino acid sequence shown in SEQ ID NO:27, LCDR1 containing the amino acid sequence shown in SEQ ID NO:28, LCDR2 containing the amino acid sequence shown in SEQ ID NO:29, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:30; or

(5) HCDR1 containing the amino acid sequence shown in SEQ ID NO:33, HCDR2 containing the amino acid sequence shown in SEQ ID NO:34, HCDR3 containing the amino acid sequence shown in SEQ ID NO:35, LCDR1 containing the amino acid sequence shown in SEQ ID NO:36, LCDR2 containing the amino acid sequence shown in SEQ ID NO:37, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:38.

In one aspect, this disclosure provides an anti-FGFR2IIIb antibody or its antigen-binding fragment, comprising:

(1) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:7, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:8;

(2) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:15, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:16;

(3) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:23, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:24;

(4) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:31, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:32;

(5) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:39, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:40;

(6) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:61, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:64;

(7) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:62, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:64;

(8) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:63, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:64;

(9) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:61, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:65;

(10) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:62, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:65;

(11) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:63, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:65;

(12) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:66, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:68;

(13) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:67, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:68;

(14) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:66, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:69;

(15) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:67, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:69;

(16) HCDR1, HCDR2, and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:96, and LCDR1, LCDR2, and LCDR3 in the light chain variable region as shown in SEQ ID NO:97; or

(17) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:98, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:99.

In one aspect, this disclosure provides isolated nucleic acids containing nucleotide sequences encoding the anti-FGFR2IIIb antibody or its antigen-binding fragment as described in this disclosure.

In one respect, this disclosure provides a carrier containing the nucleic acid described herein.

In one aspect, this disclosure provides a host cell containing the nucleic acid or the vector described in this disclosure.

In one aspect, this disclosure provides a fusion protein comprising the anti-FGFR2IIIb antibody of this disclosure or an antigen-binding fragment thereof.

In one aspect, this disclosure provides antibody-drug conjugates comprising the anti-FGFR2IIIb antibody of this disclosure or an antigen-binding fragment thereof.

In one aspect, this disclosure provides an anti-FGFR2IIIb chimeric antigen receptor comprising the anti-FGFR2IIIb antibody of this disclosure or its antigen-binding fragment.

In one aspect, this disclosure provides engineered immune effector cells that contain the chimeric antigen receptor of this disclosure.

On the other hand, this disclosure provides a method for preparing the anti-FGFR2IIIb antibody or its antigen-binding fragment as described herein, comprising culturing the host cells to express the anti-FGFR2IIIb antibody or its antigen-binding fragment, and isolating and purifying the anti-FGFR2IIIb antibody or its antigen-binding fragment in the system.

On the other hand, this disclosure provides pharmaceutical compositions comprising the anti-FGFR2IIIb antibody or its antigen-binding fragment, the fusion protein, the antibody-drug conjugate or the engineered immune effector cells, and pharmaceutically acceptable excipients.

On the other hand, this disclosure provides the use of the anti-FGFR2IIIb antibody or its antigen-binding fragment, the fusion protein, the antibody-drug conjugate, the engineered immune effector cells, or the pharmaceutical composition in the preparation of a medicament for treating diseases expressing FGFR2IIIb.

On the other hand, this disclosure provides a method for treating diseases expressing FGFR2IIIb, comprising administering to a subject the anti-FGFR2IIIb antibody or an antigen-binding fragment thereof, the fusion protein, the antibody-drug conjugate, the engineered immune effector cells, or the pharmaceutical composition.

The anti-FGFR2IIIb antibody or its antigen-binding fragment disclosed herein exhibits good anti-tumor efficacy and/or safety.

Attached Figure Description

Figure 1 shows the binding curves of anti-FGFR2IIIb chimeric antibody and human FGFR2IIIb-His protein detected by ELISA;

Figures 2A-2H show the binding curves of anti-FGFR2IIIb antibody and FGFR2IIIb-expressing cells as detected by FACS. Figures 2A-2D show the binding curves of chimeric antibody ch-Ab13 and its humanized antibody with KATOIII cells, SNU-16 cells, HEK293T-hFGFR2IIIb cells, or HEK293T-hFGFR2IIIb (S252W) cells, respectively. Figures 2E-2H show the binding curves of chimeric antibody ch-Ab41 and its humanized antibody with KATOIII cells, SNU-16 cells, HEK293T-hFGFR2IIIb cells, or HEK293T-hFGFR2IIIb (S252W) cells, respectively.

Figures 3A-3C show the binding curves of chimeric antibody ch-Ab13 and its humanized antibody with FGFR1IIIb-His protein, FGFR3IIIb-His protein, or FGFR4-His protein detected by ELISA. Figures 3D-3F show the binding curves of chimeric antibody ch-Ab41 and its humanized antibody with FGFR1IIIb-His protein, FGFR3IIIb-His protein, or FGFR4-His protein detected by ELISA.

Figure 4A shows the binding curves of chimeric antibody ch-Ab13 and its humanized antibody with HEK293T-hFGFR2IIIc cells detected by FACS, and Figure 4B shows the binding curves of chimeric antibody ch-Ab41 and its humanized antibody with HEK293T-hFGFR2IIIc cells detected by FACS.

Figures 5A-5C show the ELISA detection of the chimeric antibody ch-Ab13 and its humanized antibody inhibiting FGF1, FGF7 or FGF10-mediated FGFR2IIIb phosphorylation, and Figures 5D-5F show the ELISA detection of the chimeric antibody ch-Ab41 and its humanized antibody inhibiting FGF1, FGF7 or FGF10-mediated FGFR2IIIb phosphorylation.

Figures 6A and 6B show the ADCC effects of hzAb13-2.1 on KATOIII or SNU-16 cells, respectively.

Invention Details

Definitions and Explanations

Unless otherwise stated, the following terms as used in this disclosure have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

The term "antibody" is used in the broadest sense to encompass natural and artificial antibodies of various structures, including but not limited to monoclonal antibodies, polyclonal antibodies, monospecific antibodies and multispecific antibodies (e.g., bispecific antibodies, trispecific antibodies), and various antibody structures of single-chain antibodies, as long as they exhibit the desired antigen-binding activity.

The term “antigen-binding fragment” refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen. Examples covered by the term “antigen-binding fragment” include: (i) Fab fragments: monovalent fragments consisting of _VL , _VH , CL, and CH1 domains; (ii) F(ab') ₂ fragments, bivalent fragments containing two Fab fragments connected by disulfide bridges in the hinge region; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of VL and VH domains of an antibody single arm; (v) dAb fragments consisting of VH domains (see Ward et al., Nature. 341:544-546 (1989)); (vi) separated complementarity-determining regions (CDRs); (vii) nanobodies; and single-chain Fv (scFv).

The term "variable domain" or "variable region" refers to a domain of an antibody involved in the binding of the antibody to an antigen. For example, natural four-chain antibodies (e.g., derived from humans, mice, etc.) have a heavy chain variable region (also called a heavy chain variable domain, VH, or VH domain) and a light chain variable region (also called a light chain variable domain, VL, or VL domain). In most cases, each variable domain of a natural antibody essentially consists of four "frame regions (FRs)" and three "complementarity-determining regions (CDRs)." The four frame regions are referred to as frame region 1 (or FR1), frame region 2 (or FR2), frame region 3 (or FR3), and frame region 4 (or FR4); these frame regions are separated by three complementarity-determining regions, referred to in the art and hereinafter as complementarity-determining regions 1 (or CDR1), 2 (or CDR2), and 3 (or CDR3), respectively. Therefore, the general structure of a variable domain can be represented as: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. Variable domains endow antibodies with antigen specificity because they have antigen-binding sites.

The term "complementarity-determining region" (CDR) is also known as the "hypervariant region" (HVR). Natural four-chain antibodies typically contain six CDRs: three in the heavy chain variable region, namely heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3); and three in the light chain variable region, namely light chain CDR1 (LCDR1), light chain CDR2 (LCDR2), and light chain CDR3 (LCDR3).

Currently, there are many methods for defining CDRs. Among them, the Kabat definition, based on sequence variability, is the most commonly used (Elvin A. Kabat, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991)); while the Chothia definition is based on the location of structural loops (Cyrus Chothia, et al., Canonical Structures for the Hypervariable Regions of Immunoglobulins, J. Mol. Biol. 196:901-917 (1987)). The AbM definition is a compromise between the Kabat and Chothia definitions and is used by Oxford Molecular's AbM antibody modeling software. The "contact" definition of CDRs is based on the analysis of available complex crystal structures. In addition, there are definitions such as IMGT and CCG. However, it should be noted that the boundaries of the CDRs (Continuous Derivatives) of the same antibody variable region obtained based on different methods may differ; that is, the CDR sequences of the same antibody variable region defined by different methods may vary. Therefore, when referring to antibodies defined by a specific CDR sequence, the scope of the antibody also includes antibodies defined by CDR sequences of other arbitrary definitions (e.g., one or more combinations of definitions such as Kabat, IMGT, Chothia, Contact, AbM, CCG, etc.).

The term “treatment” means administering the compounds (e.g., antibodies) or pharmaceutical compositions described in this disclosure to prevent, improve, or eliminate a disease or one or more symptoms associated with said disease, including but not limited to: (i) preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with it; (ii) suppressing a disease or disease state, i.e., halting its development; (iii) alleviating a disease or disease state, even if the disease or disease state subsides; and (iv) reducing any direct or indirect pathological consequences of the disease or disease state.

The term “therapeutic effective amount” means the amount of the disclosed compound used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the disclosed anti-FGFR2IIIb antibody or its antigen-binding fragment, antibody-drug conjugate, engineered immune effector cells, fusion protein, or pharmaceutical composition constituting a “therapeutic effective amount” may vary depending on factors such as the compound or pharmaceutical composition and its ability to elicit a desired response in an individual, the disease state and its severity, the route of administration, and the age, sex, and weight of the mammal to be treated.

The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and/or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit/risk ratio.

The term "excipient" refers to any component other than the active ingredient (e.g., the antibody of this disclosure). The selection of excipients will depend to a great extent on factors such as the specific method of administration, the efficacy of the excipient in terms of solubility and stability, and the nature of the dosage form.

The term "isolated" refers to a target compound that has been isolated from its natural environment, such as an antibody or its antigen-binding fragment or nucleic acid.

The terms “ _Xn ” and “Xaa” are equivalent and refer to unspecified amino acids, the scope of which is specified by subsequent definitions in the relevant description.

As used herein, the term "EC ₅₀ ," or half-maximal effective concentration, refers to the antibody concentration at which the induced response is 50% of the maximum response, i.e., half the distance between the maximum response and baseline. EC ₅₀ can be measured by ELISA or FACS analysis or any other method known in the art.

"K_{_D}" refers to the equilibrium dissociation constant, which is derived from the ratio of the dissociation rate constant (k_{_d} ) to the binding rate constant ( _ka ) (i.e., k _{_d} / _ka ) and is expressed as a molar concentration (M). The K_{_D} value of an antibody can be determined using methods well established in the art. A preferred method for determining the K_{_D} of an antibody is by using surface plasmon resonance (SPR) technology, preferably using a biosensor system such as the Biacore surface plasmon resonance system.

The term "identity," also known as consistency, refers to the percentage of amino acid residues in the sequence to be aligned that are identical to those in the specific amino acid sequence shown herein, after aligning the sequence to be aligned with it and, if necessary, introducing vacancies to achieve the maximum percentage of sequence identity, and without considering any conserved substitutions as part of sequence identity. Amino acid sequence alignment for identity can be performed using various methods within the art, such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for the aligned sequences, including any algorithm required to achieve maximum alignment across the full length of the compared sequences.

The term "subject" includes any human or non-human animal. The term "non-human animal" includes all vertebrates, such as mammals and non-mammals, including non-human primates, sheep, goats, dogs, cats, horses, cattle, chickens, amphibians, reptiles, etc. Preferably, the subject according to this disclosure is a human. Unless otherwise stated, the terms "patient" or "subject" may be used interchangeably.

As used herein, “about” means within the acceptable range of error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” may, in accordance with art practice, mean within one or more standard deviations. Alternatively, “about” may mean a range of up to ±5%, such as fluctuations within ±2%, ±1%, or ±0.5% of a given specific numerical range. When a particular value is given in the scope of this disclosure, unless otherwise stated, “about” shall be understood to mean within the acceptable range of error for that particular value. In this document, unless otherwise stated, the values of step parameters or conditions are implicitly modified by “about”.

The terms “comprise,” “containing,” and “comprising” and their equivalents (e.g., contain, contains, containing, include, includes, and including) shall be understood as “including but not limited to,” meaning that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be covered.

In this document, unless the context clearly indicates otherwise, singular terms encompass plural referents, and vice versa.

Anti-FGFR2IIIb antibody or its antigen-binding fragment

This disclosure provides an anti-FGFR2IIIb antibody or its antigen-binding fragment, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 1, 9, 17, 25 or 33; HCDR2 containing the amino acid sequence shown in SEQ ID NO: 2, 10, 18, 26 or 34; HCDR3 containing the amino acid sequence shown in SEQ ID NO: 3, 11, 19, 27 or 35; LCDR1 containing the amino acid sequence shown in SEQ ID NO: 4, 12, 20, 28 or 36; LCDR2 containing the amino acid sequence shown in SEQ ID NO: 5, 13, 21, 29 or 37; and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 6, 14, 22, 30 or 38.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:17, HCDR2 containing the amino acid sequence shown in SEQ ID NO:18, HCDR3 containing the amino acid sequence shown in SEQ ID NO:19, LCDR1 containing the amino acid sequence shown in SEQ ID NO:20, LCDR2 containing the amino acid sequence shown in SEQ ID NO:21, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:22.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:25, HCDR2 containing the amino acid sequence shown in SEQ ID NO:26, HCDR3 containing the amino acid sequence shown in SEQ ID NO:27, LCDR1 containing the amino acid sequence shown in SEQ ID NO:28, LCDR2 containing the amino acid sequence shown in SEQ ID NO:29, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:30.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:33, HCDR2 containing the amino acid sequence shown in SEQ ID NO:34, HCDR3 containing the amino acid sequence shown in SEQ ID NO:35, LCDR1 containing the amino acid sequence shown in SEQ ID NO:36, LCDR2 containing the amino acid sequence shown in SEQ ID NO:37, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:38.

This disclosure also provides an anti-FGFR2IIIb antibody or its antigen-binding fragment comprising: HCDR1, HCDR2, and HCDR3 in the heavy chain variable region as shown in SEQ ID NO: 7, 15, 23, 31, 39, 61, 62, 63, 66, 67, 96, or 98, and LCDR1, LCDR2, and LCDR3 in the light chain variable region as shown in SEQ ID NO: 8, 16, 24, 32, 40, 64, 65, 68, 69, 97, or 99, wherein the CDRs are defined according to Kabat, IMGT, Chothia, Contact, AbM, and/or CCG.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:7, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:8.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:15, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:16.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:23, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:24.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:31, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:32.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:39, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:40.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2, and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:61, and LCDR1, LCDR2, and LCDR3 in the light chain variable region as shown in SEQ ID NO:64.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:62, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:64.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:63, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:64.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:61, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:65.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2, and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:62, and LCDR1, LCDR2, and LCDR3 in the light chain variable region as shown in SEQ ID NO:65.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:63, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:65.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:66, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:68.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:67, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:68.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:66, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:69.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:67, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:69.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:96, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:97.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:98, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:99.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 7, 15, 23, 31, 39, 61, 62, 63, 66, 67, 96, or 98. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 8, 16, 24, 32, 40, 64, 65, 68, 69, 97, or 99.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% of the amino acid sequence shown in SEQ ID NO: 7, 15, 23, 31, 39, 61, 62, 63, 66, 67, 96, or 98. The heavy chain variable region is 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 8, 16, 24, 32, 40, 64, 65, 68, 69, 97 or 99, and the light chain variable region is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 8, 16, 24, 32, 40, 64, 65, 68, 69, 97 or 99.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:7. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:8. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 15. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 16. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:15, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:16. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:23. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:24. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:23, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:24. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:17, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:18, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:19, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:20, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:21, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:22.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 32. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 32. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:32, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:32. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:25, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:26, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:27, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:28, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:29, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:30.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 39. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 40. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 39, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 40. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:33, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:34, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:35, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:36, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:37, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:38.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 61. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 64. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 64, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 64. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:62. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 62, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 64. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:63. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 63, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 64. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:65. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 65, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 65. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 62, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 65. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 63, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 65. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 66. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 68. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 66, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 68. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:67. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 67, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 68. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:69. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 66, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 69. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 67, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 69. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 96. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 97. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 96, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 97. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 98. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 99. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 98, and a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 99. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment further comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:8.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:15, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:16.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:23, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:24.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:31, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:32.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:39, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:40.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:61, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:64.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:62, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:64.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:63, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:64.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:61, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:65.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:62, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:65.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:63, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:65.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:66, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:68.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:67, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:68.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:66, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:69.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:67, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:69.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:96, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:97.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:98, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:99.

In this disclosure, the antigen-binding fragment is a Fab fragment, an F(ab') ₂ fragment, an Fd fragment, an Fv fragment, a separated CDR region, or a scFv. In this disclosure, the anti-FGFR2IIIb antibody or its antigen-binding fragment is murine, chimeric, or humanized. Humanization can reduce immunogenicity. Therefore, in some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment is humanized.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment of the present disclosure may further comprise a constant region of an immunoglobulin, or a fragment, analog, variant, or derivative of said constant region. In some embodiments, the constant region comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is derived from the heavy chain of human immunoglobulins, such as IgG1, IgG2, IgG3, IgG4, or other classes of immunoglobulins. In some embodiments, the light chain constant region is derived from the light chain of human immunoglobulins, such as the κ or λ light chain of human immunoglobulins. In some embodiments, the anti-FGFR2IIIb antibody is an IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments, the constant region may comprise any modification of the present disclosure or known in the art, such as the insertion, deletion, substitution, or chemical modification of amino acids. The C-terminal lysine of the heavy chain constant region may be present or absent. In some embodiments, the constant region comprises a mutation that alters effector function. In some embodiments, any amino acid residue of the constant region may be substituted with any allotype amino acid residue. In some implementations, the constant region does not contain fucose.

In some specific embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 41, 45, 49, 53, 57, 70, 72, 74, 80, or 82. In some specific embodiments, the anti-FGFR2IIIb antibody comprises a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 43, 47, 51, 55, 59, 76, 78%, 99%, or 100%.

In some specific embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 41, 45, 49, 53, 57, 70, 72, 74, 80, or 82, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 43, 47, 51, 55, 59, 76, 78, 84, or 86.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:41. In some embodiments, the anti-FGFR2IIIb antibody comprises a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:43. In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:41, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:43. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:45. In some embodiments, the anti-FGFR2IIIb antibody comprises a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:47. In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:45, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:47. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:9, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:10, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:11, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:12, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:14.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:49. In some embodiments, the anti-FGFR2IIIb antibody comprises a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:51. In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:49, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:51. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:17, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:18, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:19, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:20, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:21, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:22.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 53. In some embodiments, the anti-FGFR2IIIb antibody comprises a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 55. In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:53, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:55. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:25, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:26, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:27, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:28, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:29, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:30.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 57. In some embodiments, the anti-FGFR2IIIb antibody comprises a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 59. In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:57, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:59. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:33, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:34, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:35, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:36, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:37, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:38.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 70. In some embodiments, the anti-FGFR2IIIb antibody comprises a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 76. In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:70, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:76. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:72. In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:72, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:76. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:74. In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:74, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:76. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody comprises a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:78. In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:70, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:78. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:72, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:78. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:74, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:78. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 80. In some embodiments, the anti-FGFR2IIIb antibody comprises a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 84. In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:80, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:84. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:9, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:10, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:11, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:12, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:14.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:82. In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:82, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:84. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:9, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:10, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:11, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:12, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:14.

In some embodiments, the anti-FGFR2IIIb antibody comprises a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:86. In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:80, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:86. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:9, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:10, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:11, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:12, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:14.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:82, and a light chain having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:86. Furthermore, in some such embodiments, the anti-FGFR2IIIb antibody further comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:9, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:10, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:11, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:12, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:14.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain containing the amino acid sequence shown in SEQ ID NO:41, and a light chain containing the amino acid sequence shown in SEQ ID NO:43.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain comprising the amino acid sequence shown in SEQ ID NO:45, and a light chain comprising the amino acid sequence shown in SEQ ID NO:47.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain comprising the amino acid sequence shown in SEQ ID NO:49, and a light chain comprising the amino acid sequence shown in SEQ ID NO:51.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain containing the amino acid sequence shown in SEQ ID NO:53, and a light chain containing the amino acid sequence shown in SEQ ID NO:55.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain containing the amino acid sequence shown in SEQ ID NO:57, and a light chain containing the amino acid sequence shown in SEQ ID NO:59.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain comprising the amino acid sequence shown in SEQ ID NO:70, and a light chain comprising the amino acid sequence shown in SEQ ID NO:76.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain containing the amino acid sequence shown in SEQ ID NO:72, and a light chain containing the amino acid sequence shown in SEQ ID NO:76.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain comprising the amino acid sequence shown in SEQ ID NO:74, and a light chain comprising the amino acid sequence shown in SEQ ID NO:76.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain containing the amino acid sequence shown in SEQ ID NO:70, and a light chain containing the amino acid sequence shown in SEQ ID NO:78.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain containing the amino acid sequence shown in SEQ ID NO:72, and a light chain containing the amino acid sequence shown in SEQ ID NO:78.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain comprising the amino acid sequence shown in SEQ ID NO:74, and a light chain comprising the amino acid sequence shown in SEQ ID NO:78.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain containing the amino acid sequence shown in SEQ ID NO:80, and a light chain containing the amino acid sequence shown in SEQ ID NO:84.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain containing the amino acid sequence shown in SEQ ID NO:82, and a light chain containing the amino acid sequence shown in SEQ ID NO:84.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain comprising the amino acid sequence shown in SEQ ID NO:80, and a light chain comprising the amino acid sequence shown in SEQ ID NO:86.

In some embodiments, the anti-FGFR2IIIb antibody comprises: a heavy chain comprising the amino acid sequence shown in SEQ ID NO:82, and a light chain comprising the amino acid sequence shown in SEQ ID NO:86.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:41 and a light chain of the amino acid sequence shown in SEQ ID NO:43.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:45 and a light chain of the amino acid sequence shown in SEQ ID NO:47.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:49 and a light chain of the amino acid sequence shown in SEQ ID NO:51.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:53 and a light chain of the amino acid sequence shown in SEQ ID NO:55.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:57 and a light chain of the amino acid sequence shown in SEQ ID NO:59.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:70 and a light chain of the amino acid sequence shown in SEQ ID NO:76.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:72 and a light chain of the amino acid sequence shown in SEQ ID NO:76.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:74 and a light chain of the amino acid sequence shown in SEQ ID NO:76.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:70 and a light chain of the amino acid sequence shown in SEQ ID NO:78.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:72 and a light chain of the amino acid sequence shown in SEQ ID NO:78.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:74 and a light chain of the amino acid sequence shown in SEQ ID NO:78.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:80 and a light chain of the amino acid sequence shown in SEQ ID NO:84.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:82 and a light chain of the amino acid sequence shown in SEQ ID NO:84.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:80 and a light chain of the amino acid sequence shown in SEQ ID NO:86.

In some embodiments, the anti-FGFR2IIIb antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:82 and a light chain of the amino acid sequence shown in SEQ ID NO:86.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:41, and the amino acid sequence of the light chain is shown in SEQ ID NO:43.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:45, and the amino acid sequence of the light chain is shown in SEQ ID NO:47.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:49, and the amino acid sequence of the light chain is shown in SEQ ID NO:51.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:53, and the amino acid sequence of the light chain is shown in SEQ ID NO:55.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:57, and the amino acid sequence of the light chain is shown in SEQ ID NO:59.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:70, and the amino acid sequence of the light chain is shown in SEQ ID NO:76.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:72, and the amino acid sequence of the light chain is shown in SEQ ID NO:76.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:74, and the amino acid sequence of the light chain is shown in SEQ ID NO:76.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:70, and the amino acid sequence of the light chain is shown in SEQ ID NO:78.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:72, and the amino acid sequence of the light chain is shown in SEQ ID NO:78.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:74, and the amino acid sequence of the light chain is shown in SEQ ID NO:78.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:80, and the amino acid sequence of the light chain is shown in SEQ ID NO:84.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:82, and the amino acid sequence of the light chain is shown in SEQ ID NO:84.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:80, and the amino acid sequence of the light chain is shown in SEQ ID NO:86.

In some embodiments, the amino acid sequence of the heavy chain of the anti-FGFR2IIIb antibody is shown in SEQ ID NO:82, and the amino acid sequence of the light chain is shown in SEQ ID NO:86.

It should be understood that the anti-FGFR2IIIb antibodies involved here also include anti-FGFR2IIIb antibodies with the heavy chain C-terminal lysine deletion.

Tables S1 and S2 provide amino acid sequence information for the CDR and variable regions of some exemplary anti-FGFR2IIIb antibodies or their antigen-binding fragments (e.g., chimeric antibodies ch-Ab5, ch-Ab13, ch-Ab34, ch-Ab37, ch-Ab41 and humanized antibodies hzAb13-1.1, hzAb13-1.2, hzAb13-1.3, hzAb13-2.1, hzAb13-2.2, hzAb13-2.3, hzAb41-1.1, hzAb41-1.2, hzAb41-2.1, hzAb41-2.2).

Table S1. Amino acid sequences of CDR and variable regions (SEQ ID NO:)

The anti-FGFR2IIIb antibody or its antigen-binding fragment disclosed herein exhibits good antigen-binding activity. Any of the anti-FGFR2IIIb antibody or its antigen-binding fragment disclosed herein can bind to human FGFR2IIIb and/or monkey FGFR2IIIb. In some embodiments, any of the anti-FGFR2IIIb antibody or its antigen-binding fragment disclosed herein, when measured by surface plasmon resonance (SPR) technology, can bind to human FGFR2IIIb at the following _{concentrations} : 5.00E-08M or less, 2.00E-08M or less, 1.44E-08M or less, 1.36E-08M or less, 1.32E-08M or less, 1.31E-08M or less, 1.29E-08M or less, 1.00E-08M or less, 9.95E-09M or less, 9.15E-09M or less, 8.31E-08M or less. 9M or smaller, 6.97E-09M or smaller, 5.00E-09M or smaller, 4.38E-09M or smaller, 2.00E-09M or smaller, 1.00E-09M or smaller, 5.00E-10M or smaller, 2.00E-10M or smaller, 1.00E-10M or smaller, 5.00E-11M or smaller, 2.00E-11M or smaller, or 1.00E-11M or smaller.

The anti-FGFR2IIIb antibody or its antigen-binding fragment provided in this disclosure can inhibit or block the binding of FGFR2IIIb to FGF.

The anti-FGFR2IIIb antibody or its antigen-binding fragment provided in this disclosure can inhibit FGF-mediated FGFR2IIIb phosphorylation.

Any of the anti-FGFR2IIIb antibody or its antigen-binding fragment provided in this disclosure can kill various tumor cells through ADCC. In some embodiments, the tumor is a tumor expressing FGFR2IIIb. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment of this disclosure is unfucosylated. Defucosylation can enhance the interaction between the anti-FGFR2IIIb antibody or its antigen-binding fragment and FcγRIIIa, thereby enhancing the ADCC activity of the anti-FGFR2IIIb antibody or its antigen-binding fragment. Methods for generating antibodies or their antigen-binding fragments with little or no fucose at the Fc glycosylation site without altering the amino acid sequence are known in the art, such as adjusting the composition of the culture medium in which the host cells expressing the antibody or its antigen-binding fragment are located, or knocking out fucose expression-related genes (such as the fut8 gene) in the host cells expressing the antibody or its antigen-binding fragment.

The anti-FGFR2IIIb antibody or its antigen-binding fragment provided in this disclosure can induce tumor growth regression in vivo. In some embodiments, the tumor is a tumor expressing FGFR2IIIb.

The anti-FGFR2IIIb antibody or its antigen-binding fragment provided in this disclosure can delay tumor growth in vivo. In some embodiments, the tumor is a tumor expressing FGFR2IIIb.

The disclosed anti-FGFR2IIIb antibody or its antigen-binding fragment has good safety profile.

In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment is a monoclonal antibody. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment is a monospecific antibody. In some embodiments, the anti-FGFR2IIIb antibody or its antigen-binding fragment is a multispecific antibody (e.g., a bispecific antibody, a trispecific antibody, etc.).

isolated nucleic acids

This disclosure provides isolated nucleic acids containing nucleotide sequences encoding the anti-FGFR2IIIb antibody or its antigen-binding fragment as described in this disclosure. The sequence listing provides exemplary examples of nucleotide sequences encoding the anti-FGFR2IIIb antibody or its antigen-binding fragment.

carrier

This disclosure provides vectors comprising the described nucleic acids. In some embodiments, the vector is a cloning vector. In other embodiments, the vector is an expression vector. As a specific example, the expression vector is pcDNA3.1(+). The expression vector may optionally be capable of expressing any expression vector of the anti-FGFR2IIIb antibody or its antigen-binding fragment described herein.

host cells

This disclosure provides host cells comprising the nucleic acids or vectors of this disclosure. In some embodiments, the host cell is a suitable host cell for cloning or expressing an anti-FGFR2IIIb antibody or its antigen-binding fragment. In some embodiments, the host cell is a prokaryotic cell. In other embodiments, the host cell is a eukaryotic cell. In some embodiments, the host cell is selected from yeast cells, mammalian cells, or other cells suitable for preparing an anti-FGFR2IIIb antibody or its antigen-binding fragment. Mammalian cells include, for example, Chinese hamster ovary (CHO) cells and CHO-S cells.

Fusion protein

In some embodiments, this disclosure provides a fusion protein comprising the anti-FGFR2IIIb antibody of this disclosure or an antigen-binding fragment thereof.

Antibody-drug conjugates (ADCs)

This disclosure provides antibody-drug conjugates comprising the anti-FGFR2IIIb antibody of this disclosure or its antigen-binding fragment. In some embodiments, the antibody-drug conjugate comprises the anti-FGFR2IIIb antibody or its antigen-binding fragment, and a cytotoxic drug.

Chimeric antigen receptor (CAR)

This disclosure also provides an anti-FGFR2IIIb chimeric antigen receptor (CAR) comprising the anti-FGFR2IIIb antibody of this disclosure or its antigen-binding fragment.

Anti-FGFR2IIIb CARs may include (a) an extracellular antigen-binding domain containing FGFR2IIIb binding; (b) a transmembrane domain; and (c) an intracellular signal transduction domain.

This disclosure also provides engineered immune effector cells that contain the CAR of this disclosure. In some embodiments, the immune effector cells are T cells, NK cells, peripheral blood mononuclear cells (PBMCs), hematopoietic stem cells, pluripotent stem cells, or embryonic stem cells.

Pharmaceutical Composition

This disclosure provides pharmaceutical compositions comprising the anti-FGFR2IIIb antibody of this disclosure or an antigen-binding fragment thereof, a fusion protein, an antibody-drug conjugate, or engineered immune effector cells. In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, for example, excipients, diluents, encapsulating materials, fillers, buffers, or other reagents.

In the pharmaceutical composition, the anti-FGFR2IIIb antibody or its antigen-binding fragment may be completely defucosylated (meaning it contains no detectable fucose) or partially defucosylated. In some embodiments, 20% or less, 18% or less, 16% or less, 14% or less, 12% or less, 10% or less, 8% or less, 6% or less, 5% or less, 3% or less, 2% or less, 1.5% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, or 0% of the anti-FGFR2IIIb antibody or its antigen-binding fragment contains fucose. In some embodiments, 0 to 20%, 0 to 18%, 0 to 16%, 0 to 14%, 0 to 12%, 0 to 10%, 0 to 8%, 0 to 6%, 0 to 5%, 0 to 3%, 0 to 2%, 0 to 1.5%, 0 to 1%, 0 to 0.9%, 0 to 0.8%, 0 to 0.7%, 0 to 0.6%, 0 to 0.5%, 0 to 0.4%, 0 to 0.3%, 0 to 0.2%, or 0 to 0.1% of the anti-FGFR2IIIb antibody or its antigen-binding fragment contains fucose.

Methods for preparing anti-FGFR2IIIb antibodies or their antigen-binding fragments

In some embodiments, this disclosure provides a method for preparing an anti-FGFR2IIIb antibody or an antigen-binding fragment thereof, the method comprising: culturing host cells to express the anti-FGFR2IIIb antibody or the antigen-binding fragment thereof, and isolating and purifying the anti-FGFR2IIIb antibody or the antigen-binding fragment thereof in the system. To generate the anti-FGFR2IIIb antibody or the antigen-binding fragment thereof, a nucleic acid encoding the anti-FGFR2IIIb antibody or the antigen-binding fragment thereof is isolated and inserted into one or more vectors for further cloning and/or expression in host cells. The nucleic acid can be obtained using various methods well known in the art, such as gene splicing and chemical synthesis.

The purity of anti-FGFR2IIIb antibody or its antigen-binding fragment can be determined using any of a variety of well-known analytical methods, such as gel electrophoresis, high-performance liquid chromatography, size exclusion chromatography, etc.

The physicochemical properties and/or biological activities of the anti-FGFR2IIIb antibody or its antigen-binding fragment disclosed herein can be identified, screened or characterized by a variety of assay methods known in the art.

use

This disclosure provides the use of the anti-FGFR2IIIb antibody or its antigen-binding fragment thereof. In some specific embodiments, the anti-FGFR2IIIb antibody used may be ch-Ab5, ch-Ab13, ch-Ab34, ch-Ab37, ch-Ab41, hzAb13-1.1, hzAb13-1.2, hzAb13-1.3, hzAb13-2.1, hzAb13-2.2, hzAb13-2.3, hzAb41-1.1, hzAb41-1.2, hzAb41-2.1 and/or hzAb41-2.2.

This disclosure provides the use of the anti-FGFR2IIIb antibody or its antigen-binding fragment, the fusion protein, the antibody-drug conjugate, the engineered immune effector cells, or the pharmaceutical composition in the preparation of a medicament for treating diseases expressing FGFR2IIIb. In some embodiments, this disclosure also provides the use of the anti-FGFR2IIIb antibody or its antigen-binding fragment, the fusion protein, the antibody-drug conjugate, the engineered immune effector cells, or the pharmaceutical composition in combination with one or more additional therapeutic agents in the preparation of a medicament for treating diseases expressing FGFR2IIIb. In some embodiments, this disclosure also provides the use of the anti-FGFR2IIIb antibody or its antigen-binding fragment, the fusion protein, the antibody-drug conjugate, the engineered immune effector cells, or the pharmaceutical composition in the preparation of a medicament for treating diseases expressing FGFR2IIIb in combination with one or more additional therapeutic agents.

This disclosure provides a method for treating a disease expressing FGFR2IIIb, comprising administering to a subject the anti-FGFR2IIIb antibody or its antigen-binding fragment, the fusion protein, the antibody-drug conjugate, the engineered immune effector cells, or the pharmaceutical composition. In some embodiments, the method involves administering to a subject a therapeutically effective amount of the anti-FGFR2IIIb antibody or its antigen-binding fragment, the antibody-drug conjugate, the engineered immune effector cells, or the pharmaceutical composition to treat a disease expressing FGFR2IIIb. In some embodiments, the method includes further administering to the subject one or more additional therapeutic agents.

In some embodiments, in the above uses and methods, the disease is a tumor. In some embodiments, the tumor contains FGFR2 gene amplification. In some embodiments, the tumor overexpresses FGFR2IIIb. In some embodiments, the tumor overexpresses FGFR2IIIb but does not contain FGFR2 gene amplification. In some embodiments, the expression or overexpression of FGFR2IIIb is determined by immunohistochemistry (IHC). In some embodiments, the tumor is a non-solid tumor. In some embodiments, the tumor is a hematologic malignancy. In some embodiments, the tumor is a lymphoma, such as Hodgkin's lymphoma, non-Hodgkin's lymphoma, or B-cell lymphoma. In some embodiments, the tumor is leukemia. In some embodiments, the tumor is multiple myeloma. In some embodiments, the tumor is a solid tumor. In some implementations, the tumor is lung cancer (including non-small cell lung cancer), breast cancer, endometrial cancer, prostate cancer, cervical cancer, urothelial carcinoma, pancreatic cancer, colorectal cancer, melanoma, liver cancer (including hepatocellular carcinoma), ovarian cancer, bladder cancer, gastric cancer, esophageal cancer, gastroesophageal junction (GEJ) cancer, kidney cancer (including renal cell carcinoma), bile duct cancer, head and neck cancer, and/or glioma.

In some embodiments, the additional therapeutic agent in the above uses and methods can be a known oncology therapeutic agent. Non-limiting examples of oncology therapeutic agents include immune checkpoint inhibitors (e.g., anti-PD-1 antibodies or their antigen-binding fragments, anti-PD-L1 antibodies or their antigen-binding fragments), platinum-based agents (e.g., cisplatin, oxaliplatin, and carboplatin), taxanes (e.g., paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel), gemcitabine, capecitabine, enoxacin, epirubicin, FOLFOX (e.g., FOLFOX4, FOLFOX6, mFOLFOX6, FOLFOX7), FOLFIRI, leucovorin, 5-FU, mitomycin, and doxorubicin hydrochloride; wherein the FOLFOX is a combination of oxaliplatin, fluorouracil (5-FU), and leucovorin, and the FOLFIRI is a combination of leucovorin, 5-FU, and enoxacin. In some embodiments, the additional therapeutic agent is FOLFOX, preferably mFOLFOX6.

Reagent test kit

This disclosure provides a kit comprising the anti-FGFR2IIIb antibody of this disclosure or its antigen-binding fragment, fusion protein, antibody-drug conjugate, engineered immune effector cells, or pharmaceutical composition. In some embodiments, the kit may be used for purposes such as implementing the anti-FGFR2IIIb antibody of this disclosure or its antigen-binding fragment, fusion protein, antibody-drug conjugate, engineered immune effector cells, or pharmaceutical composition, or for other uses. In some embodiments, the kit may include the anti-FGFR2IIIb antibody of this disclosure or its antigen-binding fragment, fusion protein, antibody-drug conjugate, engineered immune effector cells, or pharmaceutical composition, and reagents for detecting the presence of FGFR2IIIb in a biological sample. The kit may also include instructions for use. The kit may also include other materials required from a commercial and user perspective, such as other buffers, diluents, needles, syringes, etc.

Detailed Implementation

This disclosure also provides the following specific implementation schemes, but the scope of protection of this disclosure is not limited thereto:

Implementation Scheme 1. An anti-FGFR2IIIb antibody or its antigen-binding fragment, comprising: HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 1, 9, 17, 25 or 33; HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 2, 10, 18, 26 or 34; HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 3, 11, 19, 27 or 35; LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 4, 12, 20, 28 or 36; LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 5, 13, 21, 29 or 37; and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 6, 14, 22, 30 or 38.

Implementation Scheme 2. The anti-FGFR2IIIb antibody or its antigen-binding fragment according to Implementation Scheme 1, wherein the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises:

(1) HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6;

(2) HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14;

(3) HCDR1 containing the amino acid sequence shown in SEQ ID NO:17, HCDR2 containing the amino acid sequence shown in SEQ ID NO:18, HCDR3 containing the amino acid sequence shown in SEQ ID NO:19, LCDR1 containing the amino acid sequence shown in SEQ ID NO:20, LCDR2 containing the amino acid sequence shown in SEQ ID NO:21, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:22;

(4) HCDR1 containing the amino acid sequence shown in SEQ ID NO:25, HCDR2 containing the amino acid sequence shown in SEQ ID NO:26, HCDR3 containing the amino acid sequence shown in SEQ ID NO:27, LCDR1 containing the amino acid sequence shown in SEQ ID NO:28, LCDR2 containing the amino acid sequence shown in SEQ ID NO:29, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:30; or

(5) HCDR1 containing the amino acid sequence shown in SEQ ID NO:33, HCDR2 containing the amino acid sequence shown in SEQ ID NO:34, HCDR3 containing the amino acid sequence shown in SEQ ID NO:35, LCDR1 containing the amino acid sequence shown in SEQ ID NO:36, LCDR2 containing the amino acid sequence shown in SEQ ID NO:37, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:38.

Implementation Scheme 3. An anti-FGFR2IIIb antibody or an antigen-binding fragment thereof, comprising: HCDR1, HCDR2, and HCDR3 in a heavy chain variable region as shown in SEQ ID NO: 7, 15, 23, 31, 39, 61, 62, 63, 66, 67, 96, or 98, and LCDR1, LCDR2, and LCDR3 in a light chain variable region as shown in SEQ ID NO: 8, 16, 24, 32, 40, 64, 65, 68, 69, 97, or 99, wherein the CDRs are defined according to Kabat, IMGT, Chothia, Contact, AbM, and/or CCG.

Implementation Scheme 4. The anti-FGFR2IIIb antibody or its antigen-binding fragment according to Implementation Scheme 3, wherein the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises:

(1) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:7, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:8;

(2) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:15, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:16;

(3) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:23, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:24;

(4) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:31, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:32;

(5) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:39, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:40;

(6) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:61, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:64;

(7) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:62, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:64;

(8) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:63, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:64;

(9) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:61, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:65;

(10) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:62, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:65;

(11) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:63, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:65;

(12) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:66, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:68;

(13) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:67, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:68;

(14) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:66, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:69;

(15) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:67, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:69;

(16) HCDR1, HCDR2, and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:96, and LCDR1, LCDR2, and LCDR3 in the light chain variable region as shown in SEQ ID NO:97; or

(17) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:98, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:99;

The CDR is defined according to Kabat, IMGT, Chothia, Contact, AbM and/or CCG.

Implementation Scheme 5. An anti-FGFR2IIIb antibody or antigen-binding fragment thereof according to any one of Implementation Schemes 1-4, wherein the anti-FGFR2IIIb antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 7, 15, 23, 31, 39, 61, 62, 63, 66, 67, 96, or 98.

Implementation Scheme 6. An anti-FGFR2IIIb antibody or antigen-binding fragment thereof according to any one of Implementation Schemes 1-5, wherein the anti-FGFR2IIIb antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 8, 16, 24, 32, 40, 64, 65, 68, 69, 97, or 99.

Implementation Scheme 7. An anti-FGFR2IIIb antibody or its antigen-binding fragment according to any one of Implementation Schemes 1-6, wherein the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises:

(1) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence shown in SEQ ID NO:8;

(2) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:15, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:16;

(3) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:23, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:24;

(4) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:31, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:32;

(5) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:39, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:40;

(6) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 61, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 64;

(7) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:62, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:64;

(8) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 63, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 64;

(9) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 61, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 65;

(10) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 62, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 65;

(11) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 63, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 65;

(12) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:66, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:68;

(13) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 67, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 68;

(14) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 66, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 69;

(15) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 67, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 69;

(16) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 96, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 97; or

(17) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 98, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 99.

Implementation Scheme 8. An anti-FGFR2IIIb antibody or its antigen-binding fragment according to any one of Implementation Schemes 1-7, wherein the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises:

(1) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:8;

(2) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:15, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:16;

(3) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:23, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:24;

(4) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:31, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:32;

(5) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:39, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:40;

(6) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:61, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:64;

(7) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:62, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:64;

(8) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:63, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:64;

(9) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:61, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:65;

(10) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:62, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:65;

(11) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:63, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:65;

(12) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:66, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:68;

(13) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:67, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:68;

(14) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:66, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:69;

(15) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:67, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:69;

(16) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:96, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:97; or

(17) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:98 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:99.

Implementation Scheme 9. An anti-FGFR2IIIb antibody or its antigen-binding fragment according to any one of Implementation Schemes 1-8, wherein the antigen-binding fragment is a Fab fragment, an F(ab') ₂ fragment, an Fd fragment, an Fv fragment, a separated CDR region, or a scFv.

Implementation Scheme 10. An anti-FGFR2IIIb antibody or antigen-binding fragment thereof according to any one of Implementation Schemes 1-9, wherein the anti-FGFR2IIIb antibody or antigen-binding fragment thereof is murine, chimeric, or humanized.

Implementation Scheme 11. An anti-FGFR2IIIb antibody or its antigen-binding fragment according to any one of Implementation Schemes 1-10, wherein the anti-FGFR2IIIb antibody is an IgG1, IgG2, IgG3 or IgG4 isotype.

Implementation Scheme 12. An anti-FGFR2IIIb antibody or an antigen-binding fragment thereof according to any one of Implementation Schemes 1-11, wherein the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 41, 45, 49, 53, 57, 70, 72, 74, 80, or 82.

Implementation Scheme 13. An anti-FGFR2IIIb antibody or an antigen-binding fragment thereof according to any one of Implementation Schemes 1-12, wherein the anti-FGFR2IIIb antibody comprises a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 43, 47, 51, 55, 59, 76, 78, 84, or 86.

Implementation Scheme 14. An anti-FGFR2IIIb antibody or an antigen-binding fragment thereof according to any one of Implementation Schemes 1-13, wherein the anti-FGFR2IIIb antibody comprises:

(1) A heavy chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence shown in SEQ ID NO:41, and a light chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence shown in SEQ ID NO:43;

(2) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:45, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:47;

(3) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:49, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:51;

(4) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:53, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:55;

(5) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:57, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:59;

(6) A heavy chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:70, and a light chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:76;

(7) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:72, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:76;

(8) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:74, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:76;

(9) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:70, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:78;

(10) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:72, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:78;

(11) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:74, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:78;

(12) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:80, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:84;

(13) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:82, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:84;

(14) A heavy chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 80, and a light chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 86; or

(15) A heavy chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:82, and a light chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:86.

Implementation Scheme 15. An anti-FGFR2IIIb antibody or an antigen-binding fragment thereof, wherein the anti-FGFR2IIIb antibody comprises:

(1) A heavy chain containing the amino acid sequence shown in SEQ ID NO:41, and a light chain containing the amino acid sequence shown in SEQ ID NO:43;

(2) A heavy chain comprising the amino acid sequence shown in SEQ ID NO:45, and a light chain comprising the amino acid sequence shown in SEQ ID NO:47;

(3) A heavy chain containing the amino acid sequence shown in SEQ ID NO:49, and a light chain containing the amino acid sequence shown in SEQ ID NO:51;

(4) A heavy chain containing the amino acid sequence shown in SEQ ID NO:53, and a light chain containing the amino acid sequence shown in SEQ ID NO:55;

(5) A heavy chain comprising the amino acid sequence shown in SEQ ID NO:57, and a light chain comprising the amino acid sequence shown in SEQ ID NO:59;

(6) A heavy chain comprising the amino acid sequence shown in SEQ ID NO:70, and a light chain comprising the amino acid sequence shown in SEQ ID NO:76;

(7) A heavy chain comprising the amino acid sequence shown in SEQ ID NO:72, and a light chain comprising the amino acid sequence shown in SEQ ID NO:76;

(8) A heavy chain comprising the amino acid sequence shown in SEQ ID NO:74, and a light chain comprising the amino acid sequence shown in SEQ ID NO:76;

(9) A heavy chain comprising the amino acid sequence shown in SEQ ID NO:70, and a light chain comprising the amino acid sequence shown in SEQ ID NO:78;

(10) A heavy chain comprising the amino acid sequence shown in SEQ ID NO:72, and a light chain comprising the amino acid sequence shown in SEQ ID NO:78;

(11) A heavy chain comprising the amino acid sequence shown in SEQ ID NO:74, and a light chain comprising the amino acid sequence shown in SEQ ID NO:78;

(12) A heavy chain comprising the amino acid sequence shown in SEQ ID NO:80, and a light chain comprising the amino acid sequence shown in SEQ ID NO:84;

(13) A heavy chain comprising the amino acid sequence shown in SEQ ID NO:82, and a light chain comprising the amino acid sequence shown in SEQ ID NO:84;

(14) A heavy chain comprising the amino acid sequence shown in SEQ ID NO:80, and a light chain comprising the amino acid sequence shown in SEQ ID NO:86; or

(15) A heavy chain comprising the amino acid sequence shown in SEQ ID NO:82, and a light chain comprising the amino acid sequence shown in SEQ ID NO:86.

Implementation Scheme 16. An anti-FGFR2IIIb antibody or its antigen-binding fragment according to any one of Implementation Schemes 1-15, wherein the anti-FGFR2IIIb antibody or its antigen-binding fragment is unfucosylated.

Implementation Scheme 17. An anti-FGFR2IIIb antibody or antigen-binding fragment thereof according to any one of Implementation Schemes 1-16, wherein the anti-FGFR2IIIb antibody or antigen-binding fragment thereof has one or more of the following properties:

(1) Binding to human FGFR2IIIb; preferably, measured by surface plasmon resonance technology, with _KD of 5E-08M or less, 1E-09M or less, or 5E-10M or less binding to human FGFR2IIIb;

(2) Combined with monkey FGFR2IIIb;

(3) Inhibit or block the binding of FGFR2IIIb to FGF;

(4) Inhibit FGF-mediated FGFR2IIIb phosphorylation;

(5) Kills various tumor cells through ADCC action;

(6) Induces tumor growth and regression in vivo; and

(7) Delay the growth of tumors in the body.

Implementation Scheme 18. An anti-FGFR2IIIb antibody or its antigen-binding fragment according to any one of Implementation Schemes 1-17, wherein the anti-FGFR2IIIb antibody or its antigen-binding fragment is a monospecific antibody or a multispecific antibody.

Implementation Scheme 19. An isolated nucleic acid comprising a nucleotide sequence encoding an anti-FGFR2IIIb antibody or an antigen-binding fragment thereof as described in any one of Implementation Schemes 1-18.

Implementation Scheme 20. A carrier comprising the nucleic acid described in Implementation Scheme 19.

Implementation Scheme 21. A host cell comprising the nucleic acid described in Implementation Scheme 19, or the vector described in Implementation Scheme 20.

Implementation Scheme 22. A method for preparing an anti-FGFR2IIIb antibody or an antigen-binding fragment thereof as described in any one of Implementation Schemes 1-18, comprising culturing the host cells described in Implementation Scheme 21 to express the anti-FGFR2IIIb antibody or the antigen-binding fragment thereof, and isolating and purifying the anti-FGFR2IIIb antibody or the antigen-binding fragment thereof in the system.

Implementation Scheme 23. A fusion protein comprising any one of the anti-FGFR2IIIb antibody or its antigen-binding fragment as described in Implementation Schemes 1-18.

Implementation Scheme 24. An antibody-drug conjugate comprising any one of the anti-FGFR2IIIb antibody or its antigen-binding fragment as described in Implementation Schemes 1-18.

Implementation Scheme 25. A chimeric antigen receptor comprising an anti-FGFR2IIIb antibody or an antigen-binding fragment thereof, as described in any one of Implementation Schemes 1-18.

Implementation Scheme 26. An engineered immune effector cell comprising the chimeric antigen receptor described in Implementation Scheme 25.

Implementation Scheme 27. A pharmaceutical composition comprising an anti-FGFR2IIIb antibody or an antigen-binding fragment thereof according to any one of Implementation Schemes 1-18, a fusion protein according to Implementation Scheme 23, an antibody-drug conjugate according to Implementation Scheme 24, or an engineered immune effector cell according to Implementation Scheme 26; optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

Implementation Scheme 28. Use of the anti-FGFR2IIIb antibody or antigen-binding fragment thereof according to any one of Implementation Schemes 1-18, the fusion protein according to Implementation Scheme 23, the antibody-drug conjugate according to Implementation Scheme 24, the engineered immune effector cells according to Implementation Scheme 26, or the pharmaceutical composition according to Implementation Scheme 27 in the preparation of a medicament for treating diseases expressing FGFR2IIIb.

Implementation Scheme 29. Use of any anti-FGFR2IIIb antibody or antigen-binding fragment thereof according to any one of Implementation Schemes 1-18, the fusion protein according to Implementation Scheme 23, the antibody-drug conjugate according to Implementation Scheme 24, the engineered immune effector cells according to Implementation Scheme 26, or the pharmaceutical composition according to Implementation Scheme 27, together with one or more additional therapeutic agents, in the preparation of a medicament for treating diseases expressing FGFR2IIIb.

Implementation Scheme 30. The use according to Implementation Scheme 28 or 29, wherein the disease is a tumor.

Implementation Scheme 31. The use according to Implementation Scheme 29 or 30, wherein the additional therapeutic agent is a tumor therapeutic agent.

Implementation Scheme 32. The use according to any one of Implementation Schemes 29-31, wherein the additional therapeutic agent is an immune checkpoint inhibitor or FOLFOX, preferably an anti-PD-1 antibody or its antigen-binding fragment, an anti-PD-L1 antibody or its antigen-binding fragment, or mFOLFOX6.

Implementation Scheme 33. The use according to any one of Implementation Schemes 30-32, wherein the tumor is a hematologic malignancy, lung cancer, breast cancer, endometrial cancer, prostate cancer, cervical cancer, urothelial carcinoma, pancreatic cancer, colorectal cancer, melanoma, liver cancer, ovarian cancer, bladder cancer, gastric cancer, esophageal cancer, gastroesophageal junction cancer, kidney cancer, bile duct cancer, head and neck cancer, and/or glioma.

Implementation Scheme 34. The use according to any one of Implementation Schemes 30-33, wherein the tumor overexpresses FGFR2IIIb.

Implementation Scheme 35. The use described in Implementation Scheme 34, wherein FGFR2IIIb expression is determined by IHC.

Implementation scheme 36. The use described in implementation scheme 34 or 35, wherein the tumor does not contain FGFR2 gene amplification.

Implementation Scheme 37. The use according to any one of Implementation Schemes 30-35, wherein the tumor comprises an amplified FGFR2 gene.

Implementation Scheme 38. A method for treating a disease expressing FGFR2IIIb, comprising administering to a subject an anti-FGFR2IIIb antibody or an antigen-binding fragment thereof as described in any one of Implementation Schemes 1-18, a fusion protein as described in Implementation Scheme 23, an antibody-drug conjugate as described in Implementation Scheme 24, engineered immune effector cells as described in Implementation Scheme 26, or a pharmaceutical composition as described in Implementation Scheme 27.

Implementation Scheme 39. The method according to Implementation Scheme 38, wherein the method includes further administering one or more additional therapeutic agents to the subject.

Implementation Scheme 40. The method according to Implementation Scheme 38 or 39, wherein the disease is a tumor.

Implementation Scheme 41. The method according to Implementation Scheme 39 or 40, wherein the additional therapeutic agent is a tumor therapeutic agent.

Implementation Scheme 42. The method according to any one of Implementation Schemes 39-41, wherein the additional therapeutic agent is an immune checkpoint inhibitor or FOLFOX, preferably an anti-PD-1 antibody or its antigen-binding fragment, an anti-PD-L1 antibody or its antigen-binding fragment, or mFOLFOX6.

Implementation Scheme 43. The method according to any one of Implementation Schemes 40-42, wherein the tumor is a hematologic malignancy, lung cancer, breast cancer, endometrial cancer, prostate cancer, cervical cancer, urothelial carcinoma, pancreatic cancer, colorectal cancer, melanoma, liver cancer, ovarian cancer, bladder cancer, gastric cancer, esophageal cancer, gastroesophageal junction cancer, kidney cancer, bile duct cancer, head and neck cancer, and/or glioma.

Implementation Scheme 44. The method according to any one of Implementation Schemes 40-43, wherein the tumor overexpresses FGFR2IIIb.

Implementation Scheme 45. The method described in Implementation Scheme 44, wherein FGFR2IIIb expression is determined by IHC.

Implementation Scheme 46. The method described in Implementation Scheme 44 or 45, wherein the tumor does not contain FGFR2 gene amplification.

Implementation Scheme 47. The method according to any one of Implementation Schemes 40-45, wherein the tumor contains an amplified FGFR2 gene.

Implementation Scheme 48. A kit comprising the anti-FGFR2IIIb antibody or its antigen-binding fragment as described in any one of Implementation Schemes 1-18, the fusion protein as described in Implementation Scheme 23, the antibody-drug conjugate as described in Implementation Scheme 24, the engineered immune effector cells as described in Implementation Scheme 26, or the pharmaceutical composition as described in Implementation Scheme 27.

For clarity, this disclosure is further illustrated by examples, but these examples are not intended to limit the scope of this disclosure. Those skilled in the art will readily identify various non-critical parameters that can be changed or modified to produce substantially similar results. The hIgG1 control antibody used in the examples is from Baiying Biotechnology, catalog number B117901.

Example 1: Construction of FGFR2 overexpression cell lines

DNA sequences encoding the full-length open reading frames (amino acid sequences as shown in SEQ ID NO: 92, 93, and 94, respectively) of human FGFR2IIIb, human FGFR2IIIc, and human FGFR2IIIb (S252W) were subcloned into the expression vector pcDNATM3.1/Zeo(+) (Invitrogen catalog number: V86020). HEK-293T cells were transfected with Lipofectamine 3000 (Gibco, catalog number: L3000001) transfection reagent. After bleomycin selection for 2-3 weeks, the cells were further divided using the limiting dilution method. Monoclonal cells were obtained, and the expression levels of human FGFR2IIIb, human FGFR2IIIc, and human FGFR2IIIb (S252W) on the surface of the monoclonal cell line HEK-293T were detected by flow cytometry (FACS). Monoclonal cell lines with high expression levels of human FGFR2IIIb, human FGFR2IIIc, and human FGFR2IIIb (S252W) were selected and named HEK293T-hFGFR2IIIb cells, HEK293T-hFGFR2IIIc cells, and HEK293T-hFGFR2IIIb (S252W) cells, respectively.

Example 2: Preparation of FGFR2IIIb antigen

The DNA sequence encoding the open reading frame of the extracellular domain of human FGFR2IIIb protein (Uniprot: P21802-3) was fused with the DNA sequence of human IgG1 Fc tag and cloned into the expression vector pcDNA3.1(+) (Invitrogen, catalog number: V-79020). The expression vector was transfected into Expi293F cells for transient expression, and the fusion protein human FGFR2IIIb-Fc Tag (amino acid sequence as shown in SEQ ID NO: 95) was obtained by purification using a protein A column (GE Healthcare).

Example 3: Production of positive monoclonal cells

To generate antibodies against human FGFR2IIIb, human FGFR2IIIb-Fc Tag was emulsified with Freund's complete adjuvant (for initial immunization) or Freund's incomplete adjuvant (for booster immunization) at a volume ratio of 1:1. BALB/c and A/J mice were subcutaneously immunized at 100 μg/mouse every 2 weeks for 4 immunizations over 6 weeks. Serum was collected after the 3rd and 4th immunizations, and antibody titers were measured by ELISA. Three days prior to cell fusion, mice were sprint-immunized by intravenous injection of adjuvant-free human FGFR2IIIb-Fc Tag. Spleen cells (approximately 1 × ^10⁸ cells) from immunized mice were fused with SP2/0-Ag14 myeloma cells (1 × ^10⁷ to 3 × ^10⁷ cells) using an electrofusion instrument (BTX, model: ECM2001). After fusion, the fused cells were diluted with 500 mL of RPMI-1640 medium containing 10% fetal bovine serum, and then aliquoted into 96-well plates at 0.1 mL/well. The plates were incubated at 37°C in a 5% _CO2 incubator. On day 2, an additional 0.1 mL of RPMI-1640 medium containing 10% serum and 2% hypoxanthine (H), aminopterin (A), and thymidine (T) supplements (HAT supplement, lifetechnology, catalog number: 21060017) was added to each well for further culture.

Positive clones were screened using a protein- and cell-based binding and ligand competition assay. Positive hybridoma cells in logarithmic growth were counted and diluted to 5-10 cells/mL with complete RPMI-1640 medium (containing 10% fetal bovine serum and 2% HT supplement, Sigma, HO137). Cells were seeded at 200 μL/well in 96-well plates and incubated at 37°C with 5% _CO2 for approximately 8 days. The supernatant from each visible monoclonal cell well was collected for further screening to obtain positive monoclonal cells.

Example 4: cDNA acquisition and chimeric antibody construction of anti-FGFR2IIIb antibody

Total RNA was isolated from positive monoclonal cells producing anti-human FGFR2IIIb antibody using the RNeasy mini kit (Qiagen, catalog number: 74104) as a template, and first-strand cDNA was synthesized using the PrimeScript 1st strand cDNA Synthesis Kit (TAKARA, catalog number: D6110A). Then, using the first-strand cDNA as a template, PCR was performed with degenerate mouse IgG primers to obtain a PCR mixture. The PCR mixture was separated by electrophoresis on a 1% agarose/Tris-borate gel containing 0.5 μg/mL ethidium bromide. DNA fragments of the expected size (approximately 450 bp for both heavy and light chains) were excised from the gel and purified. 3 μL of the purified PCR product was cloned into the pMD-18T vector (Takara, catalog number: D101A) and transformed into One Shot TOP10 chemically competent *E. coli* (Invitrogen, catalog number: C4040-03) for culture. Single colonies were selected for DNA sequencing, yielding the heavy chain variable region (VH) and light chain variable region (VL) sequences of five murine monoclonal antibodies (Ab5, Ab13, Ab34, Ab37, and Ab41).

A chimeric light chain was constructed by linking the VL region gene synthesis fragment of mouse antibody to the constant region of human κ chain, and a chimeric heavy chain was constructed by linking the VH region gene synthesis fragment of mouse antibody to the constant region of human IgG1.

Expression plasmids containing chimeric light chain DNA and chimeric heavy chain DNA were transfected into FUT8 knockout CHO-S cells (100 mL, at a cell density of 6.3 × ^10⁶ /mL) for transient expression, and then cultured in CHOgro Expression medium (Mirus Bio, catalog number: 6200A) at 32°C for 10–12 days on a shaker. The chimeric antibody in the supernatant was purified using a protein A column (GE Healthcare). The sequence information of the chimeric antibody is shown in Table 1 below.

Table 1. Sequence information of anti-FGFR2IIIb chimeric antibody (SEQ ID NO:)

Example 5: Antigen binding assay of anti-FGFR2IIIb chimeric antibody

Bayer's Aprutumab (the amino acid sequences of the heavy and light chains are shown in SEQ ID NO: 88 and 89, respectively, specifically recognizing and binding to FGFR2 antigen, including FGFR2b) and Amgen's Bemarituzumab (the amino acid sequences of the heavy and light chains are shown in SEQ ID NO: 90 and 91, respectively, specifically recognizing and binding to FGFR2b antigen) were selected as benchmarks to evaluate the antigen-binding activity of the chimeric antibodies. The preparation of Aprutumab and Bemarituzumab followed the method described in Example 4. Human FGFR2IIIb-His protein (Sino Biological, catalog number: 16485-H08H) was diluted to 2 μg/mL with pH 7.4 PBS (SmartBuffer, catalog number: PBS-2050) buffer and added to a 96-well plate (Costar, catalog number: 9018) at a volume of 100 μL/well, and incubated overnight at 4°C for 16 h. After discarding the liquid, add 300 μL of 2% BSA (SIGMA, catalog number: B2064-100G) diluted in PBS to each well for blocking, and incubate at 37°C for 2 hours. After blocking, discard the blocking solution and wash the plate three times with PBST buffer (PBS containing 0.05% Tween-20, pH 7.4). Then, add 100 μL of serially diluted (0.001-100 nM) anti-FGFR2IIIb chimeric antibody, reference, or hIgG1 control antibody to each well, and incubate at 37°C for 1 hour. After incubation, wash the plate three times with PBST, and add 100 μL of 1:5000 diluted horseradish peroxidase (HRP)-conjugated goat anti-human IgG (H+L) (Jackson Immuno Research, catalog number: 109-035-098) to each well, and incubate at 37°C for 1 hour. After washing the plate three times with PBST, 100 μL of TMB chromogenic substrate (TIANGEN, catalog number: PA107-01) was added to each well, and the plate was incubated at room temperature for 10-15 minutes. The reaction was _then stopped by adding 50 μL of 1M _H₂SO₄ to each well. The absorbance was measured using a microplate reader (Teken, Infinite F50) at a wavelength of 450 nm (reference wavelength: 620 nm). The antibody-antigen binding curve was fitted, and the _EC₅₀ was calculated. The results are shown in Figure 1 and Table 2. The results show that all the chimeric antibodies specifically bound the FGFR2IIIb antigen, and the _EC₅₀ values were comparable to those of Aprutumab and Bemarituzumab, reaching as low as E-11M.

Table 2. Binding of anti-FGFR2IIIb chimeric antibody to human FGFR2IIIb ( _EC50 and maximum binding)

Example 6: Humanization of anti-FGFR2IIIb antibody

Humanization of ch-AB13 and ch-Ab41 was performed using the CDR transplantation method (see, for example, US Patent No. 5,225,539). Humanization of ch-Ab13 yielded three heavy chain variable regions (amino acid sequences shown in SEQ ID NO: 61-63, respectively) and two light chain variable regions (amino acid sequences shown in SEQ ID NO: 64 and 65, respectively). Humanization of ch-Ab41 yielded two heavy chain variable regions (amino acid sequences shown in SEQ ID NO: 66 and 67, respectively) and two light chain variable regions (amino acid sequences shown in SEQ ID NO: 68 and 69, respectively). The humanized VH region was ligated to the human IgG1 constant region to construct the humanized heavy chain, and the humanized VL region was ligated to the human κ chain constant region to construct the humanized light chain. The humanized antibody was constructed, expressed, and purified according to the method in Example 4. The sequence information of the anti-FGFR2IIIb humanized antibody is shown in Table 3.

Table 3. Sequence information of humanized antibodies (SEQ ID NO:)

Example 7: Antigen binding assay of anti-FGFR2IIIb antibody

Aprutumab and Bemarituzumab were selected as reference standards. Surface plasmon resonance (SPR) technology was used to detect the affinity of anti-FGFR2IIIb antibody for human FGFR2IIIb-His protein; the preparation of aprutumab was as described in Example 4. Antibodies were captured using a CM5 (Cytiva, catalog number 29127556) biosensor chip coupled with Protein A. The antigen, human FGFR2IIIb-His protein (Sino Biological, catalog number: 16485-H08H), was then passed through the chip surface. Binding and dissociation curves were obtained by real-time detection of the reaction signal using a Biacore 8K instrument. Biacore 8KControl Software 3.0 was used to acquire binding and dissociation curves in real time, and Biacore Insight Evaluation Software 3.0 was used for data analysis. After double subtraction (i.e., the experimental channel signal was subtracted from the control channel signal in each cycle, and the sample signal was subtracted from the blank signal), the data were fitted using a Langmuir 1:1 model to calculate the binding rate constant _ka , dissociation rate constant _kd , and equilibrium constant _KD . The results are shown in Table 4. The results show that the affinity of the humanized antibodies ch-Ab13 and ch-Ab41 for human FGFR2IIIb is comparable to that of their parental chimeric antibodies, and is superior to or comparable to the reference standard.

Table 4. Binding affinity of anti-FGFR2IIIb antibody to FGFR2IIIb

Example 8: Cell binding assay of anti-FGFR2IIIb antibody

Gastric cancer cell lines KATOIII (high expression of FGFR2IIIb) and SNU-16 (low expression of FGFR2IIIb), which naturally express human FGFR2IIIb, as well as HEK293T-hFGFR2IIIb cells and HEK293T-hFGFR2IIIb (S252W) cells, were prepared into cell suspensions with a cell density of 1× ^10⁶ /mL using FACS buffer (Miltenyi Biotec, catalog number: 130-091-221). 100 μL/well was added to each well of a 96-well plate (Corning, catalog number: 3894). Then, 100 μL of different concentrations (0.002-200 nM) of anti-FGFR2IIIb antibody, aprutumab, bemarituzumab, or hIgG1 control antibody diluted with FACS buffer was added to each well. The plates were incubated at 4°C in the dark for 1 hour. Cells were washed three times with FACS buffer, and then 100 μL/well of PE-labeled goat anti-human IgG (H+L) (Bio-legend, catalog number: 409304) diluted 1:500 was added. Cells were incubated at 4°C in the dark for 40 minutes. After washing three times with FACS buffer, the geometric mean fluorescence intensity (MFI) was measured using a Sartorius iQue3 flow cytometer. The _EC50 values of the binding between the anti-FGFR2IIIb antibody and the cell line were obtained through four-parameter nonlinear analysis. The results are shown in Figures 2A-2H, Tables 5-1 and 5-2.

The results showed that, for ch-Ab13 and its humanized antibody, the EC50 values of its in vitro binding with KATOIII gastric cancer cell lines with high FGFR2IIIb expression, as well as cells overexpressing FGFR2IIIb (including wild-type FGFR2IIIb-overexpressing HEK293T-hFGFR2IIIb cells and mutant FGFR2IIIb-overexpressing HEK293T-hFGFR2IIIb (S252W) cells) were comparable to the two reference products, Aprutumab and Bemarituzumab; while _{the EC50} value of its in vitro binding with SNU-16 gastric cancer cell lines with low FGFR2IIIb expression was superior to that of the Aprutumab reference product.

On the other hand, regarding ch-Ab41 and its humanized antibody, the EC50 values of their in vitro binding with all tested cell _lines (including the KATOIII gastric cancer cell line with high FGFR2IIIb expression, the SNU-16 gastric cancer cell line with low FGFR2IIIb expression, the wild-type FGFR2IIIb overexpressing HEK293T-hFGFR2IIIb, and the mutant FGFR2IIIb overexpressing HEK293T-hFGFR2IIIb (S252W)) were comparable to those of the Bemarituzumab reference.

Table 5-1. Binding of anti-FGFR2IIIb antibody to cells expressing human FGFR2IIIb ( _EC50 and maximum binding value)

Table 5-2. Binding of anti-FGFR2IIIb antibody to cells expressing human FGFR2IIIb: _EC50 and maximum binding value

Example 9: Blocking analysis of ligand/receptor binding by anti-FGFR2IIIb antibody

Flow cytometry (FACS) was used to analyze the blocking activity of anti-FGFR2IIIb antibody against the binding of ligands to cells expressing human FGFR2IIIb. KATOIII cells naturally expressing FGFR2IIIb were prepared into a cell suspension with a density of 0.5 × ^10⁶ - 1 × ^10⁶ /mL using FACS buffer (Miltenyi Biotec, catalog number: 130-091-221). 100 μL/well was added to each well of a 96-well plate (Corning, catalog number: 3894), followed by 100 μL/well of anti-FGFR2IIIb antibody (40 nM) prepared using FACS buffer (Miltenyi Biotec, catalog number: 130-091-221), or either Bemarituzumab or hIgG1 control antibody. The reaction was incubated at 4°C for 30 minutes. After washing cells three times with FACS buffer, add 100 μL of biotin-labeled FGF2, FGF7, or FGF10 diluted with FACS buffer to each well (FGF2-biotin is from ACRO Biosystems, catalog number FGC-H81E3, working concentration 0.1 μg/mL; FGF7-biotin is from ACRO Biosystems, catalog number FG7-H82E7, working concentration 0.2 μg/mL; FGF10-biotin is from ACRO Biosystems, catalog number FG0-H81Q7, working concentration 0.1 μg/mL), and incubate at 4°C for 30 minutes. Then, wash cells three times with FACS buffer, add 100 μL of PE-labeled streptavidin diluted 1:500 with FACS buffer to each well (Jackson ImmunoResearch, catalog number: 016-110-084), and incubate at 4°C in the dark for 30 minutes. After washing the cells three times with FACS buffer, 50 μL of FACS buffer was added to each well to resuspend the cells. The geometric mean fluorescence intensity (MFI) on the cell surface was detected using a Sartorius iQue3 flow cytometer, and the blocking rate was calculated.

Blocking rate (%) = (1 - experimental group MFI / hIgG1 group MFI) × 100%.

The results are shown in Table 6. Overall, ch-Ab13 and its humanized antibody and ch-Ab41 and its humanized antibody can effectively block the binding of the ligand to FGFR2IIIb on the cell surface, and the blocking activity is comparable to or better than that of the reference product Bemarituzumab.

Table 6. Blocking rates of anti-FGFR2IIIb antibodies against the binding of FGF2, FGF7, or FGF10 to cells expressing FGFR2IIIb

Example 10: Specificity verification of anti-FGFR2IIIb antibody

10.1 Nonspecific binding of anti-FGFR2IIIb antibody to family proteins FGFR1IIIb, FGFR3IIIb and FGFR4

FGFR1IIIb-His (Sino Biological, catalog number 16482-H08H), FGFR3IIIb-His (Sino Biological, catalog number 16486-H08H), or FGFR4-His (Sino Biological, catalog number 10538-H08H) proteins were diluted to 2 μg/mL using PBS (SmartBuffer, catalog number: PBS-2050) at pH 7.4. 100 μL of each protein was added to a 96-well plate (Costar, catalog number: 9018) and incubated overnight at 4°C for 16 h. After discarding the liquid, 300 μL of 2% BSA (SIGMA, catalog number: B2064-100G) diluted in PBS was added to each well for blocking, and the plate was incubated at 37°C for 2 h. After blocking, discard the blocking solution and wash the plate three times with PBST buffer (PBS containing 0.05% Tween-20, pH 7.4). Add 100 μL of serially diluted (0.001-100 nM) anti-FGFR2IIIb antibody, reference aprutumab, or reference bemarituzumab to each well and incubate at 37°C for 1 hour. After incubation, wash the plate three times with PBST and add 100 μL of 1:5000 diluted horseradish peroxidase (HRP)-conjugated goat anti-human IgG (H+L) (Jackson Immuno Research, catalog number: 109-035-098) to each well and incubate at 37°C for 1 hour. After washing the plate three times with PBST, add 100 μL of TMB chromogenic substrate (TIANGEN, catalog number: PA107-01) to each well and incubate at room temperature for 10-15 minutes. Then, add 50 μL of 1M _H₂SO₄ to _each well to stop the reaction. Measure the absorbance using a microplate reader (Teken, Infinite F50, Switzerland) at a wavelength of 450 nm (reference wavelength: 620 nm). Fit the antibody-antigen binding curve, and the results are shown in Figures 3A-3F.

10.2 Nonspecific binding of anti-FGFR2IIIb antibody to FGFR2IIIc

HEK293T-hFGFR2IIIc cells were prepared into a cell suspension with a density of 0.5 × ^10⁶ - 1 × ^10⁶ /mL using FACS buffer (Miltenyi Biotec, catalog number: 130-091-221). 100 μL/well was added to each well of a 96-well plate (Corning, catalog number: 3894). Then, 100 μL of different concentrations (0.002-200 nM) of anti-FGFR2IIIb antibody, aprutumab, or bemarituzumab diluted with FACS buffer was added to each well, and the plates were incubated at 4°C in the dark for 1 hour. After washing the cells three times with FACS buffer, 100 μL/well of PE-labeled goat anti-human IgG (H+L) diluted 1:500 (Bio-legend, catalog number: 409304) was added, and the plates were incubated at 4°C in the dark for 40 minutes. After washing the cells three times with FACS buffer, the geometric mean fluorescence intensity (MFI) was measured on a Sartorius iQue3 flow cytometer. The results are shown in Figures 4A and 4B. In stark contrast to the aprutumab reference standard, ch-Ab13 and its humanized antibody, as well as ch-Ab41 and its humanized antibody, did not bind to the FGFR2IIIc protein on the cell membrane.

Example 11: Anti-FGFR2IIIb antibody inhibits FGF1, FGF7, and FGF10-mediated FGFR2IIIb phosphorylation.

Using hIgG1 as a negative control and aprutumab and bemarituzumab as references, the Phospho-FGFR2 alpha DuoSet IC ELISA kit (R&D Systems, #DYC684E) was used with the SNU-16 cell line expressing FGFR2IIIb to investigate the inhibitory effect of anti-FGFR2IIIb antibody on FGF1, FGF7, and FGF10-mediated FGFR2IIIb phosphorylation. SNU-16 cells were adjusted to a cell density of 2 × ^10⁵ /mL using RPMI-1640 basal medium containing 10% FBS, and seeded at 50 μL/well in 96-well plates. Then, 50 μL/well of the test antibody at a concentration of 20 μg/mL was added, and the plates were incubated overnight at 37°C and 5% _CO₂ . The following day, 50 ng/mL FGF1 (Sino Biological, catalog number 10013-HNAE), 50 ng/mL FGF7 (Sino Biological, catalog number 10210-H07E), and 50 ng/mL FGF10 (Sino Biological, catalog number 10573-HNAE) solutions were prepared using RPMI-1640 basal medium containing 10% FBS. A 96-well cell culture plate was taken out, and 100 μL of each of the 50 ng/mL FGF1, 50 ng/mL FGF7, or 50 ng/mL FGF10 solutions was added to each well. Untreated cells (without antibody and FGF) were set up as a blank control, and the cells were incubated at 37°C for 15 min. Afterwards, the 96-well cell culture plates were centrifuged, the supernatant was discarded, and 200 μL of cell lysis buffer was added to each well. The plates were then incubated on ice for 15 min, centrifuged at 2000 g/min for 5 min, and the supernatant was collected. The phosphorylation level of FGFR2IIIb was detected by ELISA, following the instructions for the Phospho-FGFR2 alpha DuoSet IC ELISA kit. The results are shown in Figures 5A-5F. At a concentration of 10 μg/mL, ch-Ab13 and its humanized antibody, as well as ch-Ab41 and its humanized antibody, effectively inhibited the phosphorylation level of FGFR2IIIb by FGF1, FGF7, or FGF10 to the level of the blank control group, or even lower.

Example 12: ADCC effect of anti-FGFR2IIIb antibody

The ADCC activity of anti-FGFR2IIIb antibody was detected using KATOIII and SNU-16 cells as target cells and PBMCs as effector cells. Bemarituzumab was used as a reference, and hIgG1 was used as a negative control antibody.

KATOIII and SNU-16 cells were diluted to 3 × ^10⁵ cells/mL using culture medium, and each cell suspension was aliquoted into 96-well plates at 50 μL/well. Different concentrations of the test antibody were then added to the wells of the 96-well plates to achieve final concentrations of 5000 ng/mL, 500 ng/mL, 50 ng/mL, 5 ng/mL, 0.5 ng/mL, 0.05 ng/mL, and 0.005 ng/mL, respectively. PBMC cells were resuscitated, and 100 μL of PBMC cell suspension (cell density 1.5 × ^10⁶ cells/mL) was added to each well of the 96-well plate at an effector cell:target cell ratio of 10:1. The cells were centrifuged at low speed to ensure thorough mixing and contact between effector and target cells, and incubated at 37°C in a 5% _CO₂ incubator for 18 hours. Add 20 μL of cell lysis buffer per well to the lysis buffer group (containing only culture medium and lysis buffer) and the maximum release group (containing target cells, culture medium, and lysis buffer). Incubate at 37°C in a 5% _CO2 incubator for 45 min. Then, centrifuge the 96-well plate at 250 g/min for 5 min. Transfer 50 μL of supernatant from each well to a 96-well assay plate. Prepare LDH working solution according to the CytoTox96 Non-Radio Kit (Promega, catalog number PR-G1781) instructions. Add 50 μL of LDH working solution to each well of the assay plate, mix well, and incubate at room temperature in the dark for 25-35 min. Add 50 μL of stop solution (Promega, catalog number PR-G1782) to each well, mix well, and read the OD value at 492 nm using a microplate reader (Tecan, Infinite F50) to calculate the cell lysis rate.

As shown in Table 7 and Figures 6A-6B, for KATOIII and SNU-16 cell lines, the ADCC activity of the anti-FGFR2IIIb antibody hzAb13-2.1 is comparable to that of Bemarituzumab.

Table 7. Killing _EC50 values and maximum lysis rates of each antibody against KATOIII and SNU-16 cells via ADCC.

Example 13: Pharmacodynamic evaluation of anti-FGFR2IIIb humanized antibody in SNU-16 human gastric cancer CB17-SCID mouse xenograft model

SNU-16 cells (source: Nanjing Kebai) were subcutaneously inoculated in the right axilla of SPF-grade female nude mice (source: Shanghai Lingchang), at a dose of 5 × ^10⁶ cells/mouse. When the average tumor volume reached 100-200 ^mm³ , the animals were divided into 5 groups: solvent control group, Bemarituzumab group, hzAb13-1.2 group, hzAb13-2.1 group, and hzAb41-2.2 group, with 6 mice in each group.

Day 0 (D0) was designated as the day of grouping. On day 1, the treatment group received an intravenous injection (i.v.) of the drug (2 mg/kg) once, while the solvent control group received an intravenous injection of PBS (pH 7.4). Tumor volume was measured 2-3 times per week, and mouse weight was recorded. General mouse behavior was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

The detection indicators and calculation formulas are as follows:

Tumor volume, TV (mm ³ )＝1/2×(a×b ² ); where a is the long diameter of the tumor and b is the short diameter of the tumor.

Relative tumor volume, RTV = _TVt / _TV0 ; where _TV0 is the tumor volume on day 0, and _TVt is the tumor volume at each measurement.

The relative tumor proliferation rate, T/C (%) = _TRTV / _CRTV × 100%; where _TRTV is the RTV of the treatment group and _CRTV is the RTV of the solvent control group.

Tumor growth inhibition rate, TGI(%) = (1-TW/ _TW0 )×100%; where TW is the tumor weight in the treatment group and _TW0 is the tumor weight in the solvent control group.

The rate of change in body weight, WCR(%) = (Wt _t - Wt ₀ )/Wt ₀ ×100%; where Wt ₀ is the body weight of the mouse on day 0, and Wt _t is the body weight of the mouse at each measurement.

The results of the detection indicators are shown in Table 8. In the SNU-16 human gastric cancer mouse xenograft model, hzAb13-1.2, hzAb13-2.1, and hzAb41-2.2 all showed significant tumor-suppressing effects.

Table 8. Effects of anti-FGFR2IIIb antibody on SNU-16 human gastric cancer xenografts in mice.

The p-value is compared with the blank control group.

Example 14: Pharmacodynamic evaluation of anti-FGFR2IIIb humanized antibody in JIMT-1 human breast cancer xenograft model in nude mice

SPF-grade female nude mice (source: Changzhou Cavens) were subcutaneously inoculated with JIMT-1 cells (low expression of FGFR2IIIb, source: AddexBio) in the right axilla at a dose of 2 × ^10⁶ cells/mouse. When the average tumor volume reached 100-200 ^mm³ , the animals were divided into 5 groups of 6 mice each; the day of grouping was designated as day 0 (D0). Specific grouping and drug administration regimens are shown in Table 9.

Table 9. Grouping and Dosing Regimens

Tumor volume was measured 2-3 times per week, and mouse weight was recorded. The general performance of the mice was observed and recorded daily. After the experiment, the tumor was removed, weighed, and photographed.

The detection indicators and calculation formulas are as follows:

Tumor volume, TV (mm ³ )＝1/2×(a×b ² ); where a is the long diameter of the tumor and b is the short diameter of the tumor.

Relative tumor volume, RTV = _TVt / _TV0 ; where _TV0 is the tumor volume on day 0, and _TVt is the tumor volume at each measurement.

The relative tumor proliferation rate, T/C (%) = _TRTV / _CRTV × 100%; where _TRTV is the RTV of the treatment group and _CRTV is the RTV of the solvent control group.

Tumor growth inhibition rate, TGI(%) = (1-TW/ _TW0 )×100%; where TW is the tumor weight in the treatment group and _TW0 is the tumor weight in the solvent control group.

The rate of change in body weight, WCR(%) = (Wt _t - Wt ₀ )/Wt ₀ ×100%; where Wt ₀ is the body weight of the mouse on day 0, and Wt _t is the body weight of the mouse at each measurement.

The results of the detection indicators are shown in Table 10. In the JIMT-1 human breast cancer nude mouse xenograft model, at the same dose, hzAb13-2.1 was more effective than bemarituzumab (TGI value of 50.6% vs. 43.6% in the low-dose group and 53.7% vs. 32.9% in the high-dose group).

Table 10 Effects of anti-FGFR2IIIb antibody on JIMT-1 human breast cancer xenografts in nude mice

The p-value is compared with the blank control group.

The sequence information disclosed herein is summarized in Table S2 below.

Table S2. Sequence Information

For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publications predate the filing date of this disclosure. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publications are part of the general knowledge in the art.

Although this disclosure has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, such modifications or improvements made without departing from the spirit of this disclosure are all within the scope of protection claimed by this disclosure.

Claims (15)

An anti-FGFR2IIIb antibody or its antigen-binding fragment, comprising: HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 1, 9, 17, 25 or 33; HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 2, 10, 18, 26 or 34; HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 3, 11, 19, 27 or 35; LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 4, 12, 20, 28 or 36; LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 5, 13, 21, 29 or 37; and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 6, 14, 22, 30 or 38. Preferably, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: (1) HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6; (2) HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14; (3) HCDR1 containing the amino acid sequence shown in SEQ ID NO:17, HCDR2 containing the amino acid sequence shown in SEQ ID NO:18, HCDR3 containing the amino acid sequence shown in SEQ ID NO:19, LCDR1 containing the amino acid sequence shown in SEQ ID NO:20, LCDR2 containing the amino acid sequence shown in SEQ ID NO:21, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:22; (4) HCDR1 containing the amino acid sequence shown in SEQ ID NO:25, HCDR2 containing the amino acid sequence shown in SEQ ID NO:26, HCDR3 containing the amino acid sequence shown in SEQ ID NO:27, LCDR1 containing the amino acid sequence shown in SEQ ID NO:28, LCDR2 containing the amino acid sequence shown in SEQ ID NO:29, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:30; or (5) HCDR1 containing the amino acid sequence shown in SEQ ID NO:33, HCDR2 containing the amino acid sequence shown in SEQ ID NO:34, HCDR3 containing the amino acid sequence shown in SEQ ID NO:35, LCDR1 containing the amino acid sequence shown in SEQ ID NO:36, LCDR2 containing the amino acid sequence shown in SEQ ID NO:37, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:38. An anti-FGFR2IIIb antibody or its antigen-binding fragment, comprising: HCDR1, HCDR2, and HCDR3 in the heavy chain variable region as shown in SEQ ID NO: 7, 15, 23, 31, 39, 61, 62, 63, 66, 67, 96, or 98, and LCDR1, LCDR2, and LCDR3 in the light chain variable region as shown in SEQ ID NO: 8, 16, 24, 32, 40, 64, 65, 68, 69, 97, or 99, wherein the CDRs are defined according to Kabat, IMGT, Chothia, Contact, AbM, and/or CCG; Preferably, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: (1) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:7, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:8; (2) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:15, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:16; (3) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:23, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:24; (4) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:31, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:32; (5) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:39, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:40; (6) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:61, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:64; (7) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:62, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:64; (8) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:63, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:64; (9) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:61, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:65; (10) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:62, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:65; (11) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:63, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:65; (12) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:66, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:68; (13) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:67, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:68; (14) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:66, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:69; (15) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:67, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:69; (16) HCDR1, HCDR2, and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:96, and LCDR1, LCDR2, and LCDR3 in the light chain variable region as shown in SEQ ID NO:97; or (17) HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO:98, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO:99; The CDR is defined according to Kabat, IMGT, Chothia, Contact, AbM and/or CCG. The anti-FGFR2IIIb antibody or its antigen-binding fragment according to claim 1 or 2, wherein the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 7, 15, 23, 31, 39, 61, 62, 63, 66, 67, 96, or 98; Optionally, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 8, 16, 24, 32, 40, 64, 65, 68, 69, 97, or 99. Preferably, the anti-FGFR2IIIb antibody or its antigen-binding fragment comprises: (1) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence shown in SEQ ID NO:8; (2) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:15, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:16; (3) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:23, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:24; (4) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:31, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:32; (5) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:39, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:40; (6) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 61, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 64; (7) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:62, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:64; (8) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 63, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 64; (9) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 61, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 65; (10) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 62, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 65; (11) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 63, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 65; (12) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:66, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:68; (13) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 67, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 68; (14) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 66, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 69; (15) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 67, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 69; (16) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 96, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 97; or (17) A heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 98, and a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 99. The anti-FGFR2IIIb antibody or its antigen-binding fragment according to any one of claims 1-3, wherein the antigen-binding fragment is a Fab fragment, an F(ab') ₂ fragment, an Fd fragment, an Fv fragment, a separated CDR region, or a scFv; Optionally, the anti-FGFR2IIIb antibody or its antigen-binding fragment is murine, chimeric, or humanized. Optionally, the anti-FGFR2IIIb antibody is an IgG1, IgG2, IgG3 or IgG4 isotype. The anti-FGFR2IIIb antibody or its antigen-binding fragment according to any one of claims 1-4, wherein the anti-FGFR2IIIb antibody comprises a heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 41, 45, 49, 53, 57, 70, 72, 74, 80, or 82; Optionally, the anti-FGFR2IIIb antibody comprises a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 43, 47, 51, 55, 59, 76, 78%, 99%, or 100% identical. Preferably, the anti-FGFR2IIIb antibody comprises: (1) A heavy chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence shown in SEQ ID NO:41, and a light chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence shown in SEQ ID NO:43; (2) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:45, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:47; (3) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:49, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:51; (4) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:53, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:55; (5) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:57, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:59; (6) A heavy chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:70, and a light chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:76; (7) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:72, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:76; (8) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:74, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:76; (9) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:70, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:78; (10) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:72, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:78; (11) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:74, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:78; (12) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:80, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:84; (13) A heavy chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:82, and a light chain having an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:84; (14) A heavy chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 80, and a light chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 86; or (15) A heavy chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:82, and a light chain having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:86. The anti-FGFR2IIIb antibody or its antigen-binding fragment according to any one of claims 1-5, wherein the anti-FGFR2IIIb antibody or its antigen-binding fragment is unfucosylated; Optionally, the anti-FGFR2IIIb antibody or its antigen-binding fragment is a monospecific antibody or a multispecific antibody; Optionally, the anti-FGFR2IIIb antibody or its antigen-binding fragment has one or more of the following characteristics: (1) Binding to human FGFR2IIIb; preferably, measured by surface plasmon resonance technology, with _KD of 5E-08M or less, 1E-09M or less, or 5E-10M or less binding to human FGFR2IIIb; (2) Combined with monkey FGFR2IIIb; (3) Inhibit or block the binding of FGFR2IIIb to FGF; (4) Inhibit FGF-mediated FGFR2IIIb phosphorylation; (5) Kills various tumor cells through ADCC action; (6) Induces tumor growth and regression in vivo; and (7) Delay the growth of tumors in the body. An isolated nucleic acid comprising a nucleotide sequence encoding an anti-FGFR2IIIb antibody or an antigen-binding fragment thereof as described in any one of claims 1-6. A host cell comprising the nucleic acid of claim 7. A fusion protein comprising the anti-FGFR2IIIb antibody or its antigen-binding fragment as described in any one of claims 1-6. An antibody-drug conjugate comprising the anti-FGFR2IIIb antibody or its antigen-binding fragment as described in any one of claims 1-6. A pharmaceutical composition comprising an anti-FGFR2IIIb antibody or an antigen-binding fragment thereof according to any one of claims 1-6, a fusion protein according to claim 9, or an antibody-drug conjugate according to claim 10; optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. A method for treating a disease expressing FGFR2IIIb, comprising administering to a subject an anti-FGFR2IIIb antibody or an antigen-binding fragment thereof as described in any one of claims 1-6, a fusion protein as described in claim 9, an antibody-drug conjugate as described in claim 10, or a pharmaceutical composition as described in claim 11. According to the method of claim 12, the disease is a tumor; preferably, the tumor is a hematologic malignancy, lung cancer, breast cancer, endometrial cancer, prostate cancer, cervical cancer, urothelial carcinoma, pancreatic cancer, colorectal cancer, melanoma, liver cancer, ovarian cancer, bladder cancer, stomach cancer, esophageal cancer, gastroesophageal junction cancer, kidney cancer, bile duct cancer, head and neck cancer, and/or glioma. The method according to claim 12 or 13, wherein the method includes further administering one or more additional therapeutic agents to the subject; preferably, the additional therapeutic agent is a tumor therapeutic agent; Preferably, the additional therapeutic agent is an immune checkpoint inhibitor or FOLFOX, preferably an anti-PD-1 antibody or its antigen-binding fragment, an anti-PD-L1 antibody or its antigen-binding fragment, or mFOLFOX6. The method according to claim 13 or 14, wherein the tumor overexpresses FGFR2IIIb; preferably, FGFR2IIIb expression is determined by IHC. Optionally, the tumor may or may not contain FGFR2 gene amplification.