Anti-RTK antibodies and uses thereof

Abstract

The present invention relates to RTK agonists, in particular, FGFR2b agonists, FGFR1b agonists, and DDR1 agonists, and methods of using the same.

Description

ANTI-RTK ANTIBODIES AND USES THEREOFThe present invention relates to RTK agonists, in particular, FGFR2b agonists, FGFR1b agonists, and DDR1 agonists, and methods of using the same.Receptor tyrosine kinases (RTKs) play crucial roles in various cellular processes. RTKs are known to be activated by ligand-induced dimerization. Dimerization leads to kinase activation and autophosphorylation of multiple tyrosine residues in the cytoplasmic domain of the receptor, and activation of downstream signaling of various pathways. One of the members of RTKs includes the family of fibroblast growth factor receptors (FGFRs) expressed by various mammalian cells. The family of FGFRs consists of FGFR1, FGFR2, FGFR3, and FGFR4, and comprises high affinity receptors for many different FGF ligands (NPL 1). The receptor is a transmembrane tyrosine kinase, and FGFR signaling drives downstream pathways that are essential for cell proliferation, differentiation, survival and migration (NPL 2). Binding of the FGF ligand to the receptor induces dimerization of the FGF:FGFR complex, and activation of FGF downstream signaling (NPL 3).The members of the FGF family are potent stimulators of tissue repairs, and have been shown to be helpful in numerous tissue regenerative processes, such as maintenance of cell stemness, induction of cell de-differentiation, stimulation of cell proliferation, suppression of cell senescence, suppression of cell death, regulation of inflammation, stimulation of angiogenesis, and enhancement of proteases expression etc. The FGF ligands carry out these diverse functions by binding and activating the FGFR family of RTKs.FGFR2 has two splice isoforms, FGFR2b that is normally localized in the epithelial cells, and FGFR2c which is normally localized in the mesenchymal cells (NPL 1). FGFR2b is a high affinity receptor for FGF ligands such as FGF7 and FGF10, while FGFR2c is a high affinity receptor for FGF ligands such as FGF2 (NPL 3). While various therapeutics have been developed that target FGFR2, such as anti-cancer drugs that target FGFR2 over-expressing cells, these are inhibitors to FGFR2, and there remains a significant unmet medical need for the development of FGFR2 agonists.FGFR1 also has two splice isoforms: FGFR1b is expressed in the cerebrum, tongue, preputial gland, vas deferens, and skin; and FGFR1c is expressed in various tissue (NPL 8). FGFR1b is a receptor for FGF ligands such as FGF1 and FGF2, and FGFR1b is also a weak affinity receptor for FGF7 and FGF10 (NPL 9). FGFR1c shows binding to various types of FGF ligands including FGF1, FGF2, FGF4, FGF8, FGF9, FGF19, FGF21, and FGF23 (NPL 10, NPL 11). Especially, FGF19, FGF21, and FGF23 act on β-Klotho in complex with FGFR1c. FGFR1 is also evaluated as therapeutic targets by both inhibitor and agonist for anti-cancer and chronic diseases such as obesity and diabetes. Particularly, there are several reports for agonisms of FGFR1, including homodimerization-based agonist for both FGFR1b and FGFR1c, and heterodimerization-based agonist for FGFR1c and β-Klotho (NPL 12, NPL 13, NPL 14), however, there are no reports about strong FGFR1b specific agonist that could show better agonistic activity than natural ligands.Another one of the members of RTKs includes the family of discoidin domain receptors (DDRs). The family of DDRs consists of DDR1 and DDR2. DDR1 is expressed in mainly in epithelial cells, smooth muscle cells, and in certain condition in fibroblasts, and DDR2 is expressed in cells of mesenchymal origin (NPL 15). Both DDR1 and DDR2 are activated upon collagen binding at the extracellular portion of the receptors, and then initiates downstream signaling pathways including receptor phosphorylation (NPL 16). Collagen is an important ECM component that interacts with various cellular receptors in the tissue, thus DDRs are involved in various important functions including regulation of cell proliferation, survival, differentiation, cellular aggregation, adhesion, migration, and invasions (NPL 16). Although therapeutic applications of DDRs are mainly focused on anti-fibrosis and anti-cancer treatment because various cancer cells overexpress DDRs, some of reports indicated that DDRs activation regenerates cartilage tissue and wound healing (NPL 17, NPL 18), suggesting that DDRs agonism also has potential to regenerate various tissue. As well as FGFR1 and FGFR2, however, therapeutic agonist antibody specific for DDRs has not been successfully identified.[PTL 1] WO2012021841A2[PTL 2] WO2021247718A1[PTL 3] WO2022143728A1[PTL 4] WO2022087243A1[PTL 5] WO2021157679A1Non-Patent Literature[NPL 1] Danilo Ranieri, Benedetta Rosato, Monica Nanni, Alessandra Magenta, Francesca Belleudi, Maria Rosaria Torrisi, Expression of the FGFR2 mesenchymal splicing variant in epithelial cells drives epithelial-mesenchymal transition. Oncotarget. 2016 Feb 2;7(5):5440-60.[NPL 2] Susanne Braun, Ulrich auf dem Keller, Heike Steiling, Sabine Werner, Fibroblast growth factors in epithelial repair and cytoprotection. Philos Trans R Soc Lond B Biol Sci. 2004 May 29;359(1445):753-7.[NPL 3] Allen Zinkle, Moosa Mohammadi, Structural Biology of the FGF7 Subfamily. Front Genet. 2019 Feb 12;10:102.[NPL 4] Stefan Dengl, Klaus Mayer, Felix Bormann, Harald Duerr, Eike Hoffmann, Bianca Nussbaum, Michael Tischler, Martina Wagner, Andreas Kuglstatter, Lea Leibrock, Can Buldun, Guy Georges, Ulrich Brinkmann, Format chain exchange (FORCE) for high-throughput generation of bispecific antibodies in combinatorial binder-format matrices. Nat Commun. 2020 Oct 2;11(1):4974.[NPL 5] Jun Tashiro, Gustavo A Rubio, Andrew H Limper, Kurt Williams, Sharon J Elliot, Ioanna Ninou, Vassilis Aidinis, Argyrios Tzouvelekis, Marilyn K Glassberg, Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis. Front Med (Lausanne). 2017 Jul 28:4:118.[NPL 6] Tianju Liu, Francina Gonzalez De Los Santos, Sem H Phan, The Bleomycin Model of Pulmonary Fibrosis. Methods Mol Biol. 2017:1627:27-42.[NPL 7] Dmitri Toren, Hagai Yanai, Reem Abu Taha, Gabriela Bunu, Eugen Ursu, Rolf Ziesche, Robi Tacutu, Vadim E Fraifeld, Systems biology analysis of lung fibrosis-related genes in the bleomycin mouse model. Sci Rep. 2021 Sep 29;11(1):19269.[NPL 8] Klementina Fon Tacer, Angie L Bookout, Xunshan Ding, Hiroshi Kurosu, George B John, Lei Wang, Regina Goetz, Moosa Mohammadi, Makoto Kuro-o, David J Mangelsdorf, Steven A Kliewer, Research resource : Comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol. 2010 Oct;24(10):2050-64.[NPL 9] H D Beer, L Vindevoghel, M J Gait, J M Revest, D R Duan, I Mason, C Dickson, S Werner, Fibroblast growth factor (FGF) receptor 1-IIIb is a naturally occurring functional receptor for FGFs that is preferentially expressed in the skin and the brain. J Biol Chem. 2000 May 26;275(21):16091-7.[NPL 10] D M Ornitz, J Xu, J S Colvin, D G McEwen, C A MacArthur, F Coulier, G Gao, M Goldfarb, Receptor specificity of the fibroblast growth factor family. J Biol Chem. 1996 Jun 21;271(25):15292-7.[NPL 11] Tian Lan, Donald A Morgan, Kamal Rahmouni, Junichiro Sonoda, Xiaorong Fu, Shawn C Burgess, William L Holland, Steven A Kliewer, David J Mangelsdorf, FGF19, FGF21, and an FGFR1 / β-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia. Cell Metab. 2017 Nov 7;26(5):709-718.e3.[NPL 12] Ai-Luen Wu, Ganesh Kolumam, Scott Stawicki, Yongmei Chen, Jun Li, Jose Zavala-Solorio, Khanhky Phamluong, Bo Feng, Li Li, Scot Marsters, Lance Kates, Nicholas van Bruggen, Maya Leabman, Anne Wong, David West, Howard Stern, Elizabeth Luis, Hok Seon Kim, Daniel Yansura, Andrew S Peterson, Ellen Filvaroff, Yan Wu, Junichiro Sonoda, Amelioration of type 2 diabetes by antibody-mediated activation of fibroblast growth factor receptor 1. Sci Transl Med. 2011 Dec 14;3(113):113ra126.[NPL 13] Jocelyn Chan, Joyce Chan, Lily Shao, Scott S Stawicki, Victoria C Pham, Rob W Akita, Marc Hafner, Lisa Crocker, Kebing Yu, James T Koerber, Gabriele Schaefer, Laetitia Comps-Agrar, Systematic pharmacological analysis of agonistic and antagonistic fibroblast growth factor receptor 1 Mabs reveals a similar unique mode of action. J Biol Chem. 2023 Jan;299(1):102729.[NPL 14] Xiaoshan Min, Jennifer Weiszmann, Sheree Johnstone, Wei Wang, Xinchao Yu, William Romanow, Stephen Thibault, Yang Li, Zhulun Wang, Agonistic β-Klotho antibody mimics fibroblast growth factor 21 (FGF21) functions. J Biol Chem. 2018 Sep 21;293(38):14678-14688.[NPL 15] Gurubasavaraja Swamy Purawarga Matada, Arka Das, Prasad Sanjay Dhiwar & Abhishek Ghara, DDR1 and DDR2 : a review on signaling pathway and small molecule inhibitors as an anticancer agent. Med Chem Res 30, 535-551 (2021).[NPL 16] N M Coelho, A Wang, C A McCulloch, Discoidin domain receptor 1 interactions with myosin motors contribute to collagen remodeling and tissue fibrosis. Biochim Biophys Acta Mol Cell Res. 2019 Nov;1866(11):118510.[NPL 17] Arokia Vijaya Anand Mariadoss, Chau-Zen Wang, Exploring the Cellular and Molecular Mechanism of Discoidin Domain Receptors (DDR1 and DDR2) in Bone Formation, Regeneration, and Its Associated Disease Conditions. Int J Mol Sci. 2023 Oct 4;24(19):14895.[NPL 18] Muriel Cario, DDR1 and DDR2 in skin. Cell Adh Migr. 2018;12(4):386-393.[NPL 19] D Smedley, A Demiroglu, M Abdul-Rauf, C Heath, C Cooper, J Shipley, N C Cross, ZNF198-FGFR1 transforms Ba / F3 cells to growth factor independence and results in high level tyrosine phosphorylation of STATS 1 and 5. Neoplasia. 1999 Oct;1(4):349-55.[NPL 20] Victoria Juskaite, David S Corcoran, Birgit Leitinger, Collagen induces activation of DDR1 through lateral dimer association and phosphorylation between dimers. Elife. 2017 Jun 7:6:e25716.[NPL 21] David S Corcoran, Victoria Juskaite, Yuewei Xu, Frederik Gorlitz, Yuriy Alexandrov, Christopher Dunsby, Paul M W French, Birgit Leitinger, DDR1 autophosphorylation is a result of aggregation into dense clusters. Sci Rep. 2019 Nov 19;9(1):17104.While various therapeutics have been developed to target receptor tyrosine kinases, there remains a significant medical need for activating FGFR signaling, in particular FGFR2 and FGFR1, where the FGF family are known to be potent stimulators of tissue repairs, and have been shown to be helpful in numerous tissue regenerative processes, such as maintenance of cell stemness, induction of cell de-differentiation, stimulation of cell proliferation, suppression of cell senescence, suppression of cell death, regulation of inflammation, stimulation of angiogenesis, and enhancement of proteases expression etc. There also remains a significant medical need for activating DDR signaling, in particular DDR1, where the collagen family are known to be potent regulator of cell proliferation, survival, cellular differentiation, ECM homeostasis, cytokine secretions, cellular aggregation and migration etc.The present invention provides agonistic antigen-binding molecules, such as antibodies or fragments thereof that bind to receptor tyrosine kinases (RTKs), including the family of fibroblast growth factor receptors (FGFRs) and the family of discoidin domain receptors (DDRs). The present invention provides antigen-binding molecules, such as antibodies or fragments thereof that bind human fibroblast growth factor receptor 2 protein (FGFR2), human fibroblast growth factor receptor 1 protein (FGFR1), or human discoidin domain receptor 1 (DDR1), preferably wherein the antibodies or fragments thereof specifically binds to FGFR2IIIb (FGFR2b), FGFR1IIIb (FGFR1b), or DDR1a, wherein these molecules activate FGFR2IIIb signaling, FGFR1IIIb signaling, or DDR1a signaling, and provides methods of using the same. The molecules of the invention are useful in any disease, disorder or condition, where an increase in FGFR2b signaling, FGFR1b signaling, or DDR1a signaling is helpful and can be used to treat fibrosis or inflammation, in particular lung and skin fibrosis.The molecules of the invention provided herein are agonistic antigen-binding molecules, such as antibodies or fragments thereof that bind receptor tyrosine kinases (RTKs) and promote their dimerization and activation, and wherein the antigen-binding molecules bind biparatopically. In one aspect, the molecules of the invention are antigen-binding molecules, such as antibodies or fragments thereof that bind fibroblast growth factor receptor 2 protein (FGFR2), preferably wherein the antibodies or fragments thereof specifically bind to FGFR2IIIb. The antigen-binding molecules, such as antibodies, are useful, inter alia, for targeting cells that express FGFR2, preferably FGFR2IIIb. The FGFR2b antigen-binding molecules mimic the ligands of FGFR2b such as FGF7 or FGF10 to selectively activate FGFR2b signaling and find uses in methods of activating FGF downstream signaling. In one aspect, the anti-FGFR2b antigen-binding molecules, such as antibodies, and antigen-binding fragments thereof, bind specifically to the IgII, IgIII, or IgIIIb domain of FGFR2, and selectively activate FGFR2IIIb signaling. In one aspect, the anti-FGFR2b antigen-binding molecules, such as antibodies, and antigen-binding fragments thereof, comprise a first antigen-binding domain that binds to IgIIIb and a second antigen-binding domain that binds to IgI, IgII, IgIII, or IgIIIb, and selectively activate FGFR2IIIb signaling. In one aspect, the anti-FGFR2b antigen-binding molecules, such as antibodies, and antigen-binding fragments thereof, bind biparatopically to the IgIIIb and IgI, IgIIIb and IgII, IgIIIb and IgIII, or IgIIIb and IgIIIb domains of FGFR2, and selectively activate FGFR2IIIb signaling. Agonistic antigen-binding molecules, such as antibodies, against FGFR2b, including agonistic biparatopic antibodies against FGFR2b provide a new class of therapeutics for the treatment of tissue-degenerative diseases.In one aspect, the molecules of the invention are antigen-binding molecules, such as antibodies or fragments thereof that bind fibroblast growth factor receptor 1 protein (FGFR1), preferably wherein the antibodies or fragments thereof specifically bind to FGFR1IIIb. The antigen-binding molecules, such as antibodies, are useful, inter alia, for targeting cells that express FGFR1, preferably FGFR1IIIb. The FGFR1b antigen-binding molecules mimic the ligands of FGFR1b such as FGF1 or FGF2 to selectively activate FGFR1b signaling and find uses in methods of activating FGF downstream signaling. In one aspect, the anti-FGFR1b antigen-binding molecules, such as antibodies, and antigen-binding fragments thereof, bind specifically to the IgII, IgIII, or IgIIIb domain of FGFR1, and selectively activate FGFR1IIIb signaling. In one aspect, the anti-FGFR1b antigen-binding molecules, such as antibodies, and antigen-binding fragments thereof, comprise a first antigen-binding domain that binds to IgIIIb and a second antigen-binding domain that binds to IgI, IgII, IgIII, or IgIIIb, and selectively activate FGFR1IIIb signaling. In one aspect, the anti-FGFR1b antigen-binding molecules, such as antibodies, and antigen-binding fragments thereof, bind biparatopically to the IgIIIb and IgI, IgIIIb and IgII, IgIIIb and IgIII, or IgIIIb and IgIIIb domains of FGFR1, and selectively activate FGFR1IIIb signaling. Agonistic antigen-binding molecules, such as antibodies, against FGFR1b, including agonistic biparatopic antibodies against FGFR1b provide a new class of therapeutics for the treatment of tissue-degenerative diseases.In one aspect, the molecules of the invention are antigen-binding molecules, such as antibodies or fragments thereof that bind discoidin domain receptor 1 protein (DDR1), preferably wherein the antibodies or fragments thereof specifically bind to DDR1a. The antigen-binding molecules, such as antibodies, are useful, inter alia, for targeting cells that express DDR1, preferably DDR1a. The DDR1a antigen-binding molecules mimic the ligands of DDR1a such as collagen type I, IV, V, VI, or VIII to selectively activate DDR1a signaling and find uses in methods of activating FGF downstream signaling. In one aspect, the anti-DDR1a antigen-binding molecules, such as antibodies, and antigen-binding fragments thereof, bind specifically to a discoidin (DS) domain, a DS-like domain, or an extracellular juxtamembrane (EJXM) region of DDR1a, and selectively activate DDR1a signaling. In one aspect, the anti-DDR1a antigen-binding molecules, such as antibodies, and antigen-binding fragments thereof, comprises a first antigen-binding domain that binds to a DS domain and a second antigen-binding domain that binds to a DS domain, a DS-like domain, or an EJXM region and selectively activate DDR1a signaling. In one aspect, the anti-DDR1a antigen-binding molecules, such as antibodies, and antigen-binding fragments thereof, bind biparatopically to the DS domain and the EJXM region, the DS domain and the DS-like domain, or the DS domain and the DS domain of DDR1, and selectively activate DDR1a signaling. Agonistic antigen-binding molecules, such as antibodies, against DDR1a, including agonistic biparatopic antibodies against DDR1a provide a new class of therapeutics for the treatment of tissue-degenerative diseases.The anti-FGFR2b antigen-binding molecules, the anti-FGFR1b antigen-binding molecules, or the anti-DDR1 antigen-binding molecules, such as antibodies, and antigen-binding fragments thereof, may be used alone in unmodified form, or may be included as part of an antibody-drug conjugate, or a fusion protein. In addition, molecules of the invention include, without limitation, small organic molecules and polypeptides.The invention also provides herein methods for the use of the anti-FGFR2b antigen-binding molecules, the anti-FGFR1b antigen-binding molecules, or the anti-DDR1 antigen-binding molecules, such as antibodies, and antigen-binding fragments thereof, in the treatment or alleviation of symptoms of diseases or disorders, pharmaceutical compositions comprising the anti-FGFR2b antibodies, the anti-FGFR1b antibodies, or the anti-DDR1 antibodies, and antigen-binding fragments thereof and their uses thereof.Exemplary embodimentsThe following aspects and embodiments are part of the invention - wherein it will be appreciated by the skilled reader that the embodiments included in the following are independently intended as the embodiments for each and every general embodiments and aspects set forth below. In aspects and embodiments, the invention relates to any one of [A1] and [A1a] to [A53] below:[A1] An agonistic antigen-binding molecule that binds to a human Fibroblast growth factor receptor 2 (FGFR2) protein, wherein the molecule comprises a first antigen-binding domain that binds a first epitope of an extracellular domain (ECD) of a first FGFR2 protein and a second antigen-binding domain that binds a second epitope of an extracellular domain (ECD) of the first or a second FGFR2 protein, wherein the first epitope and the second epitope are different from each other.[A1a] An agonistic antigen-binding molecule that binds to a human Fibroblast growth factor receptor 2 (FGFR2) protein, wherein the molecule comprises:a first means for binding a first epitope of an extracellular domain (ECD) of a first FGFR2 protein; anda second means for binding a second epitope of an extracellular domain (ECD) of the first or a second FGFR2 protein,wherein the first epitope and the second epitope are different from each other.[A2] The molecule of [A1] or [A1a], wherein the first antigen-binding domain or the first means binds a first FGFR2 protein and the second antigen-binding domain or the second means binds a second FGFR2 protein.[A3] The molecule of [A1], [A1a], or [A2], which is a biparatopic antigen-binding molecule.[A4] The molecule of any one of [A1] and [A1a] to [A3], wherein the human FGFR2 protein is human FGFR2b protein.[A5] The molecule of any one of [A1] and [A1a] to [A4], wherein each of the extracellular domains is independently selected from an Immunoglobulin (Ig)-like domain of the FGFR2 protein.[A6] The molecule of any one of [A1] and [A1a] to [A5], wherein the first antigen-binding domain or the first means binds to a first domain of the FGFR2 protein and the second antigen-binding domain or the second means binds to a second domain of the FGFR2 protein, wherein the first domain and the second domain is the same.[A7] The molecule of any one of [A1] and [A1a] to [A5], wherein the first antigen-binding domain or the first means binds to a first domain of the FGFR2 protein and the second antigen-binding domain or the second means binds to a second domain of the FGFR2 protein, wherein the second domain is different from the first domain.[A8] The molecule of any one of [A1] and [A1a] to [A7], wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind an Ig-like domain of the FGFR2 protein, selected from the group consisting of IgI, IgII, IgIII, IgIIIb and IgIIIc of FGFR2.[A9] The molecule of any one of [A5] to [A8], wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, binds an Ig-like domain of the FGFR2 in the following combinations selected from the group consisting of:(i) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgIIIb domain of FGFR2;(ii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgIII domain of FGFR2;(iii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgII domain of FGFR2; and(iv) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgI domain of FGFR2.[A10] The molecule of any one of [A5] to [A9], wherein (i) the first antigen-binding domain or the first means binds the IgIIIb domain of FGFR2, or wherein (ii) the first antigen-binding domain or the first means binds specifically to IgIIIb of FGFR2 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgIIIc of FGFR2 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgI and IgII of FGFR2.[A11] The molecule of any one of [A1] to [A10], wherein the second antigen-binding domain is selected from the group consisting of FFB0464, FFB0341, FFB0396, FFB0026, FFB0094, FFB0035, FFB0045, FFB0057, and FFB0080.[A12] The molecule of [A11], wherein the second antigen-binding domain is selected from the group consisting of FFB0464, FFB0341, FFB0396.[A13] The molecule of [A11], wherein the first antigen-binding domain is selected from the group consisting of FFB0057, FFB0065, FFB0080, FFB0088, FFB0185, FFB0219, FFB0261, FFB0294, FFB0299, FFB0335, FFB0365, FFB0368, FFB0374, and FFB0453.[A14] The molecule of any one of [A3] to [A13], wherein binding of the first antigen-binding domain and the second antigen-binding domain or the first means and the second means to FGFR2b protein leads to agonist activity as follows:(i) wherein binding of the molecule to FGFR2b protein via a cell-surface expressed FGFR2b in a target cell activates signaling in the target cell, thereby exhibiting agonist activity, and wherein the activated signal in the target cell is measured by an increase in expression of an intracellular protein downstream of FGFR2b by at least 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or more compared to the expression of said intracellular protein prior to binding of the molecule to the cell-surface expressed FGFR2b protein in the target cell, in particular wherein the intracellular protein downstream of FGFR2b is selected from the group consisting of: pAKT, pPLCG1, pFRS2, pPAK4, pRAS, pMAPK1 / pERK2, and pMAPK3 / pERK1; or(ii) wherein binding of the molecule to FGFR2b protein via a cell-surface expressed FGFR2b in a target cell induces proliferation of the target cell, thereby exhibiting agonist activity, wherein the induction in proliferation of the target cell is measured by an increase in ATP expression by at least 1.5-fold, or 2-fold, or 2.5-fold or more, in the target cell in the presence of the molecule compared to in the target cell in the absence of the molecule, wherein the ATP expression is directly proportional to the concentration of viable target cells,in particular wherein the target cell is a lung epithelial cell, optionally wherein the lung epithelial cell is selected from alveolar type II (AT2) cells; or(iii) wherein receptor dimerization is detected in the presence of the molecule in an in vitro cell assay, wherein receptor dimerization is indicative of agonist activity; or(iv) wherein phosphorylation of the FGFR2b protein is detected in the presence of the molecule in an in vitro cell assay, wherein FGFR2b protein phosphorylation is indicative of agonist activity.[A15] The molecule of any one of [A1] to [A14], wherein the first antigen-binding domain and the second antigen-binding domain are each independently selected from a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody, or wherein the first antigen-binding domain and the second antigen-binding domain are each a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody which are linked by at least one disulfide bond.[A16] The molecule of any one of [A1] to [A15], wherein the first antigen-binding domain and the second antigen-binding domain are characterized by having at least one disulfide bond formed between amino acid residues which are not in a hinge region.[A17] The molecule of [A16], wherein the at least one disulfide bond is an engineered disulfide bond which is not present in a wild type IgG, optionally wherein said at least one disulfide bond is formed between a CH1 region, a CL region, a VH or VHH region, or a VL region of the first antigen-binding domain and a CH1 region, a CL region, a VH or VHH region, or a VL region of the second antigen-binding domain, in particular wherein said at least one disulfide bond is formed between the group selected from the following:(i) an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CH1 region of a second antigen-binding domain;(ii) an amino acid residue in a CL region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain;(iii) an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain;(iv) an amino acid residue in a VH or VHH region of a first antigen-binding domain and an amino acid residue in a VH or VHH region of a second antigen-binding domain;(v) an amino acid residue in a VL region of a first antigen-binding domain and an amino acid residue in a VL region of a second antigen-binding domain; and(vi) an amino acid residue in a VH or VHH region of a first antigen-binding domain and an amino acid residue in a VL region of a second antigen-binding domain.[A18] The molecule of [A17], wherein said at least one disulfide bond is formed between an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CH1 region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 119, 122, 123, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 148, 150, 155, 156, 157, 159, 160, 161, 162, 163, 164, 165, 167, 174, 176, 177, 178, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 201, 203, 205, 206, 207, 208, 211, 212, 213, 214, 218, and 219, according to EU numbering, in the CH1 region.[A19] The molecule of [A17], wherein said at least one disulfide bond is formed between an amino acid residue in a CL region of a first antigen-binding domain and an amino acid residue in a CL region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 108, 109, 112, 121, 123, 126, 128, 151, 152, 153, 156, 184, 186, 188, 189, 190, 195, 196, 200, 201, 202, 203, 208, 210, 211, 212, and 213 according to Kabat numbering in the CL region.[A20] The molecule of [A17], wherein said at least one disulfide bond is formed between an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CL region of the second antigen-binding domain, and the amino acid residue in the CH1 region is selected from the group consisting of positions 188, 189, 190, 191, 192, 193, 194, 195, 196, and 197 according to EU numbering, and the amino acid residue in the CL region is selected from the group consisting of positions 121, 122, 123, 124, 125, 126, 127, and 128 according to Kabat numbering.[A21] The molecule of [A17], wherein said at least one disulfide bond is formed between an amino acid residue in a VH region of a first antigen-binding domain and an amino acid residue in a VH region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 6, 8, 16, 20, 25, 26, 28, 74, and 82b according to Kabat numbering in the VH region.[A22] The molecule of [A17], wherein said at least one disulfide bond is formed between an amino acid residue in a VHH region of a first antigen-binding domain and an amino acid residue in a VHH region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 4, 6, 7, 8, 9, 10, 11, 12, 14, 15, 17, 20, 24, 27, 29, 38, 39, 40, 41, 43, 44, 45, 46, 47, 48, 49, 67, 69, 71, 78, 80, 82, 82c, 85, 88, 91, 93, 94, and 107 according to Kabat numbering in the VHH region.[A23] The molecule of [A17], wherein said at least one disulfide bond is formed between an amino acid residue in a VL region of a first antigen-binding domain and an amino acid residue in a VL region of the second antigen-binding domain, andwherein, when the VL is of a subclass kappa, the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 21, 27, 58, 77, 100, 105, and 107 according to Kabat numbering in the VL region (subclass kappa); orwherein, when the VL is of a subclass lambda, the amino acid residue from which the bonds between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 6, 19, 33, and 34 according to Kabat numbering in the VL region (subclass lambda).[A24] The molecule of [A23], wherein the at least one disulfide bond is formed between an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain.[A25] The molecule of [A24], wherein the at least one disulfide bond is formed between the amino acid residue at position 191 in a CH1 region of a first antigen-binding domain (according to Kabat numbering) and the amino acid residue at position 126 in a CL region of a second antigen-binding domain (according to Kabat numbering).[A26] The molecule of [A25], wherein the at least one disulfide bond is formed between S191C in the CH1 region of a first antigen-binding domain (according to Kabat numbering) and K126C in a CL region of a second antigen-binding domain (according to Kabat numbering).[A27] The molecule of any one of [A1] and [A1a] to [A26], wherein the molecule comprises an antibody constant region, in particular (i) wherein the antibody constant region is a human antibody constant region, or (ii) wherein the antibody constant region is selected from a human IgG1, IgG2, IgG3 or IgG4 constant regions.[A28] The molecule of any one of [A1] to [A27], wherein the molecule comprises or is an antibody or antibody fragment thereof.[A29] The molecule of [A28], wherein the antibody fragment is a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody.[A30] The molecule of [A28] or [A29] wherein the molecule is a monoclonal antibody.[A31] The molecule of any one of [A29] to [A30], wherein the molecule is human, humanized, or chimeric antibody.[A32] The molecule of any one of [A1] to [A31], wherein the molecule is characterized by two antigen-binding domains, or wherein the molecule is a bivalent molecule, or wherein the first antigen-binding domain and second antigen-binding domain are each a monovalent Fab or a monovalent VHH, or are each a monovalent scFab.[A33] The molecule of any one of [A1] and [A1a] to [A32], wherein the molecule comprises more than two antigen-binding domains or more than two means for binding, or wherein the molecule is tri-valent, tetra-valent, or multivalent molecule, optionally wherein the molecule comprises a third antigen-binding domain, the third antigen-binding domain binds the same epitope on the same domain as the first or the second antigen-binding domain, or wherein the molecule comprises a third means for binding the same epitope on the same domain as the first or the second means.[A34] The molecule of [A33], wherein the molecule comprises a fourth antigen-binding domain, the fourth antigen-binding domain binds the same epitope on the same domain as the first or the second antigen-binding domain but not the same epitope as the third antigen-binding domain, or wherein the molecule comprises a fourth means for binding the same epitope on the same domain as the first or the second means but not the same epitope as the third means, optionallywherein the molecule comprises a third and a fourth antigen-binding domain, wherein the third antigen-binding domain binds the same epitope on the same domain as the first antigen-binding domain, and the fourth antigen-binding domain binds the same epitope on the same domain as the second antigen-binding domain, orwherein the molecule comprises a third means for binding the same epitope on the same domain as the first means, and a fourth means binding the same epitope on the same domain as the second means.[A35] A pharmaceutical composition comprising the molecule of any one of [A1] and [A1a] to [A34], and a pharmaceutically acceptable carrier.[A36] An immunoconjugate protein comprising the molecule of any one of [A1] and [A1a] to [A34].[A37] The molecule of any one of [A1] and [A1a] to [A34] or the pharmaceutical composition of [A35] or the immunoconjugate of [A36] for use in the treatment or prevention of a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof.[A38] The molecule or pharmaceutical composition or immunoconjugate for the use of [A37], wherein the condition related to the injury of lung epithelial cells in an individual is selected from the group consisting of fibrosis of the lungs, inflammation of the lungs, senescence-related fibrosis of the lungs, asthma, a condition associated with exposure to environmental toxins, a condition associated with exposure to bacteria, a condition associated with exposure to a virus, cystic fibrosis, a pneumonectomy, a condition associated with exposure to radiation, a condition associated with exposure to tobacco smoke or chemicals, and bleomycin mediated epithelial injury.[A39] The molecule of any one of [A1] and [A1a]to [A34] or the pharmaceutical composition of [A35] or the immunoconjugate of [A36] for use in the treatment of any disease, disorder, or condition susceptible of being improved or prevented by one of the following selected from the group consisting of:(i) an increase or enhancement in FGFR2b signaling;(ii) an increase in the proliferation of lung epithelial cells; and(iii) an increase in the proliferation alveolar type II (AT2) progenitor cells or alveolar type II (AT2) cells.[A40] The molecule of any one of [A1] and [A1a] to [A34] or the pharmaceutical composition of [A35] or the immunoconjugate of [A36] for use in the treatment or prevention of fibrosis or inflammation in an individual in need thereof.[A41] The molecule or pharmaceutical composition or immunoconjugate for the use of [A40], wherein the fibrosis or inflammation is selected from fibrosis or inflammation of lung, heart, blood vessel, liver, bile duct, small intestine, large intestine, pancreas, kidney, eye, brain, skin, oral mucosa, thymus, bone marrow, or muscle tissue.[A42] The molecule or pharmaceutical composition or immunoconjugate for the use of [A41], wherein(i) the fibrosis or inflammation of lung is selected from the group consisting of pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis, scleroderma, chronic obstructive pulmonary disease (COPD), obstructive bronchitis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS associated pulmonary hypertension, sarcoidosis, interstitial lung tumor, and asthma;(ii) the fibrosis or inflammation of liver or bile duct is selected from the group consisting of non-alcoholic steatohepatitis, or alcoholic steatohepatitis, or cholangitis, or Alagille syndrome;(iii) the fibrosis or inflammation of pancreas is pancreatitis;(iv) the fibrosis or inflammation of kidney is selected from the group consisting of chronic kidney disease or acute kidney disease;(v) the fibrosis or inflammation of the oral mucosal is oral mucositis;(vi) the fibrosis or inflammation of the skin is diabetic foot ulcer or epidermolysis bullosa;(vii) the fibrosis or inflammation of the thymus is graft-versus-host disease (GvHD); and(viii) the fibrosis or inflammation of the small or large intestine is an inflammatory bowel disease (IBD), optionally wherein the IBD is ulcerative colitis (UC) or Crohn’s disease.[A43] Use of the molecule of any one of [A1] and [A1a] to [A34] or the pharmaceutical composition of [A35] or the immunoconjugate of [A36], in the manufacture of a medicament for the treatment or prevention of a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof.[A44] A method of treating a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of the molecule of any one of [A1] and [A1a] to [A34], or the pharmaceutical composition of [A35], or the immunoconjugate of [A36].[A45] The use of [A43], or the method of [A44], wherein the condition related to the injury of lung epithelial cells in an individual is selected from the group consisting of fibrosis of the lungs, inflammation of the lungs, senescence-related fibrosis of the lungs, asthma, a condition associated with exposure to environmental toxins, a condition associated with exposure to bacteria, a condition associated with exposure to a virus, cystic fibrosis, a pneumonectomy, a condition associated with exposure to radiation, a condition associated with exposure to tobacco smoke or chemicals, and bleomycin mediated epithelial injury.[A46] The use of [A43], or the method of [A44], wherein the condition related to the injury of lung epithelial cells in an individual is one susceptible of being improved or prevented by one of the following selected from the group consisting of:(i) an increase or enhancement in FGFR2b signaling;(ii) an increase in the proliferation of lung epithelial cells; and(iii) an increase in the proliferation of alveolar type II (AT2) progenitor cells or alveolar type II (AT2) cells.[A47] Use of the molecule of any one of [A1] and [A1a] to [A34] or the pharmaceutical composition of [A35] or the immunoconjugate of [A36] in the manufacture of a medicament for the treatment or prevention of fibrosis or inflammation in an individual in need thereof.[A48] A method of treating fibrosis or inflammation in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of the molecule of any one of [A1] and [A1a] to [A34] or the pharmaceutical composition of [A35] or the immunoconjugate of [A36].[A49] The use of [A47], or the method of [A48], wherein the fibrosis or inflammation is selected from fibrosis or inflammation of lung, heart, blood vessel, liver, bile duct, small intestine, large intestine, pancreas, kidney, eye, brain, skin, oral mucosa, thymus, bone marrow, or muscle tissue.[A50] The use of [A47], or the method of [A48], wherein(i) the fibrosis or inflammation of lung is selected from the group consisting of pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis, scleroderma, chronic obstructive pulmonary disease (COPD), obstructive bronchitis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS associated pulmonary hypertension, sarcoidosis, interstitial lung tumor, and asthma;(ii) the fibrosis or inflammation of liver or bile duct is selected from the group consisting of non-alcoholic steatohepatitis, or alcoholic steatohepatitis, or cholangitis, or Alagille syndrome;(iii) the fibrosis or inflammation of pancreas is pancreatitis;(iv) the fibrosis or inflammation of kidney is selected from the group consisting of chronic kidney disease or acute kidney disease;(v) the fibrosis or inflammation of the oral mucosal is oral mucositis;(vi) the fibrosis or inflammation of the skin is diabetic foot ulcer or epidermolysis bullosa;(vii) the fibrosis or inflammation of the thymus is graft-versus-host disease (GvHD); and(viii) the fibrosis or inflammation of the small or large intestine is an inflammatory bowel disease (IBD), optionally wherein the IBD is ulcerative colitis (UC) or Crohn’s disease.[A51] An isolated nucleic acid encoding the molecule of any one of [A1] and [A1a] to [A34] or a plurality of isolated nucleic acids encoding the molecule of any one of [A1] and [A1a] to [A34].[A52] A host cell comprising the nucleic acid or the plurality of nucleic acids of [A51].[A53] A method of producing the molecule, or a process for producing the molecule comprising the following steps:(a) culturing the host cell of [A52], and(b) recovering the molecule that is produced in step (a).In aspects and embodiments, the invention relates to any one of [A1-1] and [A1a-1] to [A52-1] below:[A1-1] An agonistic antigen-binding molecule that binds to a human Fibroblast growth factor receptor 1 (FGFR1) protein, wherein the molecule comprises a first antigen-binding domain that binds a first epitope of an extracellular domain (ECD) of a first FGFR1 protein and a second antigen-binding domain that binds a second epitope of an extracellular domain (ECD) of the first or a second FGFR1 protein, wherein the first epitope and the second epitope are different from each other.[A1a-1] An agonistic antigen-binding molecule that binds to a human Fibroblast growth factor receptor 1 (FGFR1) protein, wherein the molecule comprises:a first means for binding a first epitope of an extracellular domain (ECD) of a first FGFR1 protein; anda second means for binding a second epitope of an extracellular domain (ECD) of the first or a second FGFR1 protein,wherein the first epitope and the second epitope are different from each other.[A2-1] The molecule of [A1-1] or [A1a-1], wherein the first antigen-binding domain or the first means binds a first FGFR1 protein and the second antigen-binding domain or the second means binds a second FGFR1 protein.[A3-1] The molecule of [A1-1], [A1a-1], or [A2-1], which is a biparatopic antigen-binding molecule.[A4-1] The molecule of any one of [A1-1] and [A1a-1] to [A3-1], wherein the human FGFR1 protein is human FGFR1b protein.[A5-1] The molecule of any one of [A1-1] and [A1a-1] to [A4-1], wherein each of the extracellular domains is independently selected from an Immunoglobulin (Ig)-like domain of the FGFR1 protein.[A6-1] The molecule of any one of [A1-1] and [A1a-1] to [A5-1], wherein the first antigen-binding domain or the first means binds to a first domain of the FGFR1 protein and the second antigen-binding domain or the second means binds to a second domain of the FGFR1 protein, wherein the first domain and the second domain is the same.[A7-1] The molecule of any one of [A1-1] and [A1a-1] to [A5-1], wherein the first antigen-binding domain or the first means binds to a first domain of the FGFR1 protein and the second antigen-binding domain or the second means binds to a second domain of the FGFR1 protein, wherein the second domain is different from the first domain.[A8-1] The molecule of any one of [A1-1] and [A1a-1] to [A7-1], wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind an Ig-like domain of the FGFR1 protein, selected from the group consisting of IgI, IgII, IgIII, IgIIIb and IgIIIc of FGFR1.[A9-1] The molecule of any one of [A5-1] to [A8-1], wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, binds an Ig-like domain of the FGFR1 in the following combinations selected from the group consisting of:(i) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgIIIb domain of FGFR1;(ii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgIII domain of FGFR1;(iii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgII domain of FGFR1; and(iv) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgI domain of FGFR1.[A10-1] The molecule of any one of [A5-1] to [A9-1], wherein (i) the first antigen-binding domain or the first means binds the IgIIIb domain of FGFR1, or wherein (ii) the first antigen-binding domain or the first means binds specifically to IgIIIb of FGFR1 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgIIIc of FGFR1 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgI and IgII of FGFR1.[A11-1] The molecule of any one of [A1-1] to [A10-1], wherein the second antigen-binding domain is selected from the group consisting of FFA0020, FFA0026, FFA0032, FFA0043, FFA0047, FFA0055, FFA0064, and FFA0088.[A12-1] The molecule of [A11-1], wherein the first antigen-binding domain is selected from the group consisting of FFA0029, and FFA0048.[A13-1] The molecule of any one of [A3-1] to [A12-1], wherein binding of the first antigen-binding domain and the second antigen-binding domain or the first means and the second means to FGFR1b protein leads to agonist activity as follows:(i) wherein binding of the molecule to FGFR1b protein via a cell-surface expressed FGFR1b in a target cell activates signaling in the target cell, thereby exhibiting agonist activity, and wherein the activated signal in the target cell is measured by an increase in expression of an intracellular protein downstream of FGFR1b by at least 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or more compared to the expression of said intracellular protein prior to binding of the molecule to the cell-surface expressed FGFR1b protein in the target cell, in particular wherein the intracellular protein downstream of FGFR1b is selected from the group consisting of: pAKT, pPLCG1, pFRS2, pPAK4, pRAS, pMAPK1 / pERK2, and pMAPK3 / pERK1; or(ii) wherein binding of the molecule to FGFR1b protein via a cell-surface expressed FGFR1b in a target cell induces proliferation of the target cell, thereby exhibiting agonist activity, wherein the induction in proliferation of the target cell is measured by an increase in ATP expression by at least 1.5-fold, or 2-fold, or 2.5-fold or more, in the target cell in the presence of the molecule compared to in the target cell in the absence of the molecule, wherein the ATP expression is directly proportional to the concentration of viable target cells,in particular wherein the target cell is a lung epithelial cell, optionally wherein the lung epithelial cell is selected from alveolar type II (AT2) cells; or(iii) wherein receptor dimerization is detected in the presence of the molecule in an in vitro cell assay, wherein receptor dimerization is indicative of agonist activity; or(iv) wherein phosphorylation of the FGFR1b protein is detected in the presence of the molecule in an in vitro cell assay, wherein FGFR1b protein phosphorylation is indicative of agonist activity.[A14-1] The molecule of any one of [A1-1] to [A13-1], wherein the first antigen-binding domain and the second antigen-binding domain are each independently selected from a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody, or wherein the first antigen-binding domain and the second antigen-binding domain are each a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody which are linked by at least one disulfide bond.[A15-1] The molecule of any one of [A1-1] to [A14-1], wherein the first antigen-binding domain and the second antigen-binding domain are characterized by having at least one disulfide bond formed between amino acid residues which are not in a hinge region.[A16-1] The molecule of [A15-1], wherein the at least one disulfide bond is an engineered disulfide bond which is not present in a wild type IgG, optionally wherein said at least one disulfide bond is formed between a CH1 region, a CL region, a VH or VHH region, or a VL region of the first antigen-binding domain and a CH1 region, a CL region, a VH or VHH region, or a VL region of the second antigen-binding domain, in particular wherein said at least one disulfide bond is formed between the group selected from the following:(vii) an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CH1 region of a second antigen-binding domain;(viii) an amino acid residue in a CL region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain;(ix) an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain;(x) an amino acid residue in a VH or VHH region of a first antigen-binding domain and an amino acid residue in a VH or VHH region of a second antigen-binding domain;(xi) an amino acid residue in a VL region of a first antigen-binding domain and an amino acid residue in a VL region of a second antigen-binding domain; and(xii) an amino acid residue in a VH or VHH region of a first antigen-binding domain and an amino acid residue in a VL region of a second antigen-binding domain.[A17-1] The molecule of [A16-1], wherein said at least one disulfide bond is formed between an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CH1 region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 119, 122, 123, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 148, 150, 155, 156, 157, 159, 160, 161, 162, 163, 164, 165, 167, 174, 176, 177, 178, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 201, 203, 205, 206, 207, 208, 211, 212, 213, 214, 218, and 219, according to EU numbering, in the CH1 region.[A18-1] The molecule of [A16-1], wherein said at least one disulfide bond is formed between an amino acid residue in a CL region of a first antigen-binding domain and an amino acid residue in a CL region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 108, 109, 112, 121, 123, 126, 128, 151, 152, 153, 156, 184, 186, 188, 189, 190, 195, 196, 200, 201, 202, 203, 208, 210, 211, 212, and 213 according to Kabat numbering in the CL region.[A19-1] The molecule of [A16-1], wherein said at least one disulfide bond is formed between an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CL region of the second antigen-binding domain, and the amino acid residue in the CH1 region is selected from the group consisting of positions 188, 189, 190, 191, 192, 193, 194, 195, 196, and 197 according to EU numbering, and the amino acid residue in the CL region is selected from the group consisting of positions 121, 122, 123, 124, 125, 126, 127, and 128 according to Kabat numbering.[A20-1] The molecule of [A16-1], wherein said at least one disulfide bond is formed between an amino acid residue in a VH region of a first antigen-binding domain and an amino acid residue in a VH region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 6, 8, 16, 20, 25, 26, 28, 74, and 82b according to Kabat numbering in the VH region.[A21-1] The molecule of [A16-1], wherein said at least one disulfide bond is formed between an amino acid residue in a VHH region of a first antigen-binding domain and an amino acid residue in a VHH region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 4, 6, 7, 8, 9, 10, 11, 12, 14, 15, 17, 20, 24, 27, 29, 38, 39, 40, 41, 43, 44, 45, 46, 47, 48, 49, 67, 69, 71, 78, 80, 82, 82c, 85, 88, 91, 93, 94, and 107 according to Kabat numbering in the VHH region.[A22-1] The molecule of [A16-1], wherein said at least one disulfide bond is formed between an amino acid residue in a VL region of a first antigen-binding domain and an amino acid residue in a VL region of the second antigen-binding domain, andwherein, when the VL is of a subclass kappa, the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 21, 27, 58, 77, 100, 105, and 107 according to Kabat numbering in the VL region (subclass kappa); orwherein, when the VL is of a subclass lambda, the amino acid residue from which the bonds between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 6, 19, 33, and 34 according to Kabat numbering in the VL region (subclass lambda).[A23-1] The molecule of [A22-1], wherein the at least one disulfide bond is formed between an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain.[A24-1] The molecule of [A23-1], wherein the at least one disulfide bond is formed between the amino acid residue at position 191 in a CH1 region of a first antigen-binding domain (according to Kabat numbering) and the amino acid residue at position 126 in a CL region of a second antigen-binding domain (according to Kabat numbering).[A25-1] The molecule of [A24-1], wherein the at least one disulfide bond is formed between S191C in the CH1 region of a first antigen-binding domain (according to Kabat numbering) and K126C in a CL region of a second antigen-binding domain (according to Kabat numbering).[A26-1] The molecule of any one of [A1-1] and [A1a-1] to [A25-1], wherein the molecule comprises an antibody constant region, in particular (i) wherein the antibody constant region is a human antibody constant region, or (ii) wherein the antibody constant region is selected from a human IgG1, IgG2, IgG3 or IgG4 constant regions.[A27-1] The molecule of any one of [A1-1] to [A26-1], wherein the molecule comprises or is an antibody or antibody fragment thereof.[A28-1] The molecule of [A27-1], wherein the antibody fragment is a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody.[A29-1] The molecule of [A27-1] or [A28-1] wherein the molecule is a monoclonal antibody.[A30-1] The molecule of any one of [A28-1] to [A29-1], wherein the molecule is human, humanized, or chimeric antibody.[A31-1] The molecule of any one of [A1-1] to [A30-1], wherein the molecule is characterized by two antigen-binding domains, or wherein the molecule is a bivalent molecule, or wherein the first antigen-binding domain and second antigen-binding domain are each a monovalent Fab or a monovalent VHH, or are each a monovalent scFab.[A32-1] The molecule of any one of [A1-1] and [A1a-1] to [A31-1], wherein the molecule comprises more than two antigen-binding domains or more than two means for binding, or wherein the molecule is tri-valent, tetra-valent, or multivalent molecule, optionally wherein the molecule comprises a third antigen-binding domain, the third antigen-binding domain binds the same epitope on the same domain as the first or the second antigen-binding domain, or wherein the molecule comprises a third means for binding the same epitope on the same domain as the first or the second means.[A33-1] The molecule of [A32-1], wherein the molecule comprises a fourth antigen-binding domain, the fourth antigen-binding domain binds the same epitope on the same domain as the first or the second antigen-binding domain but not the same epitope as the third antigen-binding domain, or wherein the molecule comprises a fourth means for binding the same epitope on the same domain as the first or the second means but not the same epitope as the third means, optionallywherein the molecule comprises a third and a fourth antigen-binding domain, wherein the third antigen-binding domain binds the same epitope on the same domain as the first antigen-binding domain, and the fourth antigen-binding domain binds the same epitope on the same domain as the second antigen-binding domain, orwherein the molecule comprises a third means for binding the same epitope on the same domain as the first means, and a fourth means binding the same epitope on the same domain as the second means.[A34-1] A pharmaceutical composition comprising the molecule of any one of [A1-1] and [A1a-1] to [A33-1], and a pharmaceutically acceptable carrier.[A35-1] An immunoconjugate protein comprising the molecule of any one of [A1-1] and [A1a-1] to [A33-1].[A36-1] The molecule of any one of [A1-1] and [A1a-1] to [A33-1] or the pharmaceutical composition of [A34-1] or the immunoconjugate of [A35-1] for use in the treatment or prevention of a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof.[A37-1] The molecule or pharmaceutical composition or immunoconjugate for the use of [A36-1], wherein the condition related to the injury of lung epithelial cells in an individual is selected from the group consisting of fibrosis of the lungs, inflammation of the lungs, senescence-related fibrosis of the lungs, asthma, a condition associated with exposure to environmental toxins, a condition associated with exposure to bacteria, a condition associated with exposure to a virus, cystic fibrosis, a pneumonectomy, a condition associated with exposure to radiation, a condition associated with exposure to tobacco smoke or chemicals, and bleomycin mediated epithelial injury.[A38-1] The molecule of any one of [A1-1] and [A1a-1] to [A33-1] or the pharmaceutical composition of [A34-1] or the immunoconjugate of [A35-1] for use in the treatment of any disease, disorder, or condition susceptible of being improved or prevented by one of the following selected from the group consisting of:(iv) an increase or enhancement in FGFR1b signaling;(v) an increase in the proliferation of lung epithelial cells; and(vi) an increase in the proliferation alveolar type II (AT2) progenitor cells or alveolar type II (AT2) cells.[A39-1] The molecule of any one of [A1-1] and [A1a-1] to [A33-1] or the pharmaceutical composition of [A34-1] or the immunoconjugate of [A35-1] for use in the treatment or prevention of fibrosis or inflammation in an individual in need thereof.[A40-1] The molecule or pharmaceutical composition or immunoconjugate for the use of [A39-1], wherein the fibrosis or inflammation is selected from fibrosis or inflammation of lung, heart, blood vessel, liver, bile duct, small intestine, large intestine, pancreas, kidney, eye, brain, skin, oral mucosa, thymus, bone marrow, or muscle tissue.[A41-1] The molecule or pharmaceutical composition or immunoconjugate for the use of [A40-1], wherein(i) the fibrosis or inflammation of lung is selected from the group consisting of pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis, scleroderma, chronic obstructive pulmonary disease (COPD), obstructive bronchitis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS associated pulmonary hypertension, sarcoidosis, interstitial lung tumor, and asthma;(ii) the fibrosis or inflammation of liver or bile duct is selected from the group consisting of non-alcoholic steatohepatitis, or alcoholic steatohepatitis, or cholangitis, or Alagille syndrome;(iii) the fibrosis or inflammation of pancreas is pancreatitis;(iv) the fibrosis or inflammation of kidney is selected from the group consisting of chronic kidney disease or acute kidney disease;(v) the fibrosis or inflammation of the oral mucosal is oral mucositis;(vi) the fibrosis or inflammation of the skin is diabetic foot ulcer or epidermolysis bullosa;(vii) the fibrosis or inflammation of the thymus is graft-versus-host disease (GvHD); and(viii) the fibrosis or inflammation of the small or large intestine is an inflammatory bowel disease (IBD), optionally wherein the IBD is ulcerative colitis (UC) or Crohn’s disease.[A42-1] Use of the molecule of any one of [A1-1] and [A1a-1] to [A33-1] or the pharmaceutical composition of [A34-1] or the immunoconjugate of [A35-1], in the manufacture of a medicament for the treatment or prevention of a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof.[A43-1] A method of treating a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of the molecule of any one of [A1-1] and [A1a-1] to [A33-1], or the pharmaceutical composition of [A34-1], or the immunoconjugate of [A35-1].[A44-1] The use of [A42-1], or the method of [A43-1], wherein the condition related to the injury of lung epithelial cells in an individual is selected from the group consisting of fibrosis of the lungs, inflammation of the lungs, senescence-related fibrosis of the lungs, asthma, a condition associated with exposure to environmental toxins, a condition associated with exposure to bacteria, a condition associated with exposure to a virus, cystic fibrosis, a pneumonectomy, a condition associated with exposure to radiation, a condition associated with exposure to tobacco smoke or chemicals, and bleomycin mediated epithelial injury.[A45-1] The use of [A42-1], or the method of [A43-1], wherein the condition related to the injury of lung epithelial cells in an individual is one susceptible of being improved or prevented by one of the following selected from the group consisting of:(i) an increase or enhancement in FGFR1b signaling;(ii) an increase in the proliferation of lung epithelial cells; and(iii) an increase in the proliferation of alveolar type II (AT2) progenitor cells or alveolar type II (AT2) cells.[A46-1] Use of the molecule of any one of [A1-1] and [A1a-1] to [A33-1] or the pharmaceutical composition of [A34-1] or the immunoconjugate of [A35-1] in the manufacture of a medicament for the treatment or prevention of fibrosis or inflammation in an individual in need thereof.[A47-1] A method of treating fibrosis or inflammation in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of the molecule of any one of [A1-1] and [A1a-1] to [A33-1] or the pharmaceutical composition of [A34-1] or the immunoconjugate of [A35-1].[A48-1] The use of [A46-1], or the method of [A47-1], wherein the fibrosis or inflammation is selected from fibrosis or inflammation of lung, heart, blood vessel, liver, bile duct, small intestine, large intestine, pancreas, kidney, eye, brain, skin, oral mucosa, thymus, bone marrow, or muscle tissue.[A49-1] The use of [A46-1], or the method of [A47-1], wherein(i) the fibrosis or inflammation of lung is selected from the group consisting of pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis, scleroderma, chronic obstructive pulmonary disease (COPD), obstructive bronchitis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS associated pulmonary hypertension, sarcoidosis, interstitial lung tumor, and asthma;(ii) the fibrosis or inflammation of liver or bile duct is selected from the group consisting of non-alcoholic steatohepatitis, or alcoholic steatohepatitis, or cholangitis, or Alagille syndrome;(iii) the fibrosis or inflammation of pancreas is pancreatitis;(iv) the fibrosis or inflammation of kidney is selected from the group consisting of chronic kidney disease or acute kidney disease;(v) the fibrosis or inflammation of the oral mucosal is oral mucositis;(vi) the fibrosis or inflammation of the skin is diabetic foot ulcer or epidermolysis bullosa;(vii) the fibrosis or inflammation of the thymus is graft-versus-host disease (GvHD); and(viii) the fibrosis or inflammation of the small or large intestine is an inflammatory bowel disease (IBD), optionally wherein the IBD is ulcerative colitis (UC) or Crohn’s disease.[A50-1] An isolated nucleic acid encoding the molecule of any one of [A1-1] and [A1a-1] to [A33-1] or a plurality of isolated nucleic acids encoding the molecule of any one of [A1-1] and [A1a-1] to [A33-1].[A51-1] A host cell comprising the nucleic acid or the plurality of nucleic acids of [A50-1].[A52-1] A method of producing the molecule, or a process for producing the molecule comprising the following steps:(a) culturing the host cell of [A51-1], and(b) recovering the molecule that is produced in step (a).In aspects and embodiments, the invention relates to any one of [A1-2] and [A1a-2] to [A52-2] below:[A1-2] An agonistic antigen-binding molecule that binds to a human discoidin domain receptor1 (DDR1) protein, wherein the molecule comprises a first antigen-binding domain that binds a first epitope of an extracellular domain (ECD) of a first DDR1 protein and a second antigen-binding domain that binds a second epitope of an extracellular domain (ECD) of the first or a second DDR1 protein, wherein the first epitope and the second epitope are different from each other.[A1a-2] An agonistic antigen-binding molecule that binds to a human discoidin domain receptor1 (DDR1) protein, wherein the molecule comprises:a first means for binding a first epitope of an extracellular domain (ECD) of a first DDR1 protein; anda second means for binding a second epitope of an extracellular domain (ECD) of the first or a second DDR1 protein,wherein the first epitope and the second epitope are different from each other.[A2-2] The molecule of [A1-2] or [A1a-2], wherein the first antigen-binding domain or the first means binds a first DDR1 protein and the second antigen-binding domain or the second means binds a second DDR1 protein.[A3-2] The molecule of [A1-2], [A1a-2], or [A2-2], which is a biparatopic antigen-binding molecule.[A4-2] The molecule of any one of [A1-2] and [A1a-2] to [A3-2], wherein the human DDR1 protein is human DDR1a protein.[A5-2] The molecule of any one of [A1-2] and [A1a-2] to [A4-2], wherein each of the extracellular domains is independently selected from a discoidin (DS) domain, a DS-like domain, or an extracellular juxtamembrane (EJXM) region of the DDR1 protein.[A6-2] The molecule of any one of [A1-2] and [A1a-2] to [A5-2], wherein the first antigen-binding domain or the first means binds to a first domain of the DDR1 protein and the second antigen-binding domain or the second means binds to a second domain of the DDR1 protein, wherein the first domain and the second domain is the same.[A7-2] The molecule of any one of [A1-2] and [A1a-2] to [A5-2], wherein the first antigen-binding domain or the first means binds to a first domain of the DDR1 protein and the second antigen-binding domain or the second means binds to a second domain of the DDR1 protein, wherein the second domain is different from the first domain.[A8-2] The molecule of any one of [A1-2] and [A1a-2] to [A7-2], wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind a discoidin (DS) domain, a DS-like domain, or an extracellular juxtamembrane (EJXM) region of the DDR1 protein.[A9-2] The molecule of any one of [A5-2] to [A8-2], wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, binds a discoidin (DS) domain, a DS-like domain, or an extracellular juxtamembrane (EJXM) region of the DDR1 in the following combinations selected from the group consisting of:(i) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the DS and DS domain of DDR1;(ii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the DS and DS-like domain of DDR1;(iii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the DS domain and EJXM region of DDR1;(iv) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the DS-like domain and DS-like domain of DDR1;(vii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the DS-like domain and EJXM region of DDR1; and(viii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the EJXM region and EJXM region of DDR1.[A10-2] The molecule of any one of [A5-2] to [A9-2], wherein (i) the first antigen-binding domain or the first means binds the DS domain of DDR1, or wherein (ii) the first antigen-binding domain or the first means binds specifically to DS domain of DDR1 and shows less than 10%, or less than 5%, or 0% cross-reactivity with DS-Like domain of DDR1 and shows less than 10%, or less than 5%, or 0% cross-reactivity with EJXM region of DDR1.[A11-2] The molecule of any one of [A1-2] to [A10-2], wherein the second antigen-binding domain is selected from the group consisting of DAA0007, DAA0012, and DAA 0024.[A12-2] The molecule of [A11-2], wherein the first antigen-binding domain is selected from the group consisting of DAA0011, and DAA0045.[A13-2] The molecule of any one of [A3-2] to [A12-2], wherein binding of the first antigen-binding domain and the second antigen-binding domain or the first means and the second means to DDR1 protein leads to agonist activity as follows:(i) wherein binding of the molecule to DDR1 protein via a cell-surface expressed DDR1 in a target cell activates signaling in the target cell, thereby exhibiting agonist activity, and wherein the activated signal in the target cell is measured by an increase in expression of an intracellular protein downstream of DDR1 by at least 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or more compared to the expression of said intracellular protein prior to binding of the molecule to the cell-surface expressed DDR1 protein in the target cell, in particular wherein the intracellular protein downstream of DDR1 is selected from the group consisting of: SHP-2, FAK, NF-kappa B, Cdc42, MAPK1, AP1, Ras / Raf / ERK, PI3K / AKT, STAT1 / 3 / 5; or(ii) wherein binding of the molecule to DDR1 protein via a cell-surface expressed DDR1 in a target cell induces proliferation of the target cell, thereby exhibiting agonist activity, wherein the induction in proliferation of the target cell is measured by an increase in ATP expression by at least 1.5-fold, or 2-fold, or 2.5-fold or more, in the target cell in the presence of the molecule compared to in the target cell in the absence of the molecule, wherein the ATP expression is directly proportional to the concentration of viable target cells,in particular wherein the target cell is a lung epithelial cell, optionally wherein the lung epithelial cell is selected from alveolar type II (AT2) cells; or(iii) wherein receptor dimerization is detected in the presence of the molecule in an in vitro cell assay, wherein receptor dimerization is indicative of agonist activity; or(iv) wherein phosphorylation of the DDR1 protein is detected in the presence of the molecule in an in vitro cell assay, wherein DDR1 protein phosphorylation is indicative of agonist activity.[A14-2] The molecule of any one of [A1-2] to [A13-2], wherein the first antigen-binding domain and the second antigen-binding domain are each independently selected from a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody, or wherein the first antigen-binding domain and the second antigen-binding domain are each a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody which are linked by at least one disulfide bond.[A15-2] The molecule of any one of [A1-2] to [A14-2], wherein the first antigen-binding domain and the second antigen-binding domain are characterized by having at least one disulfide bond formed between amino acid residues which are not in a hinge region.[A16-2] The molecule of [A15-2], wherein the at least one disulfide bond is an engineered disulfide bond which is not present in a wild type IgG, optionally wherein said at least one disulfide bond is formed between a CH1 region, a CL region, a VH or VHH region, or a VL region of the first antigen-binding domain and a CH1 region, a CL region, a VH or VHH region, or a VL region of the second antigen-binding domain, in particular wherein said at least one disulfide bond is formed between the group selected from the following:(xiii) an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CH1 region of a second antigen-binding domain;(xiv) an amino acid residue in a CL region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain;(xv) an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain;(xvi) an amino acid residue in a VH or VHH region of a first antigen-binding domain and an amino acid residue in a VH or VHH region of a second antigen-binding domain;(xvii) an amino acid residue in a VL region of a first antigen-binding domain and an amino acid residue in a VL region of a second antigen-binding domain; and(xviii) an amino acid residue in a VH or VHH region of a first antigen-binding domain and an amino acid residue in a VL region of a second antigen-binding domain.[A17-2] The molecule of [A16-2], wherein said at least one disulfide bond is formed between an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CH1 region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 119, 122, 123, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 148, 150, 155, 156, 157, 159, 160, 161, 162, 163, 164, 165, 167, 174, 176, 177, 178, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 201, 203, 205, 206, 207, 208, 211, 212, 213, 214, 218, and 219, according to EU numbering, in the CH1 region.[A18-2] The molecule of [A16-2], wherein said at least one disulfide bond is formed between an amino acid residue in a CL region of a first antigen-binding domain and an amino acid residue in a CL region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 108, 109, 112, 121, 123, 126, 128, 151, 152, 153, 156, 184, 186, 188, 189, 190, 195, 196, 200, 201, 202, 203, 208, 210, 211, 212, and 213 according to Kabat numbering in the CL region.[A19-2] The molecule of [A16-2], wherein said at least one disulfide bond is formed between an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CL region of the second antigen-binding domain, and the amino acid residue in the CH1 region is selected from the group consisting of positions 188, 189, 190, 191, 192, 193, 194, 195, 196, and 197 according to EU numbering, and the amino acid residue in the CL region is selected from the group consisting of positions 121, 122, 123, 124, 125, 126, 127, and 128 according to Kabat numbering.[A20-2] The molecule of [A16-2], wherein said at least one disulfide bond is formed between an amino acid residue in a VH region of a first antigen-binding domain and an amino acid residue in a VH region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 6, 8, 16, 20, 25, 26, 28, 74, and 82b according to Kabat numbering in the VH region.[A21-2] The molecule of [A16-2], wherein said at least one disulfide bond is formed between an amino acid residue in a VHH region of a first antigen-binding domain and an amino acid residue in a VHH region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 4, 6, 7, 8, 9, 10, 11, 12, 14, 15, 17, 20, 24, 27, 29, 38, 39, 40, 41, 43, 44, 45, 46, 47, 48, 49, 67, 69, 71, 78, 80, 82, 82c, 85, 88, 91, 93, 94, and 107 according to Kabat numbering in the VHH region.[A22-2] The molecule of [A16-2], wherein said at least one disulfide bond is formed between an amino acid residue in a VL region of a first antigen-binding domain and an amino acid residue in a VL region of the second antigen-binding domain, andwherein, when the VL is of a subclass kappa, the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 21, 27, 58, 77, 100, 105, and 107 according to Kabat numbering in the VL region (subclass kappa); orwherein, when the VL is of a subclass lambda, the amino acid residue from which the bonds between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 6, 19, 33, and 34 according to Kabat numbering in the VL region (subclass lambda).[A23-2] The molecule of [A22-2], wherein the at least one disulfide bond is formed between an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain.[A24-2] The molecule of [A23-2], wherein the at least one disulfide bond is formed between the amino acid residue at position 191 in a CH1 region of a first antigen-binding domain (according to Kabat numbering) and the amino acid residue at position 126 in a CL region of a second antigen-binding domain (according to Kabat numbering).[A25-2] The molecule of [A24-2], wherein the at least one disulfide bond is formed between S191C in the CH1 region of a first antigen-binding domain (according to Kabat numbering) and K126C in a CL region of a second antigen-binding domain (according to Kabat numbering).[A26-2] The molecule of any one of [A1-2] and [A1a-2] to [A25-2], wherein the molecule comprises an antibody constant region, in particular (i) wherein the antibody constant region is a human antibody constant region, or (ii) wherein the antibody constant region is selected from a human IgG1, IgG2, IgG3 or IgG4 constant regions.[A27-2] The molecule of any one of [A1-2] to [A26-2], wherein the molecule comprises or is an antibody or antibody fragment thereof.[A28-2] The molecule of [A27-2], wherein the antibody fragment is a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody.[A29-2] The molecule of [A27-2] or [A28-2] wherein the molecule is a monoclonal antibody.[A30-2] The molecule of any one of [A28-2] to [A29-2], wherein the molecule is human, humanized, or chimeric antibody.[A31-2] The molecule of any one of [A1-2] to [A30-2], wherein the molecule is characterized by two antigen-binding domains, or wherein the molecule is a bivalent molecule, or wherein the first antigen-binding domain and second antigen-binding domain are each a monovalent Fab or a monovalent VHH, or are each a monovalent scFab.[A32-2] The molecule of any one of [A1-2] and [A1a-2] to [A31-2], wherein the molecule comprises more than two antigen-binding domains or more than two means for binding, or wherein the molecule is tri-valent, tetra-valent, or multivalent molecule, optionally wherein the molecule comprises a third antigen-binding domain, the third antigen-binding domain binds the same epitope on the same domain as the first or the second antigen-binding domain, or wherein the molecule comprises a third means for binding the same epitope on the same domain as the first or the second means.[A33-2] The molecule of [A32-2], wherein the molecule comprises a fourth antigen-binding domain, the fourth antigen-binding domain binds the same epitope on the same domain as the first or the second antigen-binding domain but not the same epitope as the third antigen-binding domain, or wherein the molecule comprises a fourth means for binding the same epitope on the same domain as the first or the second means but not the same epitope as the third means, optionallywherein the molecule comprises a third and a fourth antigen-binding domain, wherein the third antigen-binding domain binds the same epitope on the same domain as the first antigen-binding domain, and the fourth antigen-binding domain binds the same epitope on the same domain as the second antigen-binding domain, orwherein the molecule comprises a third means for binding the same epitope on the same domain as the first means, and a fourth means binding the same epitope on the same domain as the second means.[A34-2] A pharmaceutical composition comprising the molecule of any one of [A1-2] and [A1a-2] to [A33-2], and a pharmaceutically acceptable carrier.[A35-2] An immunoconjugate protein comprising the molecule of any one of [A1-2] and [A1a-2] to [A33-2].[A36-2] The molecule of any one of [A1-2] and [A1a-2] to [A33-2] or the pharmaceutical composition of [A34-2] or the immunoconjugate of [A35-2] for use in the treatment or prevention of a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof.[A37-2] The molecule or pharmaceutical composition or immunoconjugate for the use of [A36-2], wherein the condition related to the injury of lung epithelial cells in an individual is selected from the group consisting of fibrosis of the lungs, inflammation of the lungs, senescence-related fibrosis of the lungs, asthma, a condition associated with exposure to environmental toxins, a condition associated with exposure to bacteria, a condition associated with exposure to a virus, cystic fibrosis, a pneumonectomy, a condition associated with exposure to radiation, a condition associated with exposure to tobacco smoke or chemicals, and bleomycin mediated epithelial injury.[A38-2] The molecule of any one of [A1-2] and [A1a-2] to [A33-2] or the pharmaceutical composition of [A34-2] or the immunoconjugate of [A35-2] for use in the treatment of any disease, disorder, or condition susceptible of being improved or prevented by one of the following selected from the group consisting of:(vii) an increase or enhancement in DDR1 signaling;(viii) an increase in the proliferation of lung epithelial cells; and(ix) an increase in the proliferation alveolar type II (AT2) progenitor cells or alveolar type II (AT2) cells.[A39-2] The molecule of any one of [A1-2] and [A1a-2] to [A33-2] or the pharmaceutical composition of [A34-2] or the immunoconjugate of [A35-2] for use in the treatment or prevention of fibrosis or inflammation in an individual in need thereof.[A40-2] The molecule or pharmaceutical composition or immunoconjugate for the use of [A39-2], wherein the fibrosis or inflammation is selected from fibrosis or inflammation of lung, heart, blood vessel, liver, bile duct, small intestine, large intestine, pancreas, kidney, eye, brain, skin, oral mucosa, thymus, bone marrow, or muscle tissue.[A41-2] The molecule or pharmaceutical composition or immunoconjugate for the use of [A40-2], wherein(i) the fibrosis or inflammation of lung is selected from the group consisting of pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis, scleroderma, chronic obstructive pulmonary disease (COPD), obstructive bronchitis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS associated pulmonary hypertension, sarcoidosis, interstitial lung tumor, and asthma;(ii) the fibrosis or inflammation of liver or bile duct is selected from the group consisting of non-alcoholic steatohepatitis, or alcoholic steatohepatitis, or cholangitis, or Alagille syndrome;(iii) the fibrosis or inflammation of pancreas is pancreatitis;(iv) the fibrosis or inflammation of kidney is selected from the group consisting of chronic kidney disease or acute kidney disease;(v) the fibrosis or inflammation of the oral mucosal is oral mucositis;(vi) the fibrosis or inflammation of the skin is diabetic foot ulcer or epidermolysis bullosa;(vii) the fibrosis or inflammation of the thymus is graft-versus-host disease (GvHD); and(viii) the fibrosis or inflammation of the small or large intestine is an inflammatory bowel disease (IBD), optionally wherein the IBD is ulcerative colitis (UC) or Crohn’s disease.[A42-2] Use of the molecule of any one of [A1-2] and [A1a-2] to [A33-2] or the pharmaceutical composition of [A34-2] or the immunoconjugate of [A35-2], in the manufacture of a medicament for the treatment or prevention of a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof.[A43-2] A method of treating a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of the molecule of any one of [A1-2] and [A1a-2] to [A33-2], or the pharmaceutical composition of [A34-2], or the immunoconjugate of [A35-2].[A44-2] The use of [A42-2], or the method of [A43-2], wherein the condition related to the injury of lung epithelial cells in an individual is selected from the group consisting of fibrosis of the lungs, inflammation of the lungs, senescence-related fibrosis of the lungs, asthma, a condition associated with exposure to environmental toxins, a condition associated with exposure to bacteria, a condition associated with exposure to a virus, cystic fibrosis, a pneumonectomy, a condition associated with exposure to radiation, a condition associated with exposure to tobacco smoke or chemicals, and bleomycin mediated epithelial injury.[A45-2] The use of [A42-2], or the method of [A43-2], wherein the condition related to the injury of lung epithelial cells in an individual is one susceptible of being improved or prevented by one of the following selected from the group consisting of:(i) an increase or enhancement in DDR1 signaling;(ii) an increase in the proliferation of lung epithelial cells; and(iii) an increase in the proliferation of alveolar type II (AT2) progenitor cells or alveolar type II (AT2) cells.[A46-2] Use of the molecule of any one of [A1-2] and [A1a-2] to [A33-2] or the pharmaceutical composition of [A34-2] or the immunoconjugate of [A35-2] in the manufacture of a medicament for the treatment or prevention of fibrosis or inflammation in an individual in need thereof.[A47-2] A method of treating fibrosis or inflammation in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of the molecule of any one of [A1-2] and [A1a-2] to [A33-2] or the pharmaceutical composition of [A34-2] or the immunoconjugate of [A35-2].[A48-2] The use of [A46-2], or the method of [A47-2], wherein the fibrosis or inflammation is selected from fibrosis or inflammation of lung, heart, blood vessel, liver, bile duct, small intestine, large intestine, pancreas, kidney, eye, brain, skin, oral mucosa, thymus, bone marrow, or muscle tissue.[A49-2] The use of [A46-2], or the method of [A47-2], wherein(i) the fibrosis or inflammation of lung is selected from the group consisting of pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis, scleroderma, chronic obstructive pulmonary disease (COPD), obstructive bronchitis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS associated pulmonary hypertension, sarcoidosis, interstitial lung tumor, and asthma;(ii) the fibrosis or inflammation of liver or bile duct is selected from the group consisting of non-alcoholic steatohepatitis, or alcoholic steatohepatitis, or cholangitis, or Alagille syndrome;(iii) the fibrosis or inflammation of pancreas is pancreatitis;(iv) the fibrosis or inflammation of kidney is selected from the group consisting of chronic kidney disease or acute kidney disease;(v) the fibrosis or inflammation of the oral mucosal is oral mucositis;(vi) the fibrosis or inflammation of the skin is diabetic foot ulcer or epidermolysis bullosa;(vii) the fibrosis or inflammation of the thymus is graft-versus-host disease (GvHD); and(viii) the fibrosis or inflammation of the small or large intestine is an inflammatory bowel disease (IBD), optionally wherein the IBD is ulcerative colitis (UC) or Crohn’s disease.[A50-2] An isolated nucleic acid encoding the molecule of any one of [A1-2] and [A1a-2] to [A33-2] or a plurality of isolated nucleic acids encoding the molecule of any one of [A1-2] and [A1a-2] to [A33-2].[A51-2] A host cell comprising the nucleic acid or the plurality of nucleic acids of [A50-2].[A52-2] A method of producing the molecule, or a process for producing the molecule comprising the following steps:(a) culturing the host cell of [A51-2], and(b) recovering the molecule that is produced in step (a).In further aspects and embodiments, the invention relates to any one of [1], [2], [2a], and [3] to

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [51-2], [51a-2], [52-2], [52a-2], [53-2] to [61-2],

[0062] to

[0104] below:[1] An agonistic antigen-binding molecule that binds to a receptor tyrosine kinase (RTK) protein, and wherein the molecule is an agonist of the RTK protein.[2] The molecule of [1], wherein the molecule comprises a first antigen-binding domain that binds a first epitope of a first RTK protein and a second antigen-binding domain that binds a second epitope of the first or a second RTK protein, wherein the first epitope resides in a first domain of the RTK protein, and the second epitope resides in a second domain of the RTK protein.[2a] The molecule of [1], wherein the molecule comprises a first means for binding a first epitope of a first RTK protein and a second means for binding a second epitope of the first or a second RTK protein, wherein the first epitope resides in a first domain of the RTK protein, and the second epitope resides in a second domain of the RTK protein.[3] The molecule of [2] or [2a], wherein the first antigen-binding domain or the first means binds a first RTK protein and the second antigen-binding domain or the second means binds a second RTK protein, optionally wherein the first and the second RTK proteins form a dimer.[4] The molecule of any one of [2], [2a] and [3], wherein binding of the first and second antigen-binding domains or binding of the first and second means induces dimerization of the intracellular tyrosine kinase domains of the RTK protein.[5] The molecule of [4], wherein dimerization is detected in the presence of the molecule in an in vitro cell assay, and wherein dimerization is indicative of agonist activity.[6] The molecule of any one of [2] to [3], wherein binding of the first and second antigen-binding domains or binding of the first and second means activates phosphorylation of the RTK protein.[7] The molecule of [6], wherein phosphorylation of the RTK protein is detected in the presence of the molecule in an in vitro cell assay, wherein RTK protein phosphorylation is indicative of agonist activity.[8] The molecule of any one of [2] to [7], wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means each bind to an extracellular domain (ECD) of the RTK protein.[9] The molecule of [8], wherein the extracellular domain is independently selected from an Immunoglobulin (Ig)-like domain of the ECD of the RTK protein for each of the first antigen-binding domain and the second antigen-binding domain or the first means and the second means.

[0010] The molecule of any one of [2] to [9], wherein the first antigen-binding domain or the first means binds to a first domain and the second antigen-binding domain or the second means binds to a second domain, wherein the first domain and the second domain is the same.

[0011] The molecule of any one of [2] to [9], wherein the first antigen binding-domain or the first means binds to a first domain and the second antigen-binding domain or the second means binds to a second domain, wherein the second domain is different from the first domain.

[0012] The molecule of

[0010] , wherein the first and the second epitope is the same.

[0013] The molecule of

[0010] , wherein the first epitope and the second epitope is different

[0014] The molecule of

[0011] , wherein the first epitope and the second epitope is different.

[0015] The molecule of

[0013] or

[0014] , wherein the molecule binds biparatopically.

[0016] The molecule of any one of [1] to

[0015] , wherein the RTK protein is selected from one of the Fibroblast Growth Factor Receptor (FGFR) family consisting of the members in the group consisting of: FGFR1, FGFR2, FGFR3 and FGFR4 or one of the Discoidin Domain Receptor (DDR) family consisting of the members in the group consisting of: DDR1 and DDR2.

[0017] The molecule of any one of [1] to

[0016] , wherein the RTK protein is Fibroblast growth factor receptor 2 (FGFR2), preferably the RTK protein is FGFR2b.

[0018] The molecule of

[0017] , wherein binding of the molecule to FGFR2b protein via a cell-surface expressed FGFR2b in a target cell activates signaling in the target cell, thereby exhibiting agonist activity, and wherein the activated signal in the target cell is measured by an increase in expression of an intracellular protein downstream of FGFR2b by at least 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or more compared to the expression of said intracellular protein prior to binding of the molecule to the cell-surface expressed FGFR2b protein in the target cell.

[0019] The molecule of

[0018] , wherein the intracellular protein downstream of FGFR2b is selected from the group consisting of: pAKT, pPLCG1, pFRS2, pPAK4, pRAS, pMAPK1 / pERK2, and pMAPK3 / pERK1.

[0020] The molecule of

[0019] , wherein the expression of said intracellular protein is measured using an immunoassay and normalized to the total number of FGFR2b protein and total number of AKT, PLCG1, FRS2, PAK4, RAS, MAPK1 / ERK2, and MAPK3 / ERK1 respectively.

[0021] The molecule of

[0017] , wherein binding of the molecule to FGFR2b protein via a cell-surface expressed FGFR2b in a target cell induces proliferation of the target cell, thereby exhibiting agonist activity.

[0022] The molecule of

[0021] , wherein the induction in proliferation of the target cell is measured by an increase in ATP expression by at least 1.5-fold, or 2-fold, or 2.5-fold or more, in the target cell in the presence of the molecule compared to in the target cell in the absence of the molecule, wherein the ATP expression is directly proportional to the concentration of viable target cells.

[0023] The molecule of

[0021] , wherein the induction in proliferation of the target cell is measured by an increase in BrdU expression by at least 1.5-fold, or 2-fold, or 2.5-fold or more, in the target cell in the presence of the molecule compared to in the target cell in the absence of the molecule, wherein the BrdU expression is directly proportional to the concentration of viable target cells.

[0024] The molecule of any one of

[0018] to

[0023] , wherein the target cell is a lung epithelial cell.

[0025] The molecule of

[0024] , wherein the lung epithelial cell is selected from alveolar type I (AT1) or alveolar type II (AT2) cells, in particular alveolar type II (AT2) cells.

[0026] The molecule of any one of

[0017] to

[0025] , wherein the first antigen-binding domain or the first means binds a first epitope residing in a domain of an extracellular domain (ECD) of FGFR2, or wherein the first antigen-binding domain or the first means binds a first epitope of the extracellular portion of FGFR2.

[0027] The molecule of any one of

[0017] to

[0026] , wherein the first antigen-binding domain or the first means binds an Ig-like domain of FGFR2, selected from the group consisting of IgI, IgII, IgIII, IgIIIb and IgIIIc of FGFR2.

[0028] The molecule of

[0027] , wherein the first antigen-binding domain or the first means binds the IgIIIb domain of FGFR2 and the second antigen-binding domain or the second means binds a domain of FGFR2 other than the IgIIIb domain.

[0029] The molecule of

[0027] , wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, binds an Ig-like domain of the FGFR2 in the following combinations selected from the group consisting of:(i) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgI and IgI domain of FGFR2;(ii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgI and IgII domain of FGFR2;(iii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgI and IgIII domain of FGFR2;(iv) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgI and IgIIIb domain of FGFR2;(v) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgI and IgIIIc domain of FGFR2;(vi) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgII and IgII domain of FGFR2;(vii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgII and IgIII domain of FGFR2;(viii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgII and IgIIIb domain of FGFR2;(ix) wherein the first antigen-binding domain or the first means and the second antigen-binding domain or the second means, independently of each other, bind the IgII and IgIIIc domain of FGFR2;(x) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIII and IgIII domain of FGFR2;(xi) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIII and IgIIIb domain of FGFR2;(xii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIII and IgIIIc domain of FGFR2;(xiii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgIIIb domain of FGFR2; and(xiv) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgIIIc domain of FGFR2.

[0030] The molecule of any one of

[0027] to

[0029] , wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, binds an Ig-like domain of the FGFR2 in the following combinations selected from the group consisting of:(i) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgIIIb domain of FGFR2;(ii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgIII domain of FGFR2;(iii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgII domain of FGFR2; and(iv) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgI domain of FGFR2.

[0031] The molecule of any one of

[0027] to

[0030] , wherein (i) the first antigen-binding domain or the first means binds the IgIIIb domain of FGFR2, or wherein (ii) the first antigen-binding domain or the first means binds specifically to IgIIIb of FGFR2, and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgIIIc of FGFR2, and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgI and IgII of FGFR2.

[0032] The molecule of any one of

[0027] to

[0030] , wherein (i) the first antigen-binding domain or the first means binds the IgIII domain of FGFR2.

[0033] The molecule of any one of

[0027] to

[0032] , wherein the first antigen-binding domain or the first means binds to a continuous or discontinuous epitope.

[0034] The molecule of

[0033] , wherein the continuous or discontinuous epitope resides in one ECD, or in two or three ECDs.

[0035] The molecule of any one of

[0017] to

[0034] , wherein the second antigen-binding domain or the second means binds a second epitope, and wherein the second epitope resides in the same as or different domain of the FGFR2 from the first epitope, or wherein the second antigen-binding domain or the second means binds a second epitope of the ECD of FGFR2.

[0036] The molecule of any one of

[0017] to

[0035] , wherein the second antigen-binding domain or the second means binds an Ig-like domain of FGFR2, selected from the group consisting of IgI, IgII, IgIII, IgIIIb, and IgIIIc of FGFR2.

[0037] The molecule of

[0036] , wherein the (i) second antigen-binding domain or the second means binds to IgII of FGFR2, or (ii) the second antigen-binding domain or the second means binds specifically to IgII of FGFR2 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgI, and IgIII of FGFR2.

[0038] The molecule of

[0036] , wherein the (i) second antigen-binding domain or the second means binds to IgI of FGFR2, or (ii) the second antigen-binding domain or the second means binds specifically to IgI of FGFR2 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgII, and IgIII of FGFR2.

[0039] The molecule of

[0036] , wherein the (i) second antigen-binding domain or the second means binds to IgIIIb of FGFR2, or (ii) the second antigen-binding domain or the second means binds specifically to IgIIIb of FGFR2 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgIIIc of FGFR2, and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgI and IgII of FGFR2.

[0040] The molecule of

[0036] , wherein the (i) second antigen-binding domain or the second means binds to IgIIIc of FGFR2, or (ii) the second antigen-binding domain or the second means binds specifically to IgIIIc of FGFR2 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgIIIb of FGFR2, and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgI and IgII of FGFR2.

[0041] The molecule of

[0036] , wherein the (i) second antigen-binding domain or the second means binds to IgIII of FGFR2, or (ii) the second antigen-binding domain or the second means binds specifically to IgIII of FGFR2 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgI, and IgII of FGFR2.

[0042] The molecule of any one of

[0017] to

[0041] , wherein the second antigen-binding domain or the second means binds to a continuous or discontinuous epitope.

[0043] The molecule of

[0042] , wherein the continuous or discontinuous epitope resides in one ECD, or in two or three ECD.

[0044] The molecule of any one of

[0017] to

[0043] , wherein the first epitope of the first antigen-binding domain or the first means is different from the second epitope of the second antigen-binding domain or the second means, or wherein the first epitope of the first antigen-binding domain or the first means and the second epitope of the second antigen-binding domain or the second means are non-overlapping.

[0045] The molecule of any one of

[0027] to

[0044] , wherein the first antigen-binding domain or the first means binds IgIII of FGFR2, and the second antigen-binding domain or the second means binds IgIII, or IgII, or IgI of FGFR2.

[0046] The molecule of any one of

[0027] to

[0045] , wherein the first antigen-binding domain or the first means binds IgIIIb of FGFR2, and the second antigen-binding domain or the second means binds IgIII, or IgIIIb, or IgII, or IgI of FGFR2.

[0047] The molecule of

[0045] or

[0046] , wherein the molecule binds biparatopically to IgIIIb of FGFR2 and IgIII of FGFR2.

[0048] The molecule of

[0046] , wherein the molecule binds biparatopically to IgIIIb of FGFR2 and IgIIIb of FGFR2.

[0049] The molecule of

[0046] , wherein the molecule binds biparatopically to IgIIIb of FGFR2 and IgII of FGFR2.

[0050] The molecule of

[0046] , wherein the molecule binds biparatopically to IgIIIb of FGFR2 and IgI of FGFR2.

[0051] The molecule of any one of [1] to

[0050] , wherein the RTK protein is Fibroblast growth factor receptor2 (FGFR2), and the molecule comprises a first antigen-binding domain that binds a first epitope and a second antigen-binding domain that binds a second epitope, wherein the first epitope resides in a first domain of a first FGFR2 protein, and the second epitope resides in a second domain of the first or a second FGFR2 protein, wherein the first and the second domain is the same or different, and wherein the first epitope and the second epitope is the same.[51a] The molecule of any one of [1] to

[0050] , wherein the RTK protein is Fibroblast growth factor receptor2 (FGFR2), and the molecule comprises a first means for binding a first epitope and a second means for binding a second epitope, wherein the first epitope resides in a first domain of a first FGFR2 protein, and the second epitope resides in a second domain of the first or a second FGFR2 protein, wherein the first and the second domain is the same or different, and wherein the first epitope and the second epitope is the same.

[0052] The molecule of any one of [1] to

[0050] , wherein the RTK protein is Fibroblast growth factor receptor2 (FGFR2), and the molecule comprises a first antigen-binding domain that binds a first epitope and a second antigen-binding domain that binds a second epitope, wherein the first epitope resides in a first domain of a first FGFR2 protein, and the second epitope resides in a second domain of the first or a second FGFR2 protein, wherein the first and the second domain is the same or different, and wherein the first epitope and the second epitope is different.[52a] The molecule of any one of [1] to

[0050] , wherein the RTK protein is Fibroblast growth factor receptor2 (FGFR2), and the molecule comprises a first means for binding a first epitope and a second means for binding a second epitope, wherein the first epitope resides in a first domain of a first FGFR2 protein, and the second epitope resides in a second domain of the first or a second FGFR2 protein, wherein the first and the second domain is the same or different, and wherein the first epitope and the second epitope is different.

[0053] The molecule of any one of

[0051] , [51a],

[0052] , and [52a], wherein the first antigen-binding domain or the first means binds a first FGFR2 protein and the second antigen-binding domain or the second means binds a second FGFR2 protein, optionally wherein the first and the second RTK proteins form a dimer.

[0054] The molecule of any one of

[0045] to

[0053] , wherein the second antigen-binding domain is selected from the group consisting of FFB0464, FFB0341, FFB0396, FFB0026, FFB0094, FFB0035, FFB0045, FFB0057, and FFB0080.

[0055] The molecule of any one of

[0045] to

[0053] , wherein the first antigen-binding domain is selected from the group consisting of FFB0057, FFB0065, FFB0080, FFB0088, FFB0185, FFB0219, FFB0261, FFB0294, FFB0299, FFB0335, FFB0365, FFB0368, FFB0374, and FFB0453.

[0056] The molecule of

[0054] or

[0055] , wherein the first antigen binding domain competes for binding FGFR2 with an antigen binding domain comprising any one of (a1) to (a14), or wherein the first antigen-binding domain comprises any one of (a1) to (a14), wherein (a1) to (a14) corresponds to (a1) to (a14) recited in

[0164] .

[0057] The molecule of any one of

[0054] to

[0056] , wherein the first antigen binding domain competes for binding FGFR2 with an antigen binding domain comprising any one of (b1) to (b14), or wherein the first antigen-binding domain comprises any one of (b1) to (b14), wherein (b1) to (b14) corresponds to (b1) to (b14) recited in

[0165] .

[0058] The molecule of any one of

[0054] to

[0057] , wherein the second antigen binding domain competes for binding FGFR2 with an antigen binding domain comprising any one of (c1) to (c9), or wherein the second antigen-binding domain comprises any one of (c1) to (c9), wherein (c1) to (c9) corresponds to (c1) to (c9) recited in

[0166] .

[0059] The molecule of any one of

[0054] to

[0058] , wherein the second antigen binding domain competes for binding FGFR2 with an antigen binding domain comprising any one of (d1) to (d9), or wherein the second antigen-binding domain comprises any one of (d1) to (d9), wherein (d1) to (d9) corresponds to (d1) to (d9) recited in

[0167] .

[0060] The molecule of any one of

[0054] to

[0059] , wherein the first antigen-binding domain and the second antigen-binding domain bind the same epitope and wherein the first antigen-binding domain and the second antigen-binding domain compete for binding to FGFR2 with an antigen-binding domain comprising any one of (e1) to (e21), or wherein the first antigen-binding domain and the second antigen-binding domain comprises any one of (e1) to (e21), wherein (e1) to (e21) corresponds to (e1) to (e21) recited in

[0168] .

[0061] The molecule any one of

[0054] to

[0060] , wherein the first antigen-binding domain and the second antigen-binding domain bind different epitopes and each of the first antigen-binding domain and the second antigen-binding domain compete for binding to FGFR2 with an antigen-binding domain comprising any one of (f1) to (f116), or wherein each of the first antigen-binding domain and the second antigen-binding domain comprises any one of (f1) to (f116), wherein (f1) to (f116) corresponds to (f1) to (f116) recited in

[0169] .[17-1] The molecule of any one of [1], [2], [2a], and [3] to

[0016] , wherein the RTK protein is Fibroblast growth factor receptor 1 (FGFR1), preferably the RTK protein is FGFR1b.[18-1] The molecule of [17-1], wherein binding of the molecule to FGFR1b protein via a cell-surface expressed FGFR1b in a target cell activates signaling in the target cell, thereby exhibiting agonist activity, and wherein the activated signal in the target cell is measured by an increase in expression of an intracellular protein downstream of FGFR1b by at least 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or more compared to the expression of said intracellular protein prior to binding of the molecule to the cell-surface expressed FGFR1b protein in the target cell.[19-1] The molecule of [18-1], wherein the intracellular protein downstream of FGFR1b is selected from the group consisting of: pAKT, pPLCG1, pFRS2, pPAK4, pRAS, pMAPK1 / pERK2, and pMAPK3 / pERK1.[20-1] The molecule of [19-1], wherein the expression of said intracellular protein is measured using an immunoassay and normalized to the total number of FGFR1b protein and total number of AKT, PLCG1, FRS2, PAK4, RAS, MAPK1 / ERK2, and MAPK3 / ERK1 respectively.[21-1] The molecule of [17-1], wherein binding of the molecule to FGFR1b protein via a cell-surface expressed FGFR1b in a target cell induces proliferation of the target cell, thereby exhibiting agonist activity.[22-1] The molecule of [21-1], wherein the induction in proliferation of the target cell is measured by an increase in ATP expression by at least 1.5-fold, or 2-fold, or 2.5-fold or more, in the target cell in the presence of the molecule compared to in the target cell in the absence of the molecule, wherein the ATP expression is directly proportional to the concentration of viable target cells.[23-1] The molecule of [21-1], wherein the induction in proliferation of the target cell is measured by an increase in BrdU expression by at least 1.5-fold, or 2-fold, or 2.5-fold or more, in the target cell in the presence of the molecule compared to in the target cell in the absence of the molecule, wherein the BrdU expression is directly proportional to the concentration of viable target cells.[24-1] The molecule of any one of [18-1] to [23-1], wherein the target cell is a lung epithelial cell.[25-1] The molecule of [24-1], wherein the lung epithelial cell is selected from alveolar type I (AT1) or alveolar type II (AT2) cells, in particular alveolar type II (AT2) cells.[26-1] The molecule of any one of [17-1] to [25-1], wherein the first antigen-binding domain or the first means binds a first epitope residing in a domain of an extracellular domain (ECD) of FGFR1, or wherein the first antigen-binding domain or the first means binds a first epitope of the extracellular portion of FGFR1.[27-1] The molecule of any one of [17-1] to [26-1], wherein the first antigen-binding domain or the first means binds an Ig-like domain of FGFR1, selected from the group consisting of IgI, IgII, IgIII, IgIIIb and IgIIIc of FGFR1.[28-1] The molecule of [27-1], wherein the first antigen-binding domain or the first means binds the IgIIIb domain of FGFR1 and the second antigen-binding domain or the second means binds a domain of FGFR1 other than the IgIIIb domain.[29-1] The molecule of [27-1], wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, binds an Ig-like domain of the FGFR1 in the following combinations selected from the group consisting of:(i) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgI and IgI domain of FGFR1;(ii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgI and IgII domain of FGFR1;(iii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgI and IgIII domain of FGFR1;(iv) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgI and IgIIIb domain of FGFR1;(v) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgI and IgIIIc domain of FGFR1;(vi) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgII and IgII domain of FGFR1;(vii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgII and IgIII domain of FGFR1;(viii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgII and IgIIIb domain of FGFR1;(ix) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgII and IgIIIc domain of FGFR1;(x) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIII and IgIII domain of FGFR1;(xi) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIII and IgIIIb domain of FGFR1;(xii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIII and IgIIIc domain of FGFR1;(xiii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgIIIb domain of FGFR1; and(xiv) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgIIIc domain of FGFR1.[30-1] The molecule of any one of [27-1] to [29-1], wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, binds an Ig-like domain of the FGFR1 in the following combinations selected from the group consisting of:(i) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgIIIb domain of FGFR1;(ii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgIII domain of FGFR1;(iii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgII domain of FGFR1; and(iv) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the IgIIIb and IgI domain of FGFR1.[31-1] The molecule of any one of [27-1] to [30-1], wherein (i) the first antigen-binding domain or the first means binds the IgIIIb domain of FGFR1, or wherein (ii) the first antigen-binding domain or the first means binds specifically to IgIIIb of FGFR1, and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgIIIc of FGFR1, and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgI and IgII of FGFR1.[32-1] The molecule of any one of [27-1] to [30-1], wherein (i) the first antigen-binding domain or the first means binds the IgIII domain of FGFR1.[33-1] The molecule of any one of [27-1] to [32-1], wherein the first antigen-binding domain or the first means binds to a continuous or discontinuous epitope.[34-1] The molecule of [33-1], wherein the continuous or discontinuous epitope resides in one ECD, or in two or three ECDs.[35-1] The molecule of any one of [17-1] to [34-1], wherein the second antigen-binding domain or the second means binds a second epitope, and wherein the second epitope resides in the same as or different domain of the FGFR1 from the first epitope, or wherein the second antigen-binding domain or the second means binds a second epitope of the ECD of FGFR1.[36-1] The molecule of any one of [17-1] to [35-1], wherein the second antigen-binding domain or the second means binds an Ig-like domain of FGFR1, selected from the group consisting of IgI, IgII, IgIII, IgIIIb, and IgIIIc of FGFR1.[37-1] The molecule of [36-1], wherein the (i) second antigen-binding domain or the second means binds to IgII of FGFR1, or (ii) the second antigen-binding domain or the second means binds specifically to IgII of FGFR1 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgI, and IgIII of FGFR1.[38-1] The molecule of [36-1], wherein the (i) second antigen-binding domain or the second means binds to IgI of FGFR1, or (ii) the second antigen-binding domain or the second means binds specifically to IgI of FGFR1 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgII, and IgIII of FGFR1.[39-1] The molecule of [36-1], wherein the (i) second antigen-binding domain or the second means binds to IgIIIb of FGFR1, or (ii) the second antigen-binding domain or the second means binds specifically to IgIIIb of FGFR1 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgIIIc of FGFR1, and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgI and IgII of FGFR1.[40-1] The molecule of [36-1], wherein the (i) second antigen-binding domain or the second means binds to IgIIIc of FGFR1, or (ii) the second antigen-binding domain or the second means binds specifically to IgIIIc of FGFR1 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgIIIb of FGFR1, and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgI and IgII of FGFR1.[41-1] The molecule of [36-1], wherein the (i) second antigen-binding domain or the second means binds to IgIII of FGFR1, or (ii) the second antigen-binding domain or the second means binds specifically to IgIII of FGFR1 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgI, and IgII of FGFR1.[42-1] The molecule of any one of [17-1] to [41-1], wherein the second antigen-binding domain or the second means binds to a continuous or discontinuous epitope.[43-1] The molecule of [42-1], wherein the continuous or discontinuous epitope resides in one ECD, or in two or three ECD.[44-1] The molecule of any one of [17-1] to [43-1], wherein the first epitope of the first antigen-binding domain or the first means is different from the second epitope of the second antigen-binding domain or the second means, or wherein the first epitope of the first antigen-binding domain or the first means and the second epitope of the second antigen-binding domain or the second means are non-overlapping.[45-1] The molecule of any one of [27-1] to [44-1], wherein the first antigen-binding domain or the first means binds IgIII of FGFR1, and the second antigen-binding domain or the second means binds IgIII, or IgII, or IgI of FGFR1.[46-1] The molecule of any one of [27-1] to [45-1], wherein the first antigen-binding domain or the first means binds IgIIIb of FGFR1, and the second antigen-binding domain or the second means binds IgIII, or IgIIIb, or IgII, or IgI of FGFR1.[47-1] The molecule of [45-1] or [46-1], wherein the molecule binds biparatopically to IgIIIb of FGFR1 and IgIII of FGFR1.[48-1] The molecule of [46-1], wherein the molecule binds biparatopically to IgIIIb of FGFR1 and IgIIIb of FGFR1.[49-1] The molecule of [46-1], wherein the molecule binds biparatopically to IgIIIb of FGFR1 and IgII of FGFR1.[50-1] The molecule of [46-1], wherein the molecule binds biparatopically to IgIIIb of FGFR1 and IgI of FGFR1.[51-1] The molecule of any one of [1] to

[0016] and [17-1] to [50-1], wherein the RTK protein is Fibroblast growth factor receptor1 (FGFR1), and the molecule comprises a first antigen-binding domain that binds a first epitope and a second antigen-binding domain that binds a second epitope, wherein the first epitope resides in a first domain of a first FGFR1 protein, and the second epitope resides in a second domain of the first or a second FGFR1 protein, wherein the first and the second domain is the same or different, and wherein the first epitope and the second epitope is the same.[51a-1] The molecule of any one of [1], [2], [2a], and [3] to

[0016] and [17-1] to [50-1], wherein the RTK protein is Fibroblast growth factor receptor1 (FGFR1), and the molecule comprises a first means for binding a first epitope and a second means for binding a second epitope, wherein the first epitope resides in a first domain of a first FGFR1 protein, and the second epitope resides in a second domain of the first or a second FGFR1 protein, wherein the first and the second domain is the same or different, and wherein the first epitope and the second epitope is the same.[52-1] The molecule of any one of [1] to

[0016] and [17-1] to [50-1], wherein the RTK protein is Fibroblast growth factor receptor1 (FGFR1), and the molecule comprises a first antigen-binding domain that binds a first epitope and a second antigen-binding domain that binds a second epitope, wherein the first epitope resides in a first domain of a first FGFR1 protein, and the second epitope resides in a second domain of the first or a second FGFR1 protein, wherein the first and the second domain is the same or different, and wherein the first epitope and the second epitope is different.[52a-1] The molecule of any one of [1], [2], [2a], and [3] to

[0016] and [17-1] to [50-1], wherein the RTK protein is Fibroblast growth factor receptor1 (FGFR1), and the molecule comprises a first means for binding a first epitope and a second means for binding a second epitope, wherein the first epitope resides in a first domain of a first FGFR1 protein, and the second epitope resides in a second domain of the first or a second FGFR1 protein, wherein the first and the second domain is the same or different, and wherein the first epitope and the second epitope is different.[53-1] The molecule of any one of [51-1], [51a-1], [52-1], and [52a-1], wherein the first antigen-binding domain or the first means binds a first FGFR1 protein and the second antigen-binding domain or the second means binds a second FGFR1 protein, optionally wherein the first and the second RTK proteins form a dimer.[54-1] The molecule of any one of [45-1] to [53-1], wherein the second antigen-binding domain is selected from the group consisting of FFA0020, FFA0026, FFA0032, FFA0043, FFA0047, FFA0055, FFA0064, and FFA0088.[55-1] The molecule of any one of [45-1] to [53-1], wherein the first antigen-binding domaini is selected from the group consisting of FFA0029, and FFA0048.[56-1] The molecule of [54-1] or [55-1], wherein the first antigen binding domain competes for binding FGFR1 with an antigen binding domain comprising any one of (h1) to (h2), or wherein the first antigen-binding domain comprises any one of (h1) to (h2), wherein (h1) to (h2) corresponds to (h1) to (h2) recited in

[0219] .[57-1] The molecule of any one of [54-1] to [56-1], wherein the first antigen binding domaini competes for binding FGFR1 with an antigen binding domain comprising any one of (i1) to (i2), or wherein the first antigen-binding domain comprises any one of (i1) to (i2), wherein (i2) to (i2) corresponds to (i1) to (i2) recited in

[0220] .[58-1] The molecule of any one of [54-1] to [57-1], wherein the second antigen binding domain competes for binding FGFR1 with an antigen binding domain comprising any one of (j1) to (j8), or wherein the second antigen-binding domain comprises any one of (j1) to (j8), wherein (j1) to (j8) corresponds to (j1) to (j8) recited in

[0221] .[59-1] The molecule of any one of [54-1] to [58-1], wherein the second antigen binding domain competes for binding FGFR1 with an antigen binding domain comprising any one of (k1) to (k8), or wherein the second antigen-binding domain comprises any one of (k1) to (k8), wherein (k1) to (k8) corresponds to (k1) to (k8) recited in

[0222] .[60-1] The molecule of any one of [54-1] to [59-1], wherein the first antigen-binding domain and the second antigen-binding domain bind the same epitope and wherein the first antigen-binding domain and the second antigen-binding domain compete for binding to FGFR1 with an antigen-binding domain comprising any one of (l1) to (l10), or wherein the first antigen-binding domain and the second antigen-binding domain comprises any one of (l1) to (l10), wherein (l1) to (l10) corresponds to (l1) to (l10) recited in

[0223] .[61-1] The molecule any one of [54-1] to [60-1], wherein the first antigen-binding domain and the second antigen-binding domain bind different epitopes and each of the first antigen-binding domain and the second antigen-binding domain compete for binding to FGFR1 with an antigen-binding domain comprising any one of (m1) to (m16), or wherein each of the first antigen-binding domain and the second antigen-binding domain comprises any one of (m1) to (m16), wherein (m1) to (m16) corresponds to (m1) to (m16) recited in

[0224] .[17-2] The molecule of any one of [1], [2], [2a], and [3] to

[0016] , wherein the RTK protein is discoidin domain receptor1 (DDR1).[18-2] The molecule of [17-2], wherein binding of the molecule to DDR1 protein via a cell-surface expressed DDR1 in a target cell activates signaling in the target cell, thereby exhibiting agonist activity, and wherein the activated signal in the target cell is measured by an increase in expression of an intracellular protein downstream of DDR1 by at least 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or more compared to the expression of said intracellular protein prior to binding of the molecule to the cell-surface expressed DDR1 protein in the target cell.[19-2] The molecule of [18-2], wherein the intracellular protein downstream of DDR1 is selected from the group consisting of: SHP-2, FAK, NF-kappa B, Cdc42, MAPK1, AP1, Ras / Raf / ERK, PI3K / AKT, STAT1 / 3 / 5.[20-2] The molecule of [19-2], wherein the expression of said intracellular protein is measured using an immunoassay and normalized to the total number of DDR1 protein and total number of SHP-2, FAK, NF-kappa B, Cdc42, MAPK1, AP1, Ras / Raf / ERK, PI3K / AKT, STAT1 / 3 / 5 respectively.[21-2] The molecule of [17-2], wherein binding of the molecule to DDR1 protein via a cell-surface expressed DDR1 in a target cell induces proliferation of the target cell, thereby exhibiting agonist activity.[22-2] The molecule of [21-2], wherein the induction in proliferation of the target cell is measured by an increase in ATP expression by at least 1.5-fold, or 2-fold, or 2.5-fold or more, in the target cell in the presence of the molecule compared to in the target cell in the absence of the molecule, wherein the ATP expression is directly proportional to the concentration of viable target cells.[23-2] The molecule of [21-2], wherein the induction in proliferation of the target cell is measured by an increase in BrdU expression by at least 1.5-fold, or 2-fold, or 2.5-fold or more, in the target cell in the presence of the molecule compared to in the target cell in the absence of the molecule, wherein the BrdU expression is directly proportional to the concentration of viable target cells.[24-2] The molecule of any one of [18-2] to [23-2], wherein the target cell is a lung epithelial cell.[25-2] The molecule of [24-2], wherein the lung epithelial cell is selected from alveolar type I (AT1) or alveolar type II (AT2) cells, in particular alveolar type II (AT2) cells.[26-2] The molecule of any one of [17-2] to [25-2], wherein the first antigen-binding domain or the first means binds a first epitope residing in a domain of an extracellular domain (ECD) of DDR1, or wherein the first antigen-binding domain or the first means binds a first epitope of the extracellular portion of DDR1.[27-2] The molecule of any one of [17-2] to [26-2], wherein the first antigen-binding domain or the first means binds a discoidin (DS) domain, a DS-like domain, or an extracellular juxtamembrane (EJXM) region of DDR1.[28-2] The molecule of [27-2], wherein the first antigen-binding domain or the first means binds the DS domain of DDR1 and the second antigen-binding domain or the second means binds a domain or region of DDR1 other than the DS domain.[29-2] The molecule of [27-2], wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, binds a discoidin (DS) domain, a DS-like domain, or an extracellular juxtamembrane (EJXM) region of the DDR1 in the following combinations selected from the group consisting of:(i) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the DS and DS domain of DDR1;(ii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the DS and DS-like domain of DDR1;(iii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the DS domain and EJXM region of DDR1;(iv) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the DS-like domain and DS-like domain of DDR1;(vii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the DS-like domain and EJXM region of DDR1; and(viii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the EJXM region and EJXM region of DDR1.[30-2] The molecule of any one of [27-2] to [29-2], wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, binds a discoidin (DS) domain, a DS-like domain, or an extracellular juxtamembrane (EJXM) region of the DDR1 in the following combinations selected from the group consisting of:(i) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the DS and DS domain of DDR1;(ii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the DS and DS-like domain of DDR1; and(iii) wherein the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind the DS and EJXM region of DDR1.[31-2] The molecule of any one of [27-2] to [30-2], wherein (i) the first antigen-binding domain or the first means binds the DS domain of DDR1, or wherein (ii) the first antigen-binding domain or the first means binds specifically to the DS domain of DDR1, and shows less than 10%, or less than 5%, or 0% cross-reactivity with the DS-like domain of DDR1, and shows less than 10%, or less than 5%, or 0% cross-reactivity with the EJXM region of DDR1.[32-2] The molecule of any one of [27-2] to [30-2], wherein (i) the first antigen-binding domain or the first means binds the DS domain of DDR1.[33-2] The molecule of any one of [27-2] to [32-2], wherein the first antigen-binding domain or the first means binds to a continuous or discontinuous epitope.[34-2] The molecule of [33-2], wherein the continuous or discontinuous epitope resides in one ECD, or in two or three ECDs.[35-2] The molecule of any one of [17-2] to [34-2], wherein the second antigen-binding domain or the second means binds a second epitope, and wherein the second epitope resides in the same as or different domain of the DDR1 from the first epitope, or wherein the second antigen-binding domain or the second means binds a second epitope of the ECD of DDR1.[36-2] The molecule of any one of [17-2] to [35-2], wherein the second antigen-binding domain or the second means binds a discoidin (DS) domain, a DS-like domain, or an extracellular juxtamembrane (EJXM) region of DDR1.[37-2] The molecule of [36-2], wherein the (i) second antigen-binding domain or the second means binds to the DS domain of DDR1, or (ii) the second antigen-binding domain or the second means binds specifically to the DS domain of DDR1 and shows less than 10%, or less than 5%, or 0% cross-reactivity with the DS-like domain and the EJXM region of DDR1.[38-2] The molecule of [36-2], wherein the (i) second antigen-binding domain or the second means binds to the DS-like domain and / or the EJXM region of DDR1, or (ii) the second antigen-binding domain or the second means binds specifically to the DS-like domain and / or the EJXM region of DDR1 and shows less than 10%, or less than 5%, or 0% cross-reactivity with the DS domain of DDR1.[39-2] The molecule of any one of [17-2] to [38-2], wherein the second antigen-binding domain or the second means binds to a continuous or discontinuous epitope.[40-2] The molecule of [39-2], wherein the continuous or discontinuous epitope resides in one ECD, or in two or three ECD.[41-2] The molecule of any one of [17-2] to [40-2], wherein the first epitope of the first antigen-binding domain or the first means is different from the second epitope of the second antigen-binding domain or the second means, or wherein the first epitope of the first antigen-binding domain or the first means and the second epitope of the second antigen-binding domain or the second means are non-overlapping.[42-2] The molecule of any one of [27-2] to [41-2], wherein the first antigen-binding domain or the first means binds the DS domain of DDR1, and the second antigen-binding domain or the second means binds the DS domain or the DS-like domain and / or the EJXM region of DDR1.[43-2] The molecule of any one of [27-2] to [45-2], wherein the first antigen-binding domain or the first means binds the DS-like domain and / or the EJXM region of DDR1, and the second antigen-binding domain or the second means binds the DS-like domain and / or the EJXM region of DDR1.[44-2] The molecule of [42-2], wherein the molecule binds biparatopically to the DS domain of DDR1 and the DS domain of DDR1.[45-2] The molecule of [42-2], wherein the molecule binds biparatopically to the DS domain of DDR1 and the DS-like domain and / or the EJXM region of DDR1.[46-2] The molecule of [43-2], wherein the molecule binds biparatopically to the DS-like domain and / or the EJXM region of DDR1 and the DS-like domain and / or the EJXM region of DDR1.[47-2] The molecule of any one of [1] to

[0016] and [17-2] to [46-2], wherein the RTK protein is Discoidin domain receptor1 (DDR1), and the molecule comprises a first antigen-binding domain that binds a first epitope and a second antigen-binding domain that binds a second epitope, wherein the first epitope resides in a first domain of a first DDR1 protein, and the second epitope resides in a second domain of the first or a second DDR1 protein, wherein the first and the second domain is the same or different, and wherein the first epitope and the second epitope is the same.[47a-2] The molecule of any one of [1], [2], [2a], and [3] to

[0016] and [17-2] to [46-2], wherein the RTK protein is Discoidin domain receptor1 (DDR1), and the molecule comprises a first means for binding a first epitope and a second means for binding a second epitope, wherein the first epitope resides in a first domain of a first DDR1 protein, and the second epitope resides in a second domain of the first or a second DDR1 protein, wherein the first and the second domain is the same or different, and wherein the first epitope and the second epitope is the same.[48-2] The molecule of any one of [1] to

[0016] and [17-2] to [46-2], wherein the RTK protein is Discoidin domain receptor1 (DDR1), and the molecule comprises a first antigen-binding domain that binds a first epitope and a second antigen-binding domain that binds a second epitope, wherein the first epitope resides in a first domain of a first DDR1 protein, and the second epitope resides in a second domain of the first or a second DDR1 protein, wherein the first and the second domain is the same or different, and wherein the first epitope and the second epitope is different.[48a-2] The molecule of any one of [1], [2], [2a], and [3] to

[0016] and [17-2] to [46-2], wherein the RTK protein is Discoidin domain receptor1 (DDR1), and the molecule comprises a first means for binding a first epitope and a second means for binding a second epitope, wherein the first epitope resides in a first domain of a first DDR1 protein, and the second epitope resides in a second domain of the first or a second DDR1 protein, wherein the first and the second domain is the same or different, and wherein the first epitope and the second epitope is different.[49-2] The molecule of any one of [47-2], [47a-2], [48-2], and [48a-2], wherein the first antigen-binding domain or the first means binds a first DDR1 protein and the second antigen-binding domain or the second means binds a second DDR1 protein, optionally wherein the first and the second RTK proteins form a dimer.[50-2] The molecule of any one of [42-2] to [49-2], wherein the second antigen-binding domain is selected from the group consisting of DAA0007, DAA0012, and DAA0024.[51-2] The molecule of any one of [42-2] to [49-2], wherein the first antigen-binding domain is selected from the group consisting of DAA0011, and DAA0045.[52-2] The molecule of [50-2] or [51-2], wherein the first antigen binding domain competes for binding DDR1 with an antigen binding domain comprising any one of (o1) to (o2), or wherein the first antigen-binding domain comprises any one of (o1) to (o2), wherein (o1) to (o2) corresponds to (o1) to (o2) recited in

[0267] .[53-2] The molecule of any one of [50-2] to [52-2], wherein the first antigen binding domain competes for binding DDR1 with an antigen binding domain comprising any one of (p1) to (p2), or wherein the first antigen-binding domain comprises any one of (p1) to (p2), wherein (p1) to (p2) corresponds to (p1) to (p2) recited in

[0268] .[54-2] The molecule of any one of [50-2] to [53-2], wherein the second antigen binding domain competes for binding DDR1 with an antigen binding domain comprising any one of (q1) to (q3), or wherein the second antigen-binding domain comprises any one of (q1) to (q3), wherein (q1) to (q3) corresponds to (q1) to (q3) recited in

[0269] .[55-2] The molecule of any one of [50-2] to [54-2], wherein the second antigen binding domain competes for binding DDR1 with an antigen binding domain comprising any one of (r1) to (r3), or wherein the second antigen-binding domain comprises any one of (r1) to (r3), wherein (r1) to (r3) corresponds to (r1) to (r3) recited in

[0270] .[56-2] The molecule of any one of [50-2] to [55-2], wherein the first antigen-binding domain and the second antigen-binding domain bind the same epitope and wherein the first antigen-binding domain and the second antigen-binding domain compete for binding to DDR1 with an antigen-binding domain comprising any one of (s1) to (s5), or wherein the first antigen-binding domain and the second antigen-binding domain comprises any one of (s1) to (s5), wherein (s1) to (s5) corresponds to (s1) to (s5) recited in

[0271] .[57-2] The molecule any one of [50-2] to [56-2], wherein the first antigen-binding domain and the second antigen-binding domain bind different epitopes and each of the first antigen-binding domain and the second antigen-binding domain compete for binding to DDR1 with an antigen-binding domain comprising any one of (t1) to (t6), or wherein each of the first antigen-binding domain and the second antigen-binding domain comprises any one of (t1) to (t6), wherein (t1) to (t6) corresponds to (t1) to (t6) recited in

[0272] .

[0062] The molecule of any one of [1] to

[0061] , [17-1] to [61-1], and [17-2] to [57-2], wherein the first antigen-binding domain and the second antigen-binding domain are each independently selected from an Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody, or wherein the first antigen-binding domain and the second antigen-binding domain are each a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody which are linked by at least one disulfide bond.

[0063] The molecule of any one of [1] to

[0061] , [17-1] to [61-1], [17-2] to [57-2], and

[0062] , wherein the first antigen-binding domain and the second antigen-binding domain are characterized by having at least one disulfide bond formed between amino acid residues which are not in a hinge region.

[0064] The molecule of

[0063] , wherein the at least one disulfide bond is an engineered disulfide bond which is not present in a wild type IgG.

[0065] The molecule of

[0064] , wherein said at least one disulfide bond is formed between a CH1 region, a CL region, a VH or VHH region, or a VL region of the first antigen-binding domain and a CH1 region, a CL region, a VH or VHH region, or a VL region of the second antigen-binding domain.

[0066] The molecule of

[0065] , wherein said at least one disulfide bond is formed between the group selected from the following:(i) an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CH1 region of a second antigen-binding domain;(ii) an amino acid residue in a CL region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain;(iii) an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain;(iv) an amino acid residue in a VH or VHH region of a first antigen-binding domain and an amino acid residue in a VH or VHH region of a second antigen-binding domain;(v) an amino acid residue in a VL region of a first antigen-binding domain and an amino acid residue in a VL region of a second antigen-binding domain; and(vi) an amino acid residue in a VH or VHH region of a first antigen-binding domain and an amino acid residue in a VL region of a second antigen-binding domain.

[0067] The molecule of

[0066] , wherein said at least one disulfide bond is formed between an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CH1 region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 119, 122, 123, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 148, 150, 155, 156, 157, 159, 160, 161, 162, 163, 164, 165, 167, 174, 176, 177, 178, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 201, 203, 205, 206, 207, 208, 211, 212, 213, 214, 218, and 219, according to EU numbering, in the CH1 region.

[0068] The molecule of

[0066] , wherein said at least one disulfide bond is formed between an amino acid residue in a CL region of a first antigen-binding domain and an amino acid residue in a CL region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 108, 109, 112, 121, 123, 126, 128, 151, 152, 153, 156, 184, 186, 188, 189, 190, 195, 196, 200, 201, 202, 203, 208, 210, 211, 212, and 213 according to Kabat numbering in the CL region.

[0069] The molecule of

[0066] , wherein said at least one disulfide bond is formed between an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CL region of the second antigen-binding domain, and the amino acid residue in the CH1 region is selected from the group consisting of positions 188, 189, 190, 191, 192, 193, 194, 195, 196, and 197 according to EU numbering, and the amino acid residue in the CL region is selected from the group consisting of positions 121, 122, 123, 124, 125, 126, 127, and 128 according to Kabat numbering.

[0070] The molecule of

[0066] , wherein said at least one disulfide bond is formed between an amino acid residue in a VH region of a first antigen-binding domain and an amino acid residue in a VH region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 6, 8, 16, 20, 25, 26, 28, 74, and 82b according to Kabat numbering in the VH region.

[0071] The molecule of

[0066] , wherein said at least one disulfide bond is formed between an amino acid residue in a VHH region of a first antigen-binding domain and an amino acid residue in a VHH region of the second antigen-binding domain, and wherein the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 4, 6, 7, 8, 9, 10, 11, 12, 14, 15, 17, 20, 24, 27, 29, 38, 39, 40, 41, 43, 44, 45, 46, 47, 48, 49, 67, 69, 71, 78, 80, 82, 82c, 85, 88, 91, 93, 94, and 107 according to Kabat numbering in the VHH region.

[0072] The molecule of

[0066] , wherein said at least one disulfide bond is formed between an amino acid residue in a VL region of a first antigen-binding domain and an amino acid residue in a VL region of the second antigen-binding domain, and(i) wherein when the VL is of a subclass kappa, the amino acid residue from which the bond between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 21, 27, 58, 77, 100, 105, and 107 according to Kabat numbering in the VL region (subclass kappa); or(ii) wherein when the VL is of a subclass lambda, the amino acid residue from which the bonds between the first and second antigen-binding domains originate is present at a position selected from the group consisting of positions 6, 19, 33, and 34 according to Kabat numbering in the VL region (subclass lambda).

[0073] The molecule of

[0072] , wherein the at least one disulfide bond is formed between an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain.

[0074] The molecule of

[0073] , wherein the at least one disulfide bond is formed between the amino acid residue at position 191 in a CH1 region of a first antigen-binding domain (according to Kabat numbering) and the amino acid residue at position 126 in a CL region of a second antigen-binding domain (according to Kabat numbering).

[0075] The molecule of any one of [1] to

[0061] , [17-1] to [61-1], [17-2] to [57-2], and

[0062] to

[0074] , wherein the molecule comprises an antibody constant region.

[0076] The molecule of

[0075] wherein the antibody constant region is a human antibody constant region, or wherein the antibody constant region is selected from a human IgG1, IgG2, IgG3 or IgG4 constant regions.

[0077] The molecule of any one of [1] to

[0061] , [17-1] to [61-1], [17-2] to [57-2], and

[0062] to

[0076] , wherein the molecule comprises or is an antibody or antibody fragment thereof.

[0078] The molecule of

[0077] , wherein the antibody fragment is a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody.

[0079] The molecule of

[0077] or

[0078] wherein the molecule is a monoclonal antibody.

[0080] The molecule of any one of

[0077] to

[0079] , wherein the molecule is human, humanized, or chimeric antibody.

[0081] The molecule of any one of [1] to

[0061] , [17-1] to [61-1], [17-2] to [57-2], and

[0062] to

[0080] , wherein the molecule is characterized by two antigen-binding domains, or wherein the molecule is a bivalent molecule, or wherein the first antigen-binding domain and second antigen-binding domain are each a monovalent Fab, or a monovalent VHH, or are each a monovalent scFab.

[0082] The molecule of any one of [1], [2], [2a], and [3]

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0081] , wherein the molecule comprises more than two antigen-binding domains or more than two means for binding, or wherein the molecule is tri-valent, tetra-valent, or multivalent molecule.

[0083] The molecule of

[0082] , wherein the molecule comprises a third antigen-binding domain, wherein the third antigen-binding domain binds the same epitope on the same domain as the first or the second antigen-binding domain, or wherein the molecule comprises a third means for binding the same epitope on the same domain as the first or the second means.

[0084] The molecule of

[0083] , wherein the molecule comprises a fourth antigen-binding domain, wherein the fourth antigen-binding domain binds the same epitope on the same domain as the first or the second antigen-binding domain but not the same epitope as the third antigen-binding domain, or wherein the molecule comprises a fourth means for binding the same epitope on the same domain as the first or the second means but not the same epitope as the third means.

[0085] The molecule of

[0084] , wherein the molecule comprises a third and a fourth antigen-binding domain, wherein the third antigen-binding domain binds the same epitope on the same domain as the first antigen-binding domain, and the fourth antigen-binding domain binds the same epitope on the same domain as the second antigen-binding domain, or wherein the molecule comprises a third means for binding the same epitope on the same domain as the first means, and a fourth means for binding the same epitope on the same domain as the second means.

[0086] A pharmaceutical composition comprising the molecule of any one of [1], [2], [2a], and [3]

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , and a pharmaceutically acceptable carrier.

[0087] An immunoconjugate protein comprising the molecule of any one of [1], [2], [2a], and [3]

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] .

[0088] The molecule of any one of [1], [2], [2a], and [3]

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , or the pharmaceutical composition of

[0086] , or the immunoconjugate of

[0087] , for use in the treatment or prevention of a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof.

[0089] The molecule or pharmaceutical composition or immunoconjugate for the use of

[0088] , wherein the condition related to the injury of lung epithelial cells in an individual is selected from the group consisting of fibrosis of the lungs, inflammation of the lungs, senescence-related fibrosis of the lungs, asthma, a condition associated with exposure to environmental toxins, a condition associated with exposure to bacteria, a condition associated with exposure to a virus, cystic fibrosis, a pneumonectomy, a condition associated with exposure to radiation, a condition associated with exposure to tobacco smoke or chemicals, and bleomycin mediated epithelial injury.

[0090] The molecule of any one of [1], [2], [2a], and [3]

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , or the pharmaceutical composition of

[0086] , or the immunoconjugate of

[0087] , for use in the treatment of any disease, disorder, or condition susceptible of being improved or prevented by one of the following selected from the group consisting of:(i) an increase or enhancement in FGFR2b signaling, or FGFR1b signaling, or DDR1 signaling;(ii) an increase in the proliferation of lung epithelial cells; and(iii) an increase in the proliferation alveolar type II (AT2) progenitor cells or alveolar type II (AT2) cells.

[0091] The molecule of any one of [1], [2], [2a], and [3]

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , or the pharmaceutical composition of

[0086] , or the immunoconjugate of

[0087] , for use in the treatment or prevention of fibrosis or inflammation in an individual in need thereof.

[0092] The molecule or pharmaceutical composition or immunoconjugate for the use of

[0091] , wherein the fibrosis or inflammation is selected from fibrosis or inflammation of lung, heart, blood vessel, liver, bile duct, small intestine, large intestine, pancreas, kidney, eye, brain, skin, oral mucosa, thymus, bone marrow, or muscle tissue.

[0093] The molecule or pharmaceutical composition or immunoconjugate for the use of

[0092] , wherein(i) the fibrosis or inflammation of lung is selected from the group consisting of pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis, scleroderma, chronic obstructive pulmonary disease (COPD), obstructive bronchitis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS associated pulmonary hypertension, sarcoidosis, interstitial lung tumor, and asthma;(ii) the fibrosis or inflammation of liver or bile duct is selected from the group consisting of non-alcoholic steatohepatitis, or alcoholic steatohepatitis, or cholangitis, or Alagille syndrome;(iii) the fibrosis or inflammation of pancreas is pancreatitis;(iv) the fibrosis or inflammation of kidney is selected from the group consisting of chronic kidney disease or acute kidney disease;(v) the fibrosis or inflammation of the oral mucosal is oral mucositis;(vi) the fibrosis or inflammation of the skin is diabetic foot ulcer or epidermolysis bullosa;(vii) the fibrosis or inflammation of the thymus is graft-versus-host disease (GvHD); and(viii) the fibrosis or inflammation of the small or large intestine is an inflammatory bowel disease (IBD), optionally wherein the IBD is ulcerative colitis (UC) or Crohn’s disease.

[0094] Use of the molecule of any one of [1], [2], [2a], and [3]

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , or the pharmaceutical composition of

[0086] , or the immunoconjugate of

[0087] , in the manufacture of a medicament for the treatment or prevention of a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof.

[0095] A method of treating a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of the molecule of any one of [1], [2], [2a], and [3]

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , or the pharmaceutical composition of

[0086] , or the immunoconjugate of

[0087] .

[0096] The use of

[0094] , or the method of

[0095] , wherein the condition related to the injury of lung epithelial cells in an individual is selected from the group consisting of fibrosis of the lungs, inflammation of the lungs, senescence-related fibrosis of the lungs, asthma, a condition associated with exposure to environmental toxins, a condition associated with exposure to bacteria, a condition associated with exposure to a virus, cystic fibrosis, a pneumonectomy, a condition associated with exposure to radiation, a condition associated with exposure to tobacco smoke or chemicals, and bleomycin mediated epithelial injury.

[0097] The use of

[0094] , or the method of

[0095] , wherein the condition related to the injury of lung epithelial cells in an individual is one susceptible of being improved or prevented by one of the following selected from the group consisting of:(i) an increase or enhancement in FGFR2b signaling, or FGFR1b signaling, or DDR1 signaling;(ii) an increase in the proliferation of lung epithelial cells; and(iii) an increase in the proliferation of alveolar type II (AT2) progenitor cells or alveolar type II (AT2) cells.

[0098] Use of the molecule of any one of [1], or FGFR1b signaling, or DDR1 signaling to

[0085] , or the pharmaceutical composition of

[0086] , or the immunoconjugate of

[0087] , in the manufacture of a medicament for the treatment or prevention of fibrosis or inflammation in an individual in need thereof.

[0099] A method of treating fibrosis or inflammation in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of the molecule of any one of [1], [2], [2a], and [3] to

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , or the pharmaceutical composition of

[0086] , or the immunoconjugate of

[0087] .

[0100] The use of

[0098] , or the method of

[0099] , wherein the fibrosis or inflammation is selected from fibrosis or inflammation of lung, heart, blood vessel, liver, bile duct, small intestine, large intestine, pancreas, kidney, eye, brain, skin, oral mucosa, thymus, bone marrow, or muscle tissue.

[0101] The use of

[0098] , or the method of

[0099] , wherein(i) the fibrosis or inflammation of lung is selected from the group consisting of pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis, scleroderma, chronic obstructive pulmonary disease (COPD), obstructive bronchitis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS associated pulmonary hypertension, sarcoidosis, interstitial lung tumor, and asthma;(ii) the fibrosis or inflammation of liver or bile duct is selected from the group consisting of non-alcoholic steatohepatitis, or alcoholic steatohepatitis, or cholangitis, or Alagille syndrome;(iii) the fibrosis or inflammation of pancreas is pancreatitis;(iv) the fibrosis or inflammation of kidney is selected from the group consisting of chronic kidney disease or acute kidney disease;(v) the fibrosis or inflammation of the oral mucosal is oral mucositis;(vi) the fibrosis or inflammation of the skin is diabetic foot ulcer or epidermolysis bullosa;(vii) the fibrosis or inflammation of the thymus is graft-versus-host disease (GvHD); and(viii) the fibrosis or inflammation of the small or large intestine is an inflammatory bowel disease (IBD), optionally wherein the IBD is ulcerative colitis (UC) or Crohn’s disease.

[0102] An isolated nucleic acid encoding the molecule of any one of [1], [2], [2a], and [3] to

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , or a plurality of isolated nucleic acids encoding the molecule of any one of [1], [2], [2a], and [3] to

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] .

[0103] A host cell comprising the nucleic acid or the plurality of nucleic acids of

[0102] .

[0104] A method of producing the molecule, or a process for producing the molecule comprising the following steps:(a) culturing the host cell of

[0103] , and(b) recovering the molecule that is produced in step (a).

[0105] A kit for use in the treatment or prevention of a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof, which comprises at least the the molecule of any one of [1], [2], [2a], and [3]

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , and instructions for use.In further aspects and embodiments, the invention relates to any one of [B1] to [B41] below:[B1] A method to activate FGFR2b signaling, or induce dimerization of FGFR2b, or promote phosphorylation of FGFR2b, or enhance intracellular FGF signaling, in an FGFR2b-expressing cell comprising a step of contacting the molecule of any one of [1], [2], [2a], and [3] to

[0051] , [51a],

[0052] , [52a],

[0053] to

[0085] , [A1], and [A1a] to [A34] with an FGFR2b-expressing cell in vitro, ex vivo, or in vivo.[B2] A method to activate FGFR2b signaling, or induce dimerization of FGFR2b, or promote phosphorylation of FGFR2b, or enhance intracellular FGF signaling, in an FGFR2b-expressing cell comprising a step of contacting the molecule of any one of [1], [2], [2a], and [3] to

[0051] , [51a],

[0052] , [52a],

[0053] to

[0085] , [A1], and [A1a] to [A34] with an FGFR2b-expressing cell in vitro, or ex vivo in lung organoid culture, or skin keratinocyte culture.[B3] A method to maintain and proliferate progenitor cells, comprising a step of contacting the molecule of any one of [1], [2], [2a], and [3] to

[0051] , [51a],

[0052] , [52a],

[0053] to

[0085] , [A1], and [A1a-1] to [A34] with an FGFR2b-expressing cell in vitro, or ex vivo.[B4] A method to maintain and proliferate progenitor cells, comprising a step of contacting the molecule of any one of [1], [2], [2a], and [3] to

[0051] , [51a],

[0052] , [52a],

[0053] to

[0085] , [A1], and [A1a] to [A34] with an FGFR2b-expressing cell in vitro, or ex vivo in lung organoid culture, or skin keratinocyte culture.[B5] Use of a molecule of any one of [1], [2], [2a], and [3] to

[0051] , [51a],

[0052] , [52a],

[0053] to

[0085] , [A1], and [A1a] to [A34] to activate FGFR2b signaling, or induce dimerization of FGFR2b, or promote phosphorylation of FGFR2b, or enhance intracellular FGF signaling, in an FGFR2b-expressing cell in vitro, ex vivo, or in vivo.[B6] Use of a molecule of any one of [1], [2], [2a], and [3] to

[0051] , [51a],

[0052] , [52a],

[0053] to

[0085] , [A1], and [A1a] to [A34] to activate FGFR2b signaling, or induce dimerization of FGFR2b, or promote phosphorylation of FGFR2b, or enhance intracellular FGF signaling, in an FGFR2b-expressing cell in vitro, or ex vivo in lung organoid culture, or skin keratinocyte culture.[B7] Use of a molecule of any one of [1], [2], [2a], and [3] to

[0051] , [51a],

[0052] , [52a],

[0053] to

[0085] , [A1], and [A1a] to [A34] to maintain and proliferate FGFR2b-expressing cells in vitro or ex vivo.[B8] Use of a molecule of any one of [1], [2], [2a], and [3] to

[0051] , [51a],

[0052] , [52a],

[0053] to

[0085] , [A1], and [A1a] to [A34] to maintain and proliferate FGFR2b-expressing cells in vitro, or ex vivo in lung organoid culture, or skin keratinocyte culture.[B1-1] A method to activate FGFR1b signaling, or induce dimerization of FGFR1b, or promote phosphorylation of FGFR1b, or enhance intracellular FGF signaling, in an FGFR1b-expressing cell comprising a step of contacting the molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1],

[0062] to

[0085] , [A1-1], and [A1a-1] to [A33-1] with an FGFR1b-expressing cell in vitro, ex vivo, or in vivo.[B2-1] A method to activate FGFR1b signaling, or induce dimerization of FGFR1b, or promote phosphorylation of FGFR1b, or enhance intracellular FGF signaling, in an FGFR1b-expressing cell comprising a step of contacting the molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1],

[0062] to

[0085] , [A1-1], and [A1a-1] to [A33-1] with an FGFR1b-expressing cell in vitro, or ex vivo in lung organoid culture, or skin keratinocyte culture.[B3-1] A method to maintain and proliferate progenitor cells, comprising a step of contacting the molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1],

[0062] to

[0085] , [A1-1], and [A1a-1] to [A33-1] with an FGFR1b-expressing cell in vitro, or ex vivo.[B4-1] A method to maintain and proliferate progenitor cells, comprising a step of contacting the molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1],

[0062] to

[0085] , [A1-1], and [A1a-1] to [A33-1] with an FGFR1b-expressing cell in vitro, or ex vivo in lung organoid culture, or skin keratinocyte culture.[B5-1] Use of a molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1],

[0062] to

[0085] , [A1-1], and [A1a-1] to [A33-1] to activate FGFR1b signaling, or induce dimerization of FGFR1b, or promote phosphorylation of FGFR1b, or enhance intracellular FGF signaling, in an FGFR1b-expressing cell in vitro, ex vivo, or in vivo.[B6-1] Use of a molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1],

[0062] to

[0085] , [A1-1], and [A1a-1] to [A33-1] to activate FGFR1b signaling, or induce dimerization of FGFR1b, or promote phosphorylation of FGFR1b, or enhance intracellular FGF signaling, in an FGFR1b-expressing cell in vitro, or ex vivo in lung organoid culture, or skin keratinocyte culture.[B7-1] Use of a molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1],

[0062] to

[0085] , [A1-1], and [A1a-1] to [A33-1] to maintain and proliferate FGFR1b-expressing cells in vitro or ex vivo.[B8-1] Use of a molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1],

[0062] to

[0085] , [A1-1], and [A1a-1] to [A33-1] to maintain and proliferate FGFR1b-expressing cells in vitro, or ex vivo in lung organoid culture, or skin keratinocyte culture.[B1-2] A method to activate DDR1 signaling, or induce dimerization of DDR1, or promote phosphorylation of DDR1, or enhance intracellular collagen signaling, in a DDR1-expressing cell comprising a step of contacting the molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , [A1-2], and [A1a-2] to [A33-2] with a DDR1-expressing cell in vitro, ex vivo, or in vivo.[B2-2] A method to activate DDR1 signaling, or induce dimerization of DDR1, or promote phosphorylation of DDR1, or enhance intracellular collagen signaling, in a DDR1-expressing cell comprising a step of contacting the molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , [A1-2], and [A1a-2] to [A33-2] with a DDR1-expressing cell in vitro, or ex vivo in lung organoid culture, or skin keratinocyte culture.[B3-2] A method to maintain and proliferate progenitor cells, comprising a step of contacting the molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , [A1-2], and [A1a-2] to [A33-2] with a DDR1-expressing cell in vitro, or ex vivo.[B4-2] A method to maintain and proliferate progenitor cells, comprising a step of contacting the molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , [A1-2], and [A1a-2] to [A33-2] with a DDR1-expressing cell in vitro, or ex vivo in lung organoid culture, or skin keratinocyte culture.[B5-2] Use of a molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , [A1-2], and [A1a-2] to [A33-2] to activate DDR1 signaling, or induce dimerization of DDR1, or promote phosphorylation of DDR1, or enhance intracellular collagen signaling, in a DDR1-expressing cell in vitro, ex vivo, or in vivo.[B6-2] Use of a molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , [A1-2], and [A1a-2] to [A33-2] to activate DDR1 signaling, or induce dimerization of DDR1, or promote phosphorylation of DDR1, or enhance intracellular collagen signaling, in an DDR1-expressing cell in vitro, or ex vivo in lung organoid culture, or skin keratinocyte culture.[B7-2] Use of a molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , [A1-2], and [A1a-2] to [A33-2] to maintain and proliferate DDR1-expressing cells in vitro or ex vivo.[B8-2] Use of a molecule of any one of [1], [2], [2a], and [3] to

[0016] , [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] , [A1-2], and [A1a-2] to [A33-2] to maintain and proliferate DDR1-expressing cells in vitro, or ex vivo in lung organoid culture, or skin keratinocyte culture.[B9] A method of producing an agonistic antigen-binding molecule that binds to a receptor tyrosine kinase (RTK) protein, wherein the method comprises the steps of:(a) providing a first nucleic acid encoding a polypeptide comprising the first antigen-binding domain that binds a first epitope in a first domain in the RTK protein, and a second nucleic acid encoding a polypeptide comprising the second antigen-binding domain that binds a second epitope in a second domain in the RTK protein;(b) introducing the nucleic acids encoding the two polypeptides comprising the antigen-binding domains of step (a) into a host cell capable of expressing said nucleic acids;(c) culturing the host cell obtained in step (b) such that the two polypeptides comprising the antigen-binding domains are expressed;(d) obtaining the antigen-binding molecule comprising the polypeptide comprising the first antigen-binding domain and the polypeptide comprising the second antigen-binding domain obtained in step (c);(e) subjecting the antigen-binding molecule obtained in step (d) to an assay capable of determining activation, or detecting receptor dimerization of, the RTK protein in a cell expressing said RTK protein on the cell surface; and(f) selecting the antigen-binding molecule in step (e) that exhibits activation activity or wherein receptor dimerization was detected in said assay, thereby selecting an agonistic antigen-binding molecule.[B10] The method of [B9], wherein the method comprises a step (ai) which follows step (a) and is carried out prior to step (b), wherein step (ai) comprises selecting the polypeptides comprising the first antigen-binding domain and polypeptides comprising the second antigen-binding domain that bind to the same domain, or selecting the polypeptides comprising the first antigen-binding domain and polypeptides comprising the second antigen-binding domains that bind to different domains.[B11] The method of [B9] or [B10], wherein the method comprises a step (aii) which follows step (ai) and is carried out prior to step (b), wherein step (aii) comprises selecting the polypeptides comprising the first antigen-binding domain and polypeptides comprising the second antigen-binding domain that bind to the same epitope, or selecting the polypeptides comprising the first antigen-binding domain and second antigen-binding domain that bind to different epitopes.[B12] The method of any one of [B9] to [B11], wherein the molecule binds biparatopically, and the method comprises:(a) providing a first nucleic acid encoding a polypeptide comprising the first antigen-binding domain that binds a first epitope in a first domain in the RTK protein, and a second nucleic acid encoding a polypeptide comprising the second antigen-binding domain that binds a second epitope in a second domain in the RTK protein;(ai) selecting the polypeptide comprising the first antigen-binding domains and polypeptide comprising the second antigen-binding domain that bind to the same domain, or selecting the polypeptides comprising the first antigen-binding domains and polypeptides comprising the second antigen-binding domain that bind to different domains;(aii) selecting the polypeptides comprising the first antigen-binding domain and polypeptides comprising the second antigen-binding domain that bind to different epitopes;(b) introducing the nucleic acids encoding the two polypeptides comprising the antigen-binding domains obtained in step (aiii) into a host cell capable of expressing said nucleic acids;(c) culturing the host cell in step (b) such that the two polypeptides comprising the antigen-binding domains are expressed;(d) obtaining the antigen-binding molecule comprising the polypeptide comprising first antigen-binding domain and the polypeptide comprising the second antigen-binding domain obtained in step (c);(e) subjecting the antigen-binding molecule obtained in step (d) to an assay capable of determining activation, or detecting receptor dimerization of, the RTK protein in a cell expressing said RTK protein on the cell surface; and(f) selecting the antigen-binding molecule in step (e) that exhibits activation activity or wherein receptor dimerization was detected in said assay, thereby selecting an agonistic antigen-binding molecule.[B13] The method of any one of [B9] to [B12], wherein the RTK protein is Fibroblast growth factor receptor 2 (FGFR2).[B14] The method of [B13], wherein first and second domain in step (a) is / are independently selected from an Ig-like domain of FGFR2, in particular selected from the group consisting of IgI, IgII, IgIII, IgIIIb, and IgIIIc of FGFR2.[B15] The method of [B14], wherein the first domain and second domain in step (a) is selected from the group consisting of the following:(i) the first domain is IgIIIb, and the second domain is IgIIIb,(ii) the first domain is IgIIIb, and the second domain is IgIII,(iii) the first domain is IgIIIb, and the second domain is IgII, and(iv) the first domain is IgIIIb, and the second domain is IgI,[B13-1] The method of any one of [B9] to [B12], wherein the RTK protein is Fibroblast growth factor receptor 1 (FGFR1).[B14-1] The method of [B13-1], wherein first and second domain in step (a) is / are independently selected from an Ig-like domain of FGFR1, in particular selected from the group consisting of IgI, IgII, IgIII, IgIIIb, and IgIIIc of FGFR1.[B15-1] The method of [B14-1], wherein the first domain and second domain in step (a) is selected from the group consisting of the following:(i) the first domain is IgIIIb, and the second domain is IgIIIb,(ii) the first domain is IgIIIb, and the second domain is IgIII,(iii) the first domain is IgIIIb, and the second domain is IgII, and(iv) the first domain is IgIIIb, and the second domain is IgI,[B13-2] The method of any one of [B9] to [B12], wherein the RTK protein is discoidin domain receptor1 (DDR1).[B14-2] The method of [B13-2], wherein first and second domain in step (a) is / are independently selected from a discoidin (DS) domain, a DS-like domain, or an extracellular juxtamembrane (EJXM) region of DDR1.[B15-2] The method of [B14-2], wherein the first domain and second domain in step (a) is selected from the group consisting of the following:(i) the first domain is a DS domain, and the second domain is a DS domain,(ii) the first domain is a DS domain, and the second domain is a DS-like domain, and(iii) the first domain is a DS domain, and the second domain is an EJXM region.[B16] The method of any one of [B9] to [B15], [B13-1] to [B15-1], and [B13-2] to [B15-2], wherein method comprises a step (aiii) which follows step (aii) and is carried out prior to step (b), wherein step (aiii) comprises introducing a mutation into the nucleic acids encoding the two polypeptides comprising the two antigen-binding domains such that at least one bond linking the two antigen-binding domains in the polypeptides is formed.[B17] The method of [B16], wherein the method further comprises step (g) selecting the antigen-binding molecule obtained in step (f) wherein the two antigen-binding domains are present at spatially close positions and / or the mobility of the two antigen-binding domains is reduced.[B18] A method of screening an agonistic antigen-binding molecule that binds to a receptor tyrosine kinase (RTK) protein, wherein method comprises a step of:(a) providing a first nucleic acid encoding a polypeptide comprising the first antigen-binding domain that binds a first epitope in a first domain in the RTK protein, and a second nucleic acid encoding a polypeptide comprising the second antigen-binding domain that binds a second epitope in a second domain in the RTK protein;(b) introducing the nucleic acids encoding the two polypeptides comprising the antigen-binding domains of step (a) into a host cell capable of expressing said nucleic acids;(c) culturing the host cell in step (b) such that the two polypeptides comprising the antigen-binding domains are expressed;(d) obtaining the antigen-binding molecule comprising the polypeptide comprising the first antigen-binding domain and polypeptide comprising the second antigen-binding domain obtained in step (c);(e) subjecting the antigen-binding molecule obtained in step (d) to an assay capable of determining activation, or detecting receptor dimerization of, the RTK protein in a cell expressing said RTK protein on the cell surface; and(f) selecting the antigen-binding molecule in step (e) that exhibits activation activity or wherein receptor dimerization was detected in said assay, thereby selecting an agonistic antigen-binding molecule.[B19] The method of [B18], wherein the method comprises a step (ai) which follows step (a) and is carried out prior to step (b), wherein step (ai) comprises selecting the polypeptides comprising the first antigen-binding domain and the polypeptides comprising the second antigen-binding domains that bind to the same domain, or selecting the polypeptides comprising the first antigen-binding domain and polypeptides comprising the second antigen-binding domain that bind to different domains.[B20] The method of [B18] or [B19], wherein the method comprises a step (aii) which follows step (ai) and is carried out prior to step (b), wherein step (aii) comprises selecting the polypeptides comprising the first antigen-binding domain and polypeptides comprising the second antigen-binding domain that bind to the same epitope, or selecting the polypeptides comprising the first antigen-binding domain and polypeptides comprising the second antigen-binding domain that bind to different epitopes.[B21] The method of any one of [B18] to [B20], wherein the molecule binds biparatopically, and the method comprises:(a) providing a first nucleic acid encoding a polypeptide comprising the first antigen-binding domain that binds a first epitope in a first domain in the RTK protein, and a second nucleic acid encoding a polypeptide comprising the second antigen-binding domain that binds a second epitope in a second domain in the RTK protein;(ai) comprises selecting the polypeptides comprising the first antigen-binding domain and polypeptides comprising the second antigen-binding domain that bind to the same domain, or selecting the polypeptides comprising the first antigen-binding domain and polypeptides comprising the second antigen-binding domain that bind to different domains;(aii) selecting the polypeptides comprising the first antigen-binding domain and polypeptides comprising the second antigen-binding domains that bind to different epitopes;(b) introducing the nucleic acids encoding the two polypeptides comprising the antigen-binding domains obtained in step (aii) into a host cell capable of expressing said nucleic acids;(c) culturing the host cell in step (b) such that the two polypeptides comprising the antigen-binding domains are expressed;(d) obtaining the antigen-binding molecule comprising the polypeptides comprising the first antigen-binding domain and polypeptides comprising the second antigen-binding domain obtained in step (c);(e) subjecting the antigen-binding molecule obtained in step (d) to an assay capable of determining activation, or detecting receptor dimerization of, the RTK protein in a cell expressing said RTK protein on the cell surface; and(f) selecting the antigen-binding molecule in step (e) that exhibits activation activity or wherein receptor dimerization was detected in said assay, thereby selecting an agonistic antigen-binding molecule.[B22] The method of any one of [B18] to [B21], wherein the RTK protein is Fibroblast growth factor receptor 2 (FGFR2).[B23] The method of [B22], wherein first and second domain in step (a) is / are independently selected from an Ig-like domain of FGFR2, in particular selected from the group consisting of IgI, IgII, IgIII, IgIIIb, and IgIIIc of FGFR2.[B24] The method of [B23], wherein the first domain and second domain in step (a) is selected from the group consisting of the following:(i) the first domain is IgIIIb and the second domain is IgIIIb;(ii) the first domain is IgIIIb and the second domain is IgIII;(iii) the first domain is IgIIIb and the second domain is IgII; and(iv) the first domain is IgIIIb and the second domain is IgI.[B22-1] The method of any one of [B18] to [B21], wherein the RTK protein is Fibroblast growth factor receptor 1 (FGFR1).[B23-1] The method of [B22-1], wherein first and second domain in step (a) is / are independently selected from an Ig-like domain of FGFR1, in particular selected from the group consisting of IgI, IgII, IgIII, IgIIIb, and IgIIIc of FGFR1.[B24-1] The method of [B23-1], wherein the first domain and second domain in step (a) is selected from the group consisting of the following:(i) the first domain is IgIIIb and the second domain is IgIIIb;(ii) the first domain is IgIIIb and the second domain is IgIII;(iii) the first domain is IgIIIb and the second domain is IgII; and(iv) the first domain is IgIIIb and the second domain is IgI.[B22-2] The method of any one of [B18] to [B21], wherein the RTK protein is discoidin domain receptor1 (DDR1).[B23-2] The method of [B22-2], wherein first and second domain in step (a) is / are independently selected from a discoidin (DS) domain, a DS-like domain, or an extracellular juxtamembrane (EJXM) region of DDR1.[B24-2] The method of [B23-2], wherein the first domain and second domain in step (a) is selected from the group consisting of the following:(i) the first domain is a DS domain, and the second domain is a DS domain,(ii) the first domain is a DS domain, and the second domain is a DS-like domain, and(iii) the first domain is a DS domain, and the second domain is an EJXM region.[B25] The method of any one of [B18] to [B24], [B22-1] to [B24-1], and [B22-2] to [B24-2], wherein method comprises a step (aiii) which follows step (aii) and is carried out prior to step (b), wherein step (aiii) comprises introducing a mutation into the nucleic acids encoding the two polypeptides comprising the two antigen-binding domains such that at least one bond linking the two antigen-binding domains in the polypeptides is formed.[B26] The method of [B25], wherein the method further comprises step (g) selecting the antigen-binding molecule obtained in step (f) wherein the two antigen-binding domains are present at spatially close positions and / or the mobility of the two antigen-binding domains is reduced.[B27] The method of any one of [B9] to [B26], wherein the molecule comprises an antibody constant region, in particular (i) wherein the antibody constant region is a human antibody constant region, or (ii) wherein the antibody constant region is selected from a human IgG1, IgG2, IgG3 or IgG4 constant regions[B28] The method of any one of [B9] to [B15], [B13-1] to [B15-1], and [B13-2] to [B15-2], [B16] to [B24], [B22-1] to [B24-1], and [B22-2] to [B24-2], [B25] to [B27], wherein the antigen-binding domains comprise an antibody variable region, or comprise an antibody fragment independently selected from a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, or single-domain antibody.[B29] The method of any one of [B9] to [B15], [B13-1] to [B15-1], and [B13-2] to [B15-2], [B16] to [B24], [B22-1] to [B24-1], and [B22-2] to [B24-2], [B25] to [B28], wherein the molecule comprises an antibody or antibody fragment thereof.[B30] The method of [B29], wherein the antibody fragment is a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody.[B31] The method of [B29] or [B30] wherein the molecule is a monoclonal antibody.[B32] The method of any one of [B29] to [B31], wherein the molecule is human, humanized, or chimeric antibody.[B33] The method of any one of [B29] to [B32], wherein the molecule is characterized by two antigen-binding domains, or wherein the molecule is a bivalent molecule, or wherein the first antigen-binding domain and second antigen-binding domain are each a monovalent Fab or a monovalent VHH, or are each a monovalent scFab.[B34] A diagnostic reagent comprising the molecule of any one of [1], [2], [2a], and [3] to

[0051] , [51a],

[0052] , [52a],

[0053] to

[0061] , [17-1] to [51-1], [51a-1], [52-1], [52a-1], [53-1] to [61-1], [17-2] to [47-2], [47a-2], [48-2], [48a-2], [49-2] to [57-2],

[0062] to

[0085] and [A1], [A1a] to [A34], [A1-1], [A1a-1] to [A33-1], [A1-2], and [A1a-2] to [A33-2].[B35] A library that comprises or essentially consists of:a combination of a plurality of a first group of antigen-binding domains which have different sequences from one another, and a second group of antigen-binding domains which have different sequences from one another;wherein each of the antigen-binding domain of the first group of antigen-binding domains binds to Immunoglobulin IIIb (IgIIIb) of FGFR2 protein, andwherein activation of FGFR2b signaling in a cell-surface expressed FGFR2b protein by a combination of a first and a second antigen-binding domain selected from the plurality of the first and second groups of antigen-binding domains in (i) is greater than a first antigen-binding domain on its own, or a second antigen-binding domain on its own.[B36] The library of [B35] comprising:a combination of a plurality of a first group of nucleic acids that encode a first group of antigen-binding domains which have different sequences from one another, and a plurality of a second group of nucleic acids that encode a second group of antigen-binding domains which have different sequences from one another;wherein each of the antigen-binding domain of the first group of antigen-binding domains binds to Immunoglobulin IIIb (IgIIIb) of FGFR2 protein, andwherein activation of FGFR2b signaling in a cell-surface expressed FGFR2b protein by a combination of a first and a second antigen-binding domain selected from the plurality of the first and second groups of antigen-binding domains in (i) is greater than a first antigen-binding domain on its own, or a second antigen-binding domain on its own.[B37] The library of [B35] or [B36], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in IgIIIb of FGFR2, and a second antigen-binding domain that binds a second epitope in a second domain of FGFR2;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the FGFR2 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B37-1] The library of [B35] or [B36], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in IgIIIb of FGFR2, and a second antigen-binding domain that binds a second epitope in IgIIIb of FGFR2;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the FGFR2 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B37-2] The library of [B35] or [B36], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in IgIIIb of FGFR2, and a second antigen-binding domain that binds a second epitope in IgIII of FGFR2;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the FGFR2 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B37-3] The library of [B35] or [B36], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in IgIIIb of FGFR2, and a second antigen-binding domain that binds a second epitope in IgII of FGFR2;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the FGFR2 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B37-4] The library of [B35] or [B36], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in IgIIIb of FGFR2, and a second antigen-binding domain that binds a second epitope in IgI of FGFR2;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the FGFR2 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B38] The library of any one of [B35] to [B37-4], wherein the method further comprises a step (ai) of selecting the antigen-binding domain as the first antigen-binding domain when the antigen-binding domain binds to IgIIIb of FGFR2 protein with a KD equal to or less than 10-8M as measured by surface plasmon resonance.[B39] The library of any one of [B35] to [B38], wherein the first epitope of the first antigen-binding domain is the same as the second epitope of the second antigen-binding domain.[B40] The library of any one of [B35] to [B38], wherein the first epitope of the first antigen-binding domain is different from the second epitope of the second antigen-binding domain.[B41] The library of any one of [B35] to [B40], wherein the activation of FGFR2b signaling by the combination of the first and the second antigen-binding domain is at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% greater than the activation of FGFR2b signaling by the first antigen-binding domain on its own, or the second antigen-binding domain on its own.[B35-1] A library that comprises or essentially consists of:a combination of a plurality of a first group of antigen-binding domains which have different sequences from one another, and a second group of antigen-binding domains which have different sequences from one another;wherein each of the antigen-binding domain of the first group of antigen-binding domains binds to Immunoglobulin IIIb (IgIIIb) of FGFR1 protein, andwherein activation of FGFR1b signaling in a cell-surface expressed FGFR1b protein by a combination of a first and a second antigen-binding domain selected from the plurality of the first and second groups of antigen-binding domains in (i) is greater than a first antigen-binding domain on its own, or a second antigen-binding domain on its own.[B36-1] The library of [B35-1] comprising:a combination of a plurality of a first group of nucleic acids that encode a first group of antigen-binding domains which have different sequences from one another, and a plurality of a second group of nucleic acids that encode a second group of antigen-binding domains which have different sequences from one another;wherein each of the antigen-binding domain of the first group of antigen-binding domains binds to Immunoglobulin IIIb (IgIIIb) of FGFR1 protein, andwherein activation of FGFR1b signaling in a cell-surface expressed FGFR1b protein by a combination of a first and a second antigen-binding domain selected from the plurality of the first and second groups of antigen-binding domains in (i) is greater than a first antigen-binding domain on its own, or a second antigen-binding domain on its own.[B37-1] The library of [B35-1] or [B36-1], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in IgIIIb of FGFR1, and a second antigen-binding domain that binds a second epitope in a second domain of FGFR1;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the FGFR1 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B37-1-1] The library of [B35-1] or [B36-1], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in IgIIIb of FGFR1, and a second antigen-binding domain that binds a second epitope in IgIIIb of FGFR1;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the FGFR1 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B37-2-1] The library of [B35-1] or [B36-1], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in IgIIIb of FGFR1, and a second antigen-binding domain that binds a second epitope in IgIII of FGFR1;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the FGFR1 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B37-3-1] The library of [B35-1] or [B36-1], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in IgIIIb of FGFR1, and a second antigen-binding domain that binds a second epitope in IgII of FGFR1;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the FGFR1 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B37-4-1] The library of [B35-1] or [B36-1], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in IgIIIb of FGFR1, and a second antigen-binding domain that binds a second epitope in IgI of FGFR1;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the FGFR1 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B38-1] The library of any one of [B35-1] to [B37-4-1], wherein the method further comprises a step (ai) of selecting the antigen-binding domain as the first antigen-binding domain when the antigen-binding domain binds to IgIIIb of FGFR1 protein with a KD equal to or less than 10-8M as measured by surface plasmon resonance.[B39-1] The library of any one of [B35-1] to [B38-1], wherein the first epitope of the first antigen-binding domain is the same as the second epitope of the second antigen-binding domain.[B40-1] The library of any one of [B35-1] to [B38-1], wherein the first epitope of the first antigen-binding domain is different from the second epitope of the second antigen-binding domain.[B41-1] The library of any one of [B35-1] to [B40-1], wherein the activation of FGFR1b signaling by the combination of the first and the second antigen-binding domain is at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% greater than the activation of FGFR1b signaling by the first antigen-binding domain on its own, or the second antigen-binding domain on its own.[B35-2] A library that comprises or essentially consists of:a combination of a plurality of a first group of antigen-binding domains which have different sequences from one another, and a second group of antigen-binding domains which have different sequences from one another;wherein each of the antigen-binding domain of the first group of antigen-binding domains binds to a DS domain of DDR1 protein, andwherein activation of DDR1 signaling in a cell-surface expressed DDR1 protein by a combination of a first and a second antigen-binding domain selected from the plurality of the first and second groups of antigen-binding domains in (i) is greater than a first antigen-binding domain on its own, or a second antigen-binding domain on its own.[B36-2] The library of [B35-2] comprising:a combination of a plurality of a first group of nucleic acids that encode a first group of antigen-binding domains which have different sequences from one another, and a plurality of a second group of nucleic acids that encode a second group of antigen-binding domains which have different sequences from one another;wherein each of the antigen-binding domain of the first group of antigen-binding domains binds to a DS domain of DDR1 protein, andwherein activation of DDR1 signaling in a cell-surface expressed DDR1 protein by a combination of a first and a second antigen-binding domain selected from the plurality of the first and second groups of antigen-binding domains in (i) is greater than a first antigen-binding domain on its own, or a second antigen-binding domain on its own.[B37-2] The library of [B35-2] or [B36-2], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in a DS domain of DDR1, and a second antigen-binding domain that binds a second epitope in a second domain of DDR1;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the DDR1 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B37-1-2] The library of [B35-2] or [B36-2], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in a DS domain of DDR1, and a second antigen-binding domain that binds a second epitope in a DS domain of DDR1;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the DDR1 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B37-2-2] The library of [B35-2] or [B36-2], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in a DS domain of DDR1, and a second antigen-binding domain that binds a second epitope in a DS-like domain of DDR1;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the DDR1 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B37-3-2] The library of [B35-2] or [B36-2], which is produced by a method comprising the steps of:(a) providing a first antigen-binding domain that binds a first epitope in a DS domain of DDR1, and a second antigen-binding domain that binds a second epitope in an EJXM region of DDR1;(b) obtaining an antigen-binding molecule or antigen-binding molecule comprising the combination of the first and the second antigen-binding domain in step (a);(c) subjecting the antigen-binding molecule or antigen-binding molecule in step (b) to an assay capable of determining activation, or detecting receptor dimerization of, the DDR1 protein in a cell expressing said RTK protein on the cell surface; and(d) selecting the antigen-binding molecule or antigen-binding molecule in step (c) that exhibits activation activity or wherein receptor dimerization was detected in said assay.[B38-2] The library of any one of [B35-2] to [B37-3-2], wherein the method further comprises a step (ai) of selecting the antigen-binding domain as the first antigen-binding domain when the antigen-binding domain binds to a DS domain of DDR1 protein with a KD equal to or less than 10-8M as measured by surface plasmon resonance.[B39-2] The library of any one of [B35-2] to [B38-2], wherein the first epitope of the first antigen-binding domain is the same as the second epitope of the second antigen-binding domain.[B40-2] The library of any one of [B35-2] to [B38-2], wherein the first epitope of the first antigen-binding domain is different from the second epitope of the second antigen-binding domain.[B41-2] The library of any one of [B35-2] to [B40-2], wherein the activation of DDR1 signaling by the combination of the first and the second antigen-binding domain is at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% greater than the activation of DDR1 signaling by the first antigen-binding domain on its own, or the second antigen-binding domain on its own.Figure 1 shows the process of generating biparatopic antibody using FORCE technology as described in Dengl S. et al. ("Format chain exchange (FORCE) for high-throughput generation of bispecific antibodies in combinatorial binder-format matrices." Nature Communications 11.1 (2020): 4974).Figure 2 shows molecular format and nomenclature of biparatopic antibody.Figure 3 shows the process of generating biparatopic antibody using LINC-Ig technology.Figure 4 shows molecular format and nomenclature of biparatopic LINC-Ig and UN-LINC antibody.Figure 5 shows binding activity of monoparatopic antibodies to mouse FGFR2IIIb variant stably expressing FreeStyleTM293-F cell line. Anti-KLH monoparatopic antibody IC17dK shows the level of a negative control (background).Figure 6 shows binding activity of monoparatopic antibodies to IgI deleted mouse FGFR2IIIb variant (mouse FGFR2IIIb delta IgI) stably expressing FreeStyleTM293-F cell line. Anti-KLH monoparatopic antibody IC17dK shows the level of a negative control (background).Figure 7 shows binding activity of monoparatopic antibodies to IgIII deleted mouse FGFR2IIIb variant (mouse FGFR2IIIb delta IgIII) transiently expressing FreeStyleTM293-F cell line. Anti-KLH monoparatopic antibody IC17dK shows the level of a negative control (background).Figure 8 shows binding activity of monoparatopic antibodies to mouse FGFR2IIIc variant stably expressing FreeStyleTM293-F cell line. Anti-KLH monoparatopic antibody IC17dK shows the level of a negative control (background).Figure 9 shows binding activity of monoparatopic antibodies to human FGFR2IIIb variant stably expressing FreeStyleTM293-F cell line. Anti-KLH monoparatopic antibody IC17dK shows the level of a negative control (background).Figure 10-1 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR2 monoparatopic and biparatopic antibodies in lung organoid. Luminescence of lung growth by each antibody was measured by CellTiter-Glo (registered trademark) 3D, and four-parameter logistic model was used to fit drug dose-response curves (solid line). Result of each monoparatopic and biparatopic antibody are shown, respectively (circle: FGF7, square: biparatopic antibody, open triangle and inverted triangle: monoparatopic antibody, cross: N12433). FGF7 and N12433 were used as control and are shared in each figure. (A) FFB0185 / / FFB0396, FFB0185, FFB0396, (B) FFB0219 / / FFB0341, FFB0219, FFB0341. Data points represent mean ± SEM.Figure 10-2 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR2 monoparatopic and biparatopic antibodies in lung organoid. Luminescence of lung growth by each antibody was measured by CellTiter-Glo (registered trademark) 3D, and four-parameter logistic model was used to fit drug dose-response curves (solid line). Result of each monoparatopic and biparatopic antibody are shown, respectively (circle: FGF7, square: biparatopic antibody, open triangle and inverted triangle: monoparatopic antibody, cross: N12433). FGF7 and N12433 were used as control and are shared in each figure. (C) FFB0219 / / FFB0396, FFB0219, FFB0396, (D) FFB0261 / / FFB0464, FFB0261, FFB0464. Data points represent mean ± SEM.Figure 10-3 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR2 monoparatopic and biparatopic antibodies in lung organoid. Luminescence of lung growth by each antibody was measured by CellTiter-Glo (registered trademark) 3D, and four-parameter logistic model was used to fit drug dose-response curves (solid line). Result of each monoparatopic and biparatopic antibody are shown, respectively (circle: FGF7, square: biparatopic antibody, open triangle and inverted triangle: monoparatopic antibody, cross: N12433). FGF7 and N12433 were used as control and are shared in each figure. (E) FFB0294 / / FFB0464, FFB0294, FFB0464, (F) FFB0299 / / FFB0464, FFB0299, FFB0464. Data points represent mean ± SEM.Figure 10-4 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR2 monoparatopic and biparatopic antibodies in lung organoid. Luminescence of lung growth by each antibody was measured by CellTiter-Glo (registered trademark) 3D, and four-parameter logistic model was used to fit drug dose-response curves (solid line). Result of each monoparatopic and biparatopic antibody are shown, respectively (circle: FGF7, square: biparatopic antibody, open triangle and inverted triangle: monoparatopic antibody, cross: N12433). FGF7 and N12433 were used as control and are shared in each figure. (G) FFB0335 / / FFB0464, FFB0335, FFB0464, (H) FFB0365 / / FFB0464, FFB0365, FFB0464. Data points represent mean ± SEM.Figure 10-5 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR2 monoparatopic and biparatopic antibodies in lung organoid. Luminescence of lung growth by each antibody was measured by CellTiter-Glo (registered trademark) 3D, and four-parameter logistic model was used to fit drug dose-response curves (solid line). Result of each monoparatopic and biparatopic antibody are shown, respectively (circle: FGF7, square: biparatopic antibody, open triangle and inverted triangle: monoparatopic antibody, cross: N12433). FGF7 and N12433 were used as control and are shared in each figure. (I) FFB0368 / / FFB0341, FFB0341, FFB0368, (J) FFB0374 / / FFB0464, FFB0374, FFB0464. Data points represent mean ± SEM.Figure 10-6 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR2 monoparatopic and biparatopic antibodies in lung organoid. Luminescence of lung growth by each antibody was measured by CellTiter-Glo (registered trademark) 3D, and four-parameter logistic model was used to fit drug dose-response curves (solid line). Result of each monoparatopic and biparatopic antibody are shown, respectively (circle: FGF7, square: biparatopic antibody, open triangle and inverted triangle: monoparatopic antibody, cross: N12433). FGF7 and N12433 were used as control and are shared in each figure. (K) FFB0453 / / FFB0464, FFB0453, FFB0464. Data points represent mean ± SEM.Figure 11 shows the result of agonistic activity evaluation of anti-FGFR2 monoparatopic and biparatopic antibodies in lung organoid. Luminescence of lung growth by each antibody was measured by CellTiter-Glo (registered trademark) 3D (gray: anti-FGFR2 monoparatopic antibodies, black: anti-FGFR2 biparatopic antibodies). Data points represent mean ± SEM.Figure 12-1 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR2 monoparatopic and biparatopic antibodies in keratinocyte. Absorbance of imported BrdU in keratinocyte by each antibody was measured by Cell Proliferation ELISA, and four-parameter logistic model was used to fit drug dose-response curves (solid line). Result of each monoparatopic and biparatopic antibody are shown, respectively (circle: FGF7, square: biparatopic antibody, open triangle and inverted triangle: monoparatopic antibody). FGF7 was used as a control and is shared in each figure. (A) FFB0185 / / FFB0396, FFB0185, FFB0396, (B) FFB0219 / / FFB0341, FFB0219, FFB0341. Data points represent mean ± SEM.Figure 12-2 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR2 monoparatopic and biparatopic antibodies in keratinocyte. Absorbance of imported BrdU in keratinocyte by each antibody was measured by Cell Proliferation ELISA, and four-parameter logistic model was used to fit drug dose-response curves (solid line). Result of each monoparatopic and biparatopic antibody are shown, respectively (circle: FGF7, square: biparatopic antibody, open triangle and inverted triangle: monoparatopic antibody). FGF7 was used as a control and is shared in each figure. (C) FFB0219 / / FFB0396, FFB0219, FFB0396, (D) FFB0261 / / FFB0464, FFB0261, FFB0464. Data points represent mean ± SEM.Figure 12-3 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR2 monoparatopic and biparatopic antibodies in keratinocyte. Absorbance of imported BrdU in keratinocyte by each antibody was measured by Cell Proliferation ELISA, and four-parameter logistic model was used to fit drug dose-response curves (solid line). Result of each monoparatopic and biparatopic antibody are shown, respectively (circle: FGF7, square: biparatopic antibody, open triangle and inverted triangle: monoparatopic antibody). FGF7 was used as a control and is shared in each figure. (E) FFB0294 / / FFB0464, FFB0294, FFB0464, (F) FFB0299 / / FFB0464, FFB0299, FFB0464. Data points represent mean ± SEM.Figure 12-4 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR2 monoparatopic and biparatopic antibodies in keratinocyte. Absorbance of imported BrdU in keratinocyte by each antibody was measured by Cell Proliferation ELISA, and four-parameter logistic model was used to fit drug dose-response curves (solid line). Result of each monoparatopic and biparatopic antibody are shown, respectively (circle: FGF7, square: biparatopic antibody, open triangle and inverted triangle: monoparatopic antibody). FGF7 was used as a control and is shared in each figure. (G) FFB0368 / / FFB0341, FFB0368, FFB0341, (H) FFB0374 / / FFB0464, FFB0374, FFB0464. Data points represent mean ± SEM.Figure 13-1 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR2 monoparatopic and biparatopic antibodies in NIH3T3. Absorbance of imported BrdU in NIH3T3 by each antibody was measured by Cell Proliferation ELISA, and four-parameter logistic model was used to fit drug dose-response curves (dotted line, samples with no lines were not converged). (A) Each monoparatopic antibody, FGF2, FGF18, and FGF7 are shown (circle: FGF2, square: FGF18, triangle: FFB0185, diamond: FFB0219, hexagon: FFB0261, open circle: FFB0294, open square: FFB0299, open triangle: FFB0335, open diamond: FFB0365, open hexagon: FFB0368, cross: FGF7). (B) Each monoparatopic antibody, FGF2, FGF18, and FGF7 are shown (circle: FGF2, square: FGF18, triangle: FFB0341, diamond: FFB0374, hexagon: FFB0396, open circle: FFB0453, open square: FFB0464, cross: FGF7). FGF2, FGF18, and FGF7 were used as control and are shared in each figure. Data points represent mean ± SEM.Figure 13-2 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR2 monoparatopic and biparatopic antibodies in NIH3T3. Absorbance of imported BrdU in NIH3T3 by each antibody was measured by Cell Proliferation ELISA, and four-parameter logistic model was used to fit drug dose-response curves (dotted line, samples with no lines were not converged). (C) Each biparatopic antibody, FGF2, FGF18, and FGF7 are shown (circle: FGF2, square: FGF18, triangle: FFB0185 / / FFB0396, diamond: FFB0219 / / FFB0341, hexagon: FFB0219 / / FFB0396, open circle: FFB0261 / / FFB0464, open square: FFB0294 / / FFB0464, cross: FGF7). (D) Each biparatopic antibody, FGF2, FGF18, and FGF7 are shown (circle: FGF2, square: FGF18, triangle: FFB0299 / / FFB0464, diamond: FFB0335 / / FFB0464, hexagon: FFB0365 / / FFB0464, open circle: FFB0368 / / FFB0341, open square: FFB0374 / / FFB0464, open triangle: FFB0453 / / FFB0464, cross: FGF7). FGF2, FGF18, and FGF7 were used as control and are shared in each figure. Data points represent mean ± SEM.Figure 14 shows the result of agonistic activity evaluation of anti-FGFR2b biparatopic LINC-Ig antibodies in lung organoid. 1 micro g / mL of each Un-LINC and HL-LINC-Ig or LL-LINC-Ig antibody were used in this study. (A) Luminescence of lung growth by each Un-LINC and HL-LINC-Ig antibody were measured by CellTiter-Glo (registered trademark) 3D, and the ratio to each average value of Un-LINC format is shown (gray: FFB0065 / / FFB0045, black: FFB0065 / / FFB0057). (B) Luminescence of lung growth by each Un-LINC and LL-LINC-Ig antibody were measured by CellTiter-Glo (registered trademark) 3D, and the ratio to each average value of Un-LINC format is shown (gray: FFB0065 / / FFB0045,white: FFB0065 / / FFB0035, black: FFB0065 / / FFB0057). Data points represent mean ± SEM.Figure 15 shows the image of lung organoid growth by anti-FGFR2b biparatopic LINC-Ig antibodies. 50nM of FGF7 and each anti-FGFR2b biparatopic LINC-Ig antibody were used in this study. Image was captured by CellVoyagerTMCV8000 and Z stack image was combined by CellPathfinder software. FGF7, Control (culture without exogenous FGF7), LL-LINC_FFB0065 / / FFB0035, and LL-LINC_FFB0065 / / FFB0045 are shown. Each scale bar represents 100 micro m.Figure 16-1 shows the result of proliferation marker induction by anti-FGFR2b biparatopic LINC-Ig antibodies in vivo. Each proliferation marker gene was normalized by Glyceraldehyde-3-phosphate dehydrogenase (Gapdh) expression and each normalized value calculated as ratio to average Vehicle value. Mki67 expression in lung tissue (A), and Cdc20 expression in lung tissue (B) are shown. (circle: Vehicle, square: FGF7, triangle: LL-LINC_FFB0065 / / FFB0035, diamond: LL-LINC_FFB0065 / / FFB0045, ns: not significant, ***P<0.001, ****P<0.0001). Data points represent mean ± SEM.Figure 16-2 shows the result of proliferation marker induction by anti-FGFR2b biparatopic LINC-Ig antibodies in vivo. Each proliferation marker gene was normalized by Glyceraldehyde-3-phosphate dehydrogenase (Gapdh) expression and each normalized value calculated as ratio to average Vehicle value. Mki67 expression in ear skin tissue (C), and Cdc20 expression in ear skin tissue (D) are shown. (circle: Vehicle, square: FGF7, triangle: LL-LINC_FFB0065 / / FFB0035, diamond: LL-LINC_FFB0065 / / FFB0045, ns: not significant, ***P<0.001, ****P<0.0001). Data points represent mean ± SEM.Figure 17 shows the antibody treatment regimen in bleomycin induced mouse lung fibrosis model (BLM model).Figure 18 shows the result of alveolar type II (AT2) cells marker induction and fibrotic markers reduction by anti-FGFR2b biparatopic LINC-Ig antibodies in mouse lung fibrosis model (BLM model). Each marker gene was normalized to Glyceraldehyde-3-phosphate dehydrogenase (Gapdh) expression and each normalized value calculated as ratio to average Sham value. Sftpc expression in lung tissue (A), Fn1 expression in lung tissue (B), and Col1a1 expression in lung tissue (C) are shown. (circle: Sham, square: bleomycin administration control (BLM), triangle: bleomycin administration LL-LINC_FFB0065 / / FFB0035, diamond: bleomycin administration with LL-LINC_FFB0065 / / FFB0045, ns: not significant, **P<0.01, ****P<0.0001). Data points represent mean ± SEM.Figure 19 shows the result of proliferation marker induction by anti-FGFR2b biparatopic antibodies in vivo. Each proliferation marker gene was normalized to Glyceraldehyde-3-phosphate dehydrogenase (Gapdh) expression and each normalized value was calculated as ratio to average Vehicle value. Mki67 expression in lung tissue (A), and Cdc20 expression in lung tissue (B) are shown. (circle: Vehicle, square: FGF7, triangle: FFB0219 / / FFB0396, diamond: FFB0261 / / FFB0464, hexagon: FFB0335 / / FFB0464, open circle: FFB0365 / / FFB0464, open square: FFB0368 / / FFB0341, open triangle: FFB374 / / FFB0464, ns: not significant, ***P<0.001, ****P<0.0001). Data points represent mean ± SEM.Figure 20 shows the efficacy study result of alveolar type II (AT2) cells marker induction and fibrotic markers reduction by anti-FGFR2b biparatopic antibodies in mouse lung fibrosis model (BLM model). Each marker gene was normalized to Glyceraldehyde-3-phosphate dehydrogenase (Gapdh) expression and each normalized value was calculated as ratio to average Sham + KLH value (Anti-KLH monoparatopic antibody IC17dK was used as a negative control). Sftpc expression in lung tissue (A), Fn1 expression in lung tissue (B), and Col1a1 expression in lung tissue (C) are shown. (circle: Sham with KLH, square: bleomycin administration (BLM) with KLH, triangle: bleomycin administration with FFB0219 / / FFB0396, diamond: bleomycin administration with FFB0261 / / FFB0464, hexagon: bleomycin administration with FFB0335 / / FFB0464, ns: not significant, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). Data points represent mean ± SEM.Figure 21 shows the efficacy study result of alveolar type II (AT2) cells marker induction and fibrotic markers reduction by anti-FGFR2b biparatopic antibodies in mouse lung fibrosis model (BLM model). Each marker gene was normalized to Glyceraldehyde-3-phosphate dehydrogenase (Gapdh) expression and each normalized value was calculated as ratio to average Sham + KLH value (Anti-KLH monoparatopic antibody IC17dK was used as a negative control). Sftpc expression in lung tissue (A), Fn1 expression in lung tissue (B), and Col1a1 expression in lung tissue (C) are shown. (circle: Sham with KLH, square: bleomycin administration (BLM) with KLH, triangle: bleomycin administration with FFB0365 / / FFB0464, diamond: bleomycin administration with FFB0368 / / FFB0341, hexagon: bleomycin administration with FFB0374 / / FFB0464, ns: not significant, *P<0.05, **P<0.01, ***P<0.001). Data points represent mean ± SEM.Figure 22 shows the results of histopathological evaluation for effects by anti-FGFR2b biparatopic antibodies in mouse lung fibrosis model (BLM model). Lung tissue sections were immunohistochemically stained with antibody against Prosurfactant Protein C (ProSPC; ab211326, abcam, Cambridge, UK), captured as digital images with NanoZoomer S360 (Hamamatsu Photonics K.K., Shizuoka, Japan), and the number of ProSPC positive cells was counted using the Multiplex IHC module of HALO AI (Indica labs, New Mexico, USA, v3.4). The number of positive cells per area (mm2) were summarized in (A) (circle: Sham with KLH, square: bleomycin administration (BLM) with KLH, triangle: bleomycin administration with FFB0219 / / FFB0396, inverted triangle: bleomycin administration with FFB0261 / / FFB0464, diamond: bleomycin administration with FFB0335 / / FFB0464, **P<0.01, ***P< 0.001, ****P< 0.0001 vs. BLM + KLH group compared by Tukey’s multiple comparisons test) and (B) (circle: Sham with KLH, square: bleomycin administration (BLM) with KLH, triangle: bleomycin administration with FFB0365 / / FFB0464, inverted triangle: bleomycin administration with FFB0368 / / FFB0341, diamond: bleomycin administration with FFB0374 / / FFB0464, *P<0.05, **P<0.01, ****P< 0.0001 vs. BLM + KLH group compared by Tukey’s multiple comparisons test). Data points represent mean ± SEM.Figure 23-1 shows the result of concentration-dependent agonistic activity evaluation of anti-DDR1 monoparatopic and biparatopic antibodies in mouse DDR1 stably expressing Ba / F3 cell line (Ba / F3-DDR1). Luminescence of Ba / F3-DDR1 growth by each monoparatopic and biparatopic antibody was measured by CellTiter-Glo (registered trademark) 3D, and four-parameter logistic model was used to fit drug dose-response curves (solid line). (A) (open circle: DAA0007, open triangle: DAA0045, square: DAA0045 / / DAA0007, star: collagen control), (B) (open circle: DAA0024, open triangle: DAA0011, square: DAA0011 / / DAA0024, star: collagen control). Collagen control is shared in (A) and (B). Data points represent mean ± SEM.Figure 23-2 shows the result of concentration-dependent agonistic activity evaluation of anti-DDR1 monoparatopic and biparatopic antibodies in mouse DDR1 stably expressing Ba / F3 cell line (Ba / F3-DDR1). Luminescence of Ba / F3-DDR1 growth by each monoparatopic and biparatopic antibody was measured by CellTiter-Glo (registered trademark) 3D, and four-parameter logistic model was used to fit drug dose-response curves (solid line). (C) (open circle: DAA0012, open triangle: DAA0045, square: DAA0045 / / DAA0012, star: collagen control). Data points represent mean ± SEM.Figure 24 shows the result of agonistic activity evaluation of anti-DDR1 monoparatopic and biparatopic antibodies in Ba / F3-DDR1. Absorbance of phosphorylated DDR1 in Ba / F3-DDR1 by each antibody was measured by ELISA. (A, B) Result of each monoparatopic and biparatopic antibody are shown, respectively (gray: monoparatopic antibody, black: biparatopic antibody). Data points represent mean ± SEM.Figure 25-1 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR1b monoparatopic and biparatopic antibodies in mouse FGFR1IIIb variant stably expressing Ba / F3 cell line (Ba / F3-FGFR1b). Luminescence of Ba / F3-FGFR1b cells growth by each monoparatopic and biparatopic antibody was measured by CellTiter-Glo (registered trademark) 3D, and four-parameter logistic model was used to fit drug dose-response curves (solid line). (A) (open circle: FFA0026, open triangle: FFA0029, square: FFA0029 / / DAA0026, star: FGF2 control), (B) (open circle: FFA0064, open triangle: FFA0029, square: FFA0029 / / FFA0064, star: FGF2 control). FGF2 is shared in (A) and (B). Data points represent mean ± SEM.Figure 25-2 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR1b monoparatopic and biparatopic antibodies in mouse FGFR1IIIb variant stably expressing Ba / F3 cell line (Ba / F3-FGFR1b). Luminescence of Ba / F3-FGFR1b cells growth by each monoparatopic and biparatopic antibody was measured by CellTiter-Glo (registered trademark) 3D, and four-parameter logistic model was used to fit drug dose-response curves (solid line). (C) (open circle: FFA0088, open triangle: FFA0029, square: FFA0029 / / FFA0088, star: FGF2 control), (D) (open circle: FFA0032, open triangle: FFA0048, square: FFA0048 / / FFA0032, star: FGF2 control). FGF2 is shared in (C) and (D). Data points represent mean ± SEM.Figure 25-3 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR1b monoparatopic and biparatopic antibodies in mouse FGFR1IIIb variant stably expressing Ba / F3 cell line (Ba / F3-FGFR1b). Luminescence of Ba / F3-FGFR1b cells growth by each monoparatopic and biparatopic antibody was measured by CellTiter-Glo (registered trademark) 3D, and four-parameter logistic model was used to fit drug dose-response curves (solid line). (E) (open circle: FFA0043, open triangle: FFA0048, square: FFA0048 / / FFA0043, star: FGF2 control), (F) (open circle: FFA0047, open triangle: FFA0048, square: FFA0048 / / FFA0047, star: FGF2 control). FGF2 is shared in (E) and (F). Data points represent mean ± SEM.Figure 25-4 shows the result of concentration-dependent agonistic activity evaluation of anti-FGFR1b monoparatopic and biparatopic antibodies in mouse FGFR1IIIb variant stably expressing Ba / F3 cell line (Ba / F3-FGFR1b). Luminescence of Ba / F3-FGFR1b cells growth by each monoparatopic and biparatopic antibody was measured by CellTiter-Glo (registered trademark) 3D, and four-parameter logistic model was used to fit drug dose-response curves (solid line). (G) (open circle: FAA0055, open triangle: FFA0048, square: FFA0048 / / FFA0055, star: FGF2 control), and (H) (open circle: FFA0020, open triangle: FFA0048, square: FFA0048 / / FFA0020, star: FGF2 control). FGF2 is shared in (G) and (H). Data points represent mean ± SEM.The definitions and detailed description below are provided to facilitate understanding of the present invention illustrated herein. Especially, these definitions and detailed description serve to interpret the aspects and embodiments above.DEFINITIONSAcceptor human frameworkAn "acceptor human framework" for the purposes herein is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.Affinity"Affinity" refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, "binding affinity" refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described in the following.Affinity maturedAn "affinity matured" antibody refers to an antibody with one or more alterations in one or more hypervariable regions (HVRs), compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen.FGFR2The term "FGFR2" and the like, as used herein, refers to any native FGFR2 from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g. mice and rats), unless otherwise indicated. The term encompasses "full-length" unprocessed FGFR2 as well as any form of FGFR2 that results from processing in the cell. The term also encompasses naturally occurring variants of FGFR2, e.g. splice variants or allelic variants.FGFR2b / FGFR2IIIbThe terms "FGFR2b" and "FGFR2IIIb", as used herein, and as used herein interchangeably, refer to the epithelial FGFR2b isoform, and refers to the amino acid sequence as set forth in SEQ ID NO: 5, and / or having the amino acid sequence as set forth in NCBI accession No. NP_075259.4, and is encoded by the FGFR2 gene residing on chromosome 10. The epithelial splicing regulatory protein 1 (ESRP1) isoform is responsible for the FGFR2 splicing and consequent expression of the epithelial FGFR2b isoform.An exemplary amino acid sequence for the FGFR2IIIb isoform is presented as SEQ ID NO:5:SEQ ID NO: 5 (FGFR2IIIb isoform)1 mvswgrficl vvvtmatlsl arpsfslved ttlepeeppt kyqisqpevy vaapgeslev61 rcllkdaavi swtkdgvhlg pnnrtvlige ylqikgatpr dsglyactas rtvdsetwyf121 mvnvtdaiss gddeddtdga edfvsensnn krapywtnte kmekrlhavp aantvkfrcp181 aggnpmptmr wlkngkefkq ehriggykvr nqhwslimes vvpsdkgnyt cvveneygsi241 nhtyhldvve rsphrpilqa glpanastvv ggdvefvckv ysdaqphiqw ikhvekngsk301 ygpdglpylk vlkhsginss naevlalfnv teadageyic kvsnyigqan qsawltvlpk361 qqapgrekei taspdyleia iycigvflia cmvvtvilcr mknttkkpdf ssqpavhklt421 kriplrrqvt vsaessssmn sntplvritt rlsstadtpm lagvseyelp edpkwefprd481 kltlgkplge gcfgqvvmae avgidkdkpk eavtvavkml kddatekdls dlvsememmk541 migkhkniin llgactqdgp lyviveyask gnlreylrar rppgmeysyd inrvpeeqmt601 fkdlvsctyq largmeylas qkcihrdlaa rnvlvtennv mkiadfglar dinnidyykk661 ttngrlpvkw mapealfdrv ythqsdvwsf gvlmweiftl ggspypgipv eelfkllkeg721 hrmdkpanct nelymmmrdc whavpsqrpt fkqlvedldr iltlttneey ldlsqpleqy781 spsypdtrss cssgddsvfs pdpmpyepcl pqyphingsv ktFGFR2c / FGFR2IIIcThe terms "FGFR2c" and "FGFR2IIIc", as used herein, refer to the epithelial FGFR2c isoform, and refers to the amino acid sequence as set forth in SEQ ID NO: 6, and / or having the amino acid sequence as set forth in NCBI accession No. NP_000132.3.An exemplary amino acid sequence for the FGFR2IIIc isoform is presented as SEQ ID NO:6:SEQ ID NO: 6 (FGFR2IIIc isoform)1 mvswgrficl vvvtmatlsl arpsfslved ttlepeeppt kyqisqpevy vaapgeslev61 rcllkdaavi swtkdgvhlg pnnrtvlige ylqikgatpr dsglyactas rtvdsetwyf121 mvnvtdaiss gddeddtdga edfvsensnn krapywtnte kmekrlhavp aantvkfrcp181 aggnpmptmr wlkngkefkq ehriggykvr nqhwslimes vvpsdkgnyt cvveneygsi241 nhtyhldvve rsphrpilqa glpanastvv ggdvefvckv ysdaqphiqw ikhvekngsk301 ygpdglpylk vlkaagvntt dkeievlyir nvtfedagey tclagnsigi sfhsawltvl361 papgrekeit aspdyleiai ycigvfliac mvvtvilcrm knttkkpdfs sqpavhkltk421 riplrrqvtv saessssmns ntplvrittr lsstadtpml agvseyelpe dpkwefprdk481 ltlgkplgeg cfgqvvmaea vgidkdkpke avtvavkmlk ddatekdlsd lvsememmkm541 igkhkniinl lgactqdgpl yviveyaskg nlreylrarr ppgmeysydi nrvpeeqmtf601 kdlvsctyql argmeylasq kcihrdlaar nvlvtennvm kiadfglard innidyykkt661 tngrlpvkwm apealfdrvy thqsdvwsfg vlmweiftlg gspypgipve elfkllkegh721 rmdkpanctn elymmmrdcw havpsqrptf kqlvedldri ltlttneeyl dlsqpleqys781 psypdtrssc ssgddsvfsp dpmpyepclp qyphingsvk tFGFR1The term "FGFR1" and the like, as used herein, refers to any native FGFR1 from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g. mice and rats), unless otherwise indicated. The term encompasses "full-length" unprocessed FGFR1 as well as any form of FGFR1 that results from processing in the cell. The term also encompasses naturally occurring variants of FGFR1, e.g. splice variants or allelic variants.FGFR1b / FGFR1IIIbThe terms "FGFR1b" and "FGFR1IIIb", as used herein, and as used herein interchangeably, refer to the epithelial FGFR1b isoform, and refers to the amino acid sequence as set forth in NCBI accession No. NP_001167536.1, and is encoded by the FGFR1 gene residing on chromosome 8. The epithelial splicing regulatory protein 1 (ESRP1) isoform is responsible for the FGFR1 splicing and consequent expression of the epithelial FGFR1b isoform.FGFR1c / FGFR1IIIcThe terms "FGFR1c" and "FGFR1IIIc", as used herein, refer to the epithelial FGFR1c isoform, and refers to the amino acid sequence as set forth in NCBI accession No. NP_001167534.1.DDR1The term "DDR1" and the like, as used herein, refers to any nativeDDR1 from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g. mice and rats), unless otherwise indicated. The term encompasses "full-length" unprocessed DDR1 as well as any form of DDR1 that results from processing in the cell. The term also encompasses naturally occurring variants of DDR1, e.g. splice variants or allelic variants.DDR1aThe term "DDR1a", as used herein, refers to the amino acid sequence as set forth in NCBI accession No. NP_001945.3, and is encoded by the DDR1 gene residing on chromosome 6DDR1bThe term "DDR1b", as used herein, refers to the amino acid sequence as set forth in NCBI accession No. NP_054699.2, and is encoded by the DDR1 gene residing on chromosome 6The term "DDR1c", as used herein, refers the amino acid sequence as set forth in NCBI accession No. NP_054700.2, and is encoded by the DDR1 gene residing on chromosome 6.The term "DDR1d", as used herein, refers the amino acid sequence as set forth in NCBI accession No. NP_001189450.1, and is encoded by the DDR1 gene residing on chromosome 6.The term "DDR1e", as used herein, refers the amino acid sequence as set forth in NCBI accession No. NP_001189451.1, and is encoded by the DDR1 gene residing on chromosome 6.Agonist / agonistic antigen-binding moleculeAn "agonist antigen-binding molecule", "agonistic antigen-binding molecule" or "agonist antibody" or "agonistic antibody" as used herein, is a molecule or antibody which significantly potentiates a biological activity of the antigen it binds. In embodiments, "agonist" or "agonistic" in the context of a cell receptor is understood as "activating" the signaling of said cell receptor. The term "anti-FGFR2 agonist antigen-binding molecule" or "anti-FGFR2 agonist antibody", as used herein, refers to an antigen-binding molecule or an antibody that is capable of binding its antigen with sufficient affinity such that the antigen-binding molecule or antibody is useful as a therapeutic agent in activating FGFR2. The term "anti-FGFR1 agonist antigen-binding molecule" or "anti-FGFR1 agonist antibody", as used herein, refers to an antigen-binding molecule or an antibody that is capable of binding its antigen with sufficient affinity such that the antigen-binding molecule or antibody is useful as a therapeutic agent in activating FGFR1. The term "anti-DDR1 agonist antigen-binding molecule" or "anti- DDR1 agonist antibody", as used herein, refers to an antigen-binding molecule or an antibody that is capable of binding its antigen with sufficient affinity such that the antigen-binding molecule or antibody is useful as a therapeutic agent in activating DDR1. As used herein, the agonistic activity of the antigen-binding molecule or agonist antibody is observed when the binding of the molecule or antibody to its antigen induces dimerization of the intracellular tyrosine kinase domains of the antigen, or wherein the binding of the molecule or antibody to its antigen activates phosphorylation of the antigen.In one embodiment, the extent of binding of an anti-FGFR2 antigen-binding molecule or antibody to an unrelated, non-FGFR2 protein is less than about 10% of the binding of the antigen-binding molecule or antibody to FGFR2 as measured, e.g. by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to FGFR2 has a dissociation constant (Kd) of < 1 micro Μ, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g. 10-8M or less, e.g. from 10-8M to 10-13M, e.g., from 10-9M to 10-13M). In certain embodiments, an anti-FGFR2 antigen-binding molecule or anti-FGFR2 antibody binds to an epitope of FGFR2 that is conserved among FGFR2 from different species.In one embodiment, the extent of binding of an anti-FGFR1 antigen-binding molecule or antibody to an unrelated, non-FGFR1 protein is less than about 10% of the binding of the antigen-binding molecule or antibody to FGFR1 as measured, e.g. by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to FGFR1 has a dissociation constant (Kd) of < 1 micro Μ, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g. 10-8M or less, e.g. from 10-8M to 10-13M, e.g., from 10-9M to 10-13M). In certain embodiments, an anti-FGFR1 antigen-binding molecule or anti-FGFR1 antibody binds to an epitope of FGFR1 that is conserved among FGFR1 from different species.In one embodiment, the extent of binding of an anti-DDR1 antigen-binding molecule or antibody to an unrelated, non- DDR1 protein is less than about 10% of the binding of the antigen-binding molecule or antibody to DDR1 as measured, e.g. by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to DDR1 has a dissociation constant (Kd) of < 1 micro Μ, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g. 10-8M or less, e.g. from 10-8M to 10-13M, e.g., from 10-9M to 10-13M). In certain embodiments, an anti- DDR1 antigen-binding molecule or anti- DDR1 antibody binds to an epitope of DDR1 that is conserved among DDR1 from different species.In one embodiment, Kd is measured by a radiolabeled antigen binding assay (RIA). In one embodiment, an RIA is performed with the Fab version of an antibody of interest and its antigen. For example, solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of (125I)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol. 293:865-881(1999)). To establish conditions for the assay, MICROTITER (registered trademark) multi-well plates (Thermo Scientific) are coated overnight with 5 micro g / ml of a capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w / v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23 degrees C). In a non-adsorbent plate (Nunc #269620), 100 pM or 26 pM [125I]-antigen are mixed with serial dilutions of a Fab of interest (e.g., consistent with assessment of the anti-VEGF antibody, Fab-12, in Presta et al., Cancer Res. 57:4593-4599 (1997)). The Fab of interest is then incubated overnight; however, the incubation may continue for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate washed eight times with 0.1% polysorbate 20 (TWEEN-20 (registered trademark)) in PBS. When the plates have dried, 150 micro l / well of scintillant (MICROSCINT-20 TM; Packard) is added, and the plates are counted on a TOPCOUNTTM gamma counter (Packard) for ten minutes. Concentrations of each Fab that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays.According to another embodiment, Kd is measured using a BIACORE (registered trademark) surface plasmon resonance assay. For example, an assay using a BIACORE (registered trademark)-2000 or a BIACORE(registered trademark)-3000 (BIAcore, Inc., Piscataway, NJ) is performed at 25 degrees C with immobilized antigen CM5 chips at ~10 response units (RU). In one embodiment, carboxymethylated dextran biosensor chips (CM5, BIACORE, Inc.) are activated with N-ethyl-N’- (3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier’s instructions. Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 micro g / ml (~0.2 micro M) before injection at a flow rate of 5 micro l / minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20TM) surfactant (PBST) at 25 degrees C at a flow rate of approximately 25 micro l / min. Association rates (kon) and dissociation rates (koff) are calculated using a simple one-to-one Langmuir binding model (BIACORE (registered trademark) Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams. The equilibrium dissociation constant (Kd) is calculated as the ratio koff / kon. See, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999). If the on-rate exceeds 106 M-1 s-1 by the surface plasmon resonance assay above, then the on-rate can be determined by using a fluorescent quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm band-pass) at 25 degrees C of a 20 nM anti-antigen antibody (Fab form) in PBS, pH 7.2, in the presence of increasing concentrations of antigen as measured in a spectrometer, such as a stop-flow equipped spectrophotometer (Aviv Instruments) or a 8000-series SLM-AMINCO (registered trademark) spectrophotometer (ThermoSpectronic) with a stirred cuvette.Specific bindingAs used herein, the term "specifically binds" refers to a binding interaction that is determinative of the presence of a target (FGFR2b, FGFR1b, or DDR1) protein in a population of proteins including proteins in their different isoforms. As the skilled artisan will recognize that isoform-binding molecule, i.e. anti-FGFR2b antigen binding molecule, anti-FGFR1b antigen binding molecule, or anti-DDR1 antigen binding molecule, may show some degree of cross-reactivity between isoforms depending on the conditions used, e.g. target protein concentration, salt and buffer conditions used, among others. In certain embodiments, the term "specifically binds", or "specific binding" refers to a property of the isoform-binding molecule, i.e. anti-FGFR2b antigen binding molecule to bind to one or more isoform polypeptides or fragments thereof, or nucleic acids encoding one or more isoform polypeptides or fragments thereof, with high affinity, e.g., with an affinity constant of at least about 107M-1, typically about 108M-1, and more typically, about 109M-1to 1010M-1or stronger, and preferentially bind to the isoform with an affinity that is at least two-fold, 50-fold, 100-fold, 1000-fold, or more greater than its affinity for binding to the another isoform. In certain embodiments, anti-FGFR2b antigen binding molecule binds preferentially to FGFR2b isoform, but does not substantially bind to (e.g., shows less than 10%, 8%, 5%, 4%, 3%, 2%, 1%, or 0% cross-reactivity with) to FGFR2c isoform. In certain embodiments, anti-FGFR1b antigen binding molecule binds preferentially to FGFR1b isoform, but does not substantially bind to (e.g., shows less than 10%, 8%, 5%, 4%, 3%, 2%, 1%, or 0% cross-reactivity with) to FGFR1c isoform. In certain embodiments, anti-DDR1a antigen binding molecule binds preferentially to DDR1a isoform, but does not substantially bind to (e.g., shows less than 10%, 8%, 5%, 4%, 3%, 2%, 1%, or 0% cross-reactivity with) to DDR1b isoform.Cell surface-expressed FGFR2As used herein, the expression "cell surface-expressed FGFR2" or the like, means one or more FGFR2 protein(s), or the extracellular domain thereof, that is / are expressed on the surface of a cell in vitro or in vivo, such that at least a portion of a FGFR2 protein is exposed to the extracellular side of the cell membrane and is accessible to an antigen-binding portion of an antibody or antigen-binding fragment. A "cell surface-expressed FGFR2" can comprise or consist of an FGFR2 protein expressed on the surface of a cell which normally expresses FGFR2 protein.Cell surface-expressed FGFR1As used herein, the expression "cell surface-expressed FGFR1" or the like, means one or more FGFR1 protein(s), or the extracellular domain thereof, that is / are expressed on the surface of a cell in vitro or in vivo, such that at least a portion of a FGFR1 protein is exposed to the extracellular side of the cell membrane and is accessible to an antigen-binding portion of an antibody or antigen-binding fragment. A "cell surface-expressed FGFR1" can comprise or consist of an FGFR1 protein expressed on the surface of a cell which normally expresses FGFR1 protein.Cell surface-expressed DDR1As used herein, the expression "cell surface-expressed DDR1" or the like, means one or more DDR1 protein(s), or the extracellular domain thereof, that is / are expressed on the surface of a cell in vitro or in vivo, such that at least a portion of a DDR1 protein is exposed to the extracellular side of the cell membrane and is accessible to an antigen-binding portion of an antibody or antigen-binding fragment. A "cell surface-expressed DDR1" can comprise or consist of an DDR1 protein expressed on the surface of a cell which normally expresses DDR1 protein.Biparatopic antibodyAs used herein, the term "biparatopic antibody" refers to, for example, an antibody that is capable of binding to two different epitopes on a single target. Without intending to be limiting, bispecific antibodies provide the ability to recognize and bind to two different antigens or epitopes (antigen domains) simultaneously as a single molecule. Biparatopic antibodies, which constitute a subset of bispecific antibodies, comprise antigen binding sites (paratopes) that provide the ability to recognize and bind to two different epitopes or antigenic sites on the same target antigen. In an embodiment, the antigen binding domains of biparatopic antibodies recognize and bind unique, non-overlapping epitopes on the same target antigen, such as a receptor, such as FGFR2, FGFR1, and DDR1.And / orThe term "and / or" herein is used to indicate any one of the subjects shown before and after "and / or", or any combination thereof. For example, "A, B, and / or C" includes the individual subjects "A", "B", and "C", and also combinations "A and B", "A and C", "B and C", and "A and B and C".Antigen-binding moleculeThe term "antigen-binding molecule" as used herein may refer to any molecule having any structure as long as it binds to an antigen. The structure of the "antigen-binding molecule" may include but is not limited to, a polypeptide or a portion thereof, or a small or medium chemical compound or a portion thereof, or a polynucleotide or a portion thereof. The polypeptide or a portion thereof includes an antigen-binding domain (also referred as a portion, a part or a fragment of an antibody).Antigen-binding domainThe term "antigen-binding domain" includes but is not limited to an antibody heavy chain variable (VH) region, an antibody light chain variable (VL) region (preferably a combination of an antibody heavy chain variable (VH) region and an antibody light chain variable (VL) region,), a single-domain antibody (sdAb), a VHH, a single-chain Fv (scFv), a single-chain antibody, a Fv, a single-chain Fv2 (scFv2), a Fab, Fab’, single chain Fab (scFab), and F (ab')2.AntibodyThe term "antibody" herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.Antibody fragmentAn "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. An "antibody fragment" comprises at least one "antigen-binding domain". Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab’-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); VHH, Fab’, single chain Fab (scFab), and multispecific antibodies formed from antibody fragments such as bispecific antibodies.Antibody that binds to the same / different epitopeAn "antibody that binds to the same epitope" as a reference antibody refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50% or more. An exemplary competition assay is provided herein. In the alternative, an "antibody that binds to a different epitope" as a reference antibody refers to an antibody which does not bind to the same epitope. The same applies where reference is made to "an antigen binding domain" instead of "an antibody".EpitopeAn "epitope" may be referred to as defining the site or sites of interaction between an antibody and its antigen(s). Accordingly, in Nilvebrant J, Rockberg J. An Introduction to Epitope Mapping. Methods Mol Biol. 2018;1785:1-10, "Antibody epitopes can conceptually be divided into linear and non-linear epitopes. Linear epitopes, which are also known as continuous or sequential epitopes, can be mimicked by short peptide sequences. Epitopes in which amino acids in distant parts of the sequence are brought together by protein folding are called non-linear, conformational, or discontinuous epitopes. For example, discontinuous epitopes often contain short segments of contiguous residues that can be independently bound by an antibody". As used herein, the terms "conformational epitope" or "non-linear epitope" or "discontinuous epitope" are used interchangeably to refer to an epitope which is composed of at least two amino acids which are not consecutive amino acids in a single protein chain or single polypeptide chain.Substantially reducedThe phrase "substantially reduced" or "substantially different", as used herein, refers to a sufficiently high degree of difference between two numeric values (generally one associated with a molecule and the other associated with a reference / comparator molecule) such that one of skill in the art would consider the difference between the two values to be of statistical significance within the context of the biological characteristic measured by said values (e.g., Kd values).Substantially similarThe term "substantially similar" or "substantially the same," as used herein, refers to a sufficiently high degree of similarity between two numeric values (for example, one associated with an antibody of the invention and the other associated with a reference / comparator antibody), such that one of skill in the art would consider the difference between the two values to be of little or no biological and / or statistical significance within the context of the biological characteristic measured by said values (e.g., Kd values).ChimericThe term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.Class of an antibodyThe "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively.Effective amountAn "effective amount" of an agent, e.g., a pharmaceutical formulation, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.Extracellular domainAn "extracellular domain" or "ECD" is understood as a domain or portion of a membrane-associated protein which is located extracellularly when expressed in a cell. RTKs are single-pass transmembrane (TM) proteins. In RTK, the extracellular domains are typically located N-terminal of the transmembrane region. Another term for an "extracellular domain" is "ectodomain" as understood in the art.Fc regionThe term "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) or glycine-lysine (residues 446-447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.Framework or FR"Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.Full length antibody / intact antibody / whole antibodyThe terms "full length antibody," "intact antibody," and "whole antibody" are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.Host cell / host cell line / host cell cultureThe terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.Human antibodyA "human antibody" is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.Human consensus frameworkA "human consensus framework" is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one embodiment, for the VL, the subgroup is subgroup kappa I as in Kabat et al., supra. In one embodiment, for the VH, the subgroup is subgroup III as in Kabat et al., supra.Humanized antibodyA "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.Hypervariable region / HVRThe term "hypervariable region" or "HVR" as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence ("complementarity determining regions" or "CDRs") and / or form structurally defined loops ("hypervariable loops") and / or contain the antigen-contacting residues ("antigen contacts"). Generally, antibodies comprise six HVRs: three in the VH (H1, H2, H3), and three in the VL (L1, L2, L3). Exemplary HVRs herein include:(a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));(b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991));(c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996)); and(d) combinations of (a), (b), and / or (c), including HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3), and 94-102 (H3).In one embodiment, HVR residues of anti-FGFR2b antigen-binding molecules, antibodies, or antigen-binding fragments thereof comprise those identified in Table 1 or elsewhere in the specification.In one embodiment, HVR residues of anti-FGFR1b antigen-binding molecules, antibodies, or antigen-binding fragments thereof comprise those identified in Table 9 or elsewhere in the specification.In one embodiment, HVR residues of anti-DDR1 antigen-binding molecules, antibodies, or antigen-binding fragments thereof comprise those identified in Table 10 or elsewhere in the specification.Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.ImmunoconjugateAn "immunoconjugate" is an antibody conjugated to one or more heterologous molecule(s). The heterologous molecule conjugated to the antibody can also be termed a secondary or adjunctive agent. Exemplary secondary or adjunctive agent are mitogenic growth factor, epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), Wnt family member including WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4, WNT5, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, WNT16, brain-derived neurotrophic factor (BDNF), Noggin, granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), Insulin-like growth factor (IGF) including IGF-1, IGF-2, and hepatocyte growth factor (HGF). Further examples are directed at cytokines, such as interleukin family including IL-22, IL-10, IL-28, IL-26, IL-29, IL-24, and IL-20. The secondary or adjunctive agent can also be suitable to treat or help in treating inflammation or fibrosis, and can be a non-steroidal anti-inflammatory agent, steroid, a disease-modifying antirheumatic drug, an immunosuppressant, tumor necrosis factor inhibitor, adalimumab, azathioprine, chloroquine, hydroxychloroquine, ciclosporin, D-penicillamine, etanercept, golimumab, gold salts, infliximab, leflunomide, methotrexate, minocycline, sulfasalazine, anakinra, abatacept, rituximab, and tocilizumab. The secondary or adjunctive agent can also be a multi-kinase inhibitor, such as axitinib, nintedanib, pirfenidone, riociguat, sorafenib, sunitinib, lenvatinib, regorafenib, ponatinib, and pazopanib. The secondary or adjunctive agent can also be a phosphodiesterase inhibitor, such as meribendan, arinone Xi Luo acyl Amine, BI 1015550, Apremilast (apremilast), mesembranone, Ibudilast, pyrrole Rummy department spy, luteolin, roflumilast, cilomilast, diazepam, rolipram, YM796, icariin, silaenafil, he Da Lafei, Vardenafil, avanaphil, Yi Dina be non-, meter Luo Nafei, udenafil and Zaprinast. The secondary or adjunctive agent can also be an integrin inhibitor, such as ProAgio, and GSK-3008348. The secondary or adjunctive agent can also be a (cyto)toxic reagent, including a senolytic compound, such as MDM2 inhibitors (Nutlin 3a, RG-7112), BCL-2 anti-apoptotic protein family members, which inhibitors inhibit a function of at least the anti-apoptotic protein, BCL-xL (ABT-263, ABT-737, WEHI-539, A-1155463), GLS1 inhibitor (CB-839), Akt specific inhibitors (MK-2206), and radioisotopes.Individual / subjectAn "individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human.Isolated antibodyAn "isolated" antibody is one which has been separated from a component of its natural environment. In some embodiments, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC). For review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).Isolated nucleic acidAn "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.Isolated nucleic acid encoding an anti-FGFR2 antibody, an anti-FGFR1 antibody, or an anti-DDR1 antibody"Isolated nucleic acid encoding an anti-FGFR2 antibody", "isolated nucleic acid encoding an anti-FGFR1 antibody", or "isolated nucleic acid encoding an anti-DDR1 antibody" refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.Monoclonal antibodyThe term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies composing the population are identical and / or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.Naked antibodyA "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical formulation.Native antibodies"Native antibodies" refer to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.Package insertThe term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products.Percent (%) amino acid sequence identity"Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR) software, or GENETYX (registered trademark) (Genetyx Co., Ltd.). Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:100 times the fraction X / Ywhere X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program’s alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.Pharmaceutical formulationThe term "pharmaceutical formulation" refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.Pharmaceutically acceptable carrierA "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.Treatment / treating / to treatAs used herein, "treatment" (and grammatical variations thereof such as "treat" or "treating") refers to preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, antibodies of the invention are used to delay development of a disease or to slow the progression of a disease. A "method of treating" or its equivalent, when applied to, for example, fibrosis, refers to a procedure or course of action that is designed to reduce or eliminate the number of fibrotic cells in a patient, or to alleviate the symptoms of fibrosis. It does not necessarily mean that the fibrotic cells or other disorder will, in fact, be eliminated, that the number of cells or disorder will, in fact, be reduced, or that the symptoms of fibrosis or other disorder will, in fact, be alleviated. Often, a method of treatment of fibrosis will be performed even with a low likelihood of success, but which, given the medical history and estimated survival expectancy of a patient, is nevertheless deemed to induce an overall beneficial course of action.Variable region / variable domainThe term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).VectorThe term "vector," as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors." The vector can be introduced into a host cell by a method using a virus, an electroporation method, or the like, but the introduction of a vector is not limited to in vitro introduction, and it is also possible to directly introduce a vector into a body.DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTIONThe activation of receptor tyrosine kinases (RTKs) plays an important role in the regulation of kinase activity and activation of downstream signaling pathways in the cell. Autophosphorylation of RTKs is mediated by sequential and precisely ordered intermolecular reaction upon binding to their natural ligands. The aspects and embodiments described herein are based, at least in part, on the discovery that activation of RTK can be achieved with the use of an antigen-binding molecule that mimics the binding of the natural ligands to the RTKs, including wherein the ligand-receptor interaction includes binding of the ligand to different domains, or binding to unique, non-overlapping epitopes on the same domain, on the same receptor protein. Without wishing to be bound by theory, it is hypothesized that the antigen-binding molecule described herein, at least in part, mimic the binding of the ligands to their receptors and induce receptor dimerization and autophosphorylation, thereby activating the downstream intracellular signals thereof.In one aspect, an antigen-binding molecule that binds to a receptor tyrosine kinase (RTK) protein, wherein the molecule is an agonist is provided. Henceforth, referred herein as the anti-RTK agonist antigen-binding molecule.In one embodiment, the anti-RTK agonist antigen-binding molecule comprises a first antigen-binding domain that binds a first epitope of a first RTK protein and a second antigen-binding domain that binds a second epitope of the first or a second RTK protein, wherein the first epitope resides in a first domain of the RTK protein, and the second epitope resides in a second domain of the RTK protein.In embodiments, the first antigen-binding domain binds a first RTK protein and a second antigen-binding domain binds a second RTK protein, optionally wherein the first and the second RTK proteins form a dimer.In such embodiments, activation, and optionally dimerization, of the RTK protein takes place in trans, between different RTK proteins.In other embodiments, the first antigen-binding domain binds a first RTK protein and a second antigen-binding domain binds the first RTK protein.In such embodiments, activation, and optionally dimerization, of the RTK protein takes place in cis, within one RTK protein.In embodiments of the molecules herein, binding of the first and second antigen-binding domains induces dimerization of the intracellular tyrosine kinase domains of the RTK protein.Dimerization of the intracellular tyrosine kinase domains of RTK proteins typically results in activation of intracellular signaling of the RTK domain. An agonist molecule for an RTK may therefore induce dimerization of the intracellular tyrosine kinase domains. Dimerization may by detected in vitro using appropriate assays.Accordingly, in embodiments, dimerization is detected in the presence of the molecule in an in vitro cell assay, and wherein dimerization is indicative of agonist activity.Further, activation of an RTK typically results in phosphorylation of the RTK via the tyrosine kinase domain of the RTK. Accordingly, in embodiments, an agonist molecule or agonist antibody provided herein, when binding to the RTK, activates phosphorylation of the RTK protein. Dimerization may be detected in vitro using appropriate assays. Phosphorylation of the RTK may by detected in vitro using appropriate assays.Accordingly, in embodiments, binding of the first and second antigen-binding domains activates phosphorylation of the RTK protein.Further, in embodiments, phosphorylation of the RTK protein is detected in the presence of the molecule in an in vitro cell assay, wherein RTK protein phosphorylation is indicative of agonist activity.In vitro assays for detecting in vitro RTK phosphorylation are well known in the art.Moreover, it is preferred that the molecules provided herein bind to an extracellular domain (ECD) of the RTK protein.Binding of the antigen-binding domain(s) of the agonist molecules provided herein to ECD(s) of an RTK protein may activate intracellular signaling.Accordingly, in embodiments, the first antigen-binding domain and the second antigen-binding domain each bind to an extracellular domain (ECD) of the RTK protein.Several RTK proteins, such as the members of Fibroblast Growth Factor Receptor (FGFR) family of RTK comprise a plurality of Ig-like domains as extracellular domains.Accordingly, in embodiments, the extracellular domain is independently selected from an Immunoglobulin (Ig)-like domain of the ECD of the RTK protein for each of the first antigen-binding domain and the second antigen-binding domain.It is possible that the first and second antigen-binding domains bind to the same or to different domain. Moreover, in case the first and second antigen-binding domains bind to the same domain, the epitope of the first and second antigen-binding domains may be the same epitope or may be a different epitope.In certain embodiments, the first antigen-binding domain binds to a first domain and the second antigen-binding domain binds to a second domain, wherein the first domain and the second domain is the same.In embodiments thereof, the first and the second epitope is the same. In such embodiment, the molecule provided herein binds monoparatopically.In different embodiments thereof, the first epitope and the second epitope are different. In such embodiment, the molecule provided herein binds biparatopically.In different embodiments thereof, the first epitope and the second epitopes are different, and wherein the first epitope and second epitope are unique, non-overlapping epitopes. In such embodiment, the molecule provided herein binds biparatopically.In further embodiments of molecules provided herein, the first antigen binding-domain binds to a first domain and the second antigen-binding domain binds to a second domain, wherein the second domain is different from the first domain.In such embodiment, the first epitope and the second epitope are different. In such embodiment, the molecule provided herein binds biparatopically.In one embodiment, the RTK protein is selected from the group consisting of Fibroblast growth factor receptor 2 (FGFR2), Fibroblast growth factor receptor 1 (FGFR1), Fibroblast growth factor receptor 3 (FGFR3), Fibroblast growth factor receptor 4 (FGFR4), Epidermal growth factor receptor (EGFR), Hepatocyte growth factor receptor (HGFR) or MET proto-oncogene receptor tyrosine kinase (MET), Bone morphogenetic protein receptor 1 (BMR1), Bone morphogenetic protein receptor 2 (BMR2), HER2(Erb-B2) receptor, HER3(Erb-B3) receptor, HER4(Erb-B4) receptor, insulin receptor (InsR), insulin-like growth factor I receptor (IGF1R), insulin receptor-related receptor (IRR), Platelet derived growth factor receptor alpha (PDGFRa), Platelet derived growth factor receptor beta (PDGFRb), Colony stimulating factor 1 receptor (CSFR), KIT proto-oncogene receptor tyrosine kinase (Kit), FMS related receptor tyrosine kinase (FLT3), vascular endothelial growth factor receptor (VEGFR), fms related receptor tyrosine kinase 1 (VEGFR-1), kinase insert domain receptor (VEGFR-2), fms related receptor tyrosine kinase 4 (VEGFR-3), Protein tyrosine kinase 7 (PTK7 / CCK4), Neurotrophin receptor A (TrkA), Neurotrophin receptor B (TrkB), Neurotrophin receptor C (TrkC), Receptor tyrosine kinase like orphan receptor 1 (ROR1), Receptor tyrosine kinase like orphan receptor 2 (ROR2), Muscle associated receptor tyrosine kinase (MuSK), macrophage stimulating 1 receptor (Ron), TYRO3 protein tyrosine kinase (Tyro3), AXL receptor tyrosine kinase (AXL), and MER proto-oncogene tyrosine kinase (Mer), Tyrosine kinase with immunoglobulin like and EGF like domain 1 (TIE1) TEK receptor tyrosine kinase (TIE2), Ephrin receptor A1 (EphA1), Ephrin receptor A2 (EphA2), Ephrin receptor A3 (EphA3), Ephrin receptor A4 (EphA4), Ephrin receptor A5 (EphA5), Ephrin receptor A6 (EphA6), Ephrin receptor A7 (EphA7), Ephrin receptor A8 (EphA8), Ephrin receptor A9 (EphA9), Ephrin receptor A10 (EphA10), Ephrin receptor B1 (EphB1), Ephrin receptor B2 (EphB2), Ephrin receptor B3 (EphB3), Ephrin receptor B4 (EphB4), Ephrin receptor B6 (EphB6), Ret proto-oncogene (RET), receptor like tyrosine kinase (RYK), Discoidin domain receptor tyrosine kinase 1 (DDR1), Discoidin domain receptor tyrosine kinase 2 (DDR2), c-ros oncogene 1, receptor tyrosine kinase (ROS), apoptosis associated tyrosine kinase (Lmr1), lemur tyrosine kinase 2 (Lmr2), lemur tyrosine kinase 3 (Lmr3), leukocyte receptor tyrosine kinase (LTK), ALK receptor tyrosine kinase (ALK) and serine / threonine / tyrosine kinase 1 (STYK1).In certain embodiments, the RTK protein is a protein of the Fibroblast Growth Factor Receptor (FGFR) family. Members of this family include FGFR1, FGFR2, FGFR3 and FGFR4.In one embodiment, the RTK protein is selected from one of the Fibroblast Growth Factor Receptor (FGFR) family consisting of the members in the group consisting of: FGFR1, FGFR2, FGFR3 and FGFR4.The family of FGFRs consists of FGFR1, FGFR2, FGFR3 and FGFR4. FGFRs contain three extracellular domains that belong to the immunoglobulin superfamily (IgI, IgII, and IgIII), a single transmembrane helix, and an intracellular tyrosine kinase domain. The IgIII domains of FGFR2 is produced by the IIIa exon being spliced to one of two other exons - IIIb or IIIc, to form FGFR2IIIb that is normally localized in the epithelial cells, and FGFR2IIIc which is normally localized in the mesenchymal cells and is tightly regulated in a tissue-specific expression manner (NPL 1).An extracellular domain that belongs to the immunoglobulin superfamily, such as IgI, IgII, or IgIII in FGFR2 or FGFR1 is also referred herein as "Ig-like domain".In a preferred embodiment, the RTK protein is Fibroblast growth factor receptor 2 (FGFR2) or Fibroblast growth factor receptor 1 (FGFR1).anti-FGFR2 agonistic antigen-binding moleculesFGFR2 refers to a tyrosine protein kinase that acts as a cell-surface receptor for fibroblast growth factors. The protein is also known as keratinocyte growth factor receptor and CD332. Structurally, a FGFR2 amino acid sequence is a receptor tyrosine kinase protein having a signal peptide, at least one or more immunoglobulin (Ig)-like domains, an acidic box, a transmembrane domain, and a split tyrosine kinase domain and has over its full length at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of NCBI accession No. NP_000132.3, NP_001138385.1, NP_001138386.1, NP_001138387.1, NP_001138388.1. Structurally, a FGFR2 nucleic acid sequence has over its full length at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the nucleic acid sequence of NCBI accession No. NM_000141.4, NM_001144913.1, NM_001144914.1, NM_001144915.1, NM_001144916.1. The FGFR2 signal peptide may be retained or cleaved off.FGFR2 plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic development. Activation of FGFR2 results in phosphorylation of PLCG1, FRS2, and PAK4 and activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1 / ERK2, MAPK3 / ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. FGFR2 signaling is down-regulated by ubiquitination, internalization and degradation. Mutations that lead to constitutive kinase activation or impair normal FGFR2 maturation, internalization and degradation lead to aberrant signaling. Likewise, over-expressed FGFR2 promotes activation of STAT1. In some of these cases, such as in some cancers, FGFR2 aberrations result in the formation of FGFR2 fusion proteins, or FGFR2 oncogenic isoforms, such as FGFR2-BICC, FGFR2-PHGDH, FGFR2-AHCYL, FGFR2-NDC80, FGFR2-CIT, or FGFR2-OFD1 (Nita-et al; Xu et al).Fibroblast growth factor (FGF) 7 (FGF-7) and its homologue FGF-10 act as a specific agonist for epithelial IIIb FGFR2 (FGFR2b) by binding to IgIII domain of epithelial IIIb in FGFR2 (NPL 2). In addition to the binding to IgIII domain of epithelial IIIb, binding of FGF-7 or FGF-10 to IgII domain in FGFR2 with heparin or heparan sulfate proteoglycans (HSPGs) is thought to be essential for agonistic FGF signaling activation (NPL 3), however, mechanisms of agonistic signal activation are not completely understood yet.Without wishing to be bound by theory, the present inventors hypothesized that the antigen-binding molecules described herein in part mimic the binding of FGF7 with FGFR2, wherein binding of FGF7 to FGFR2 has been elucidated to involve binding to more than one domain of FGFR2. The aspects and embodiments described herein are based, at least in part, on the discovery that antigen-binding molecules that bind FGFR2 on different domains or bind to FGFR2 on different, or different (i.e. unique and non-overlapping) epitopes on the same domain is capable of activating FGFR2. In a preferred embodiment, an anti-FGFR2b antigen-binding molecule that binds FGFR2 on different domains or binds to FGFR2 on different, or different (i.e. unique and non-overlapping) epitopes on the same domain, wherein the antigen-binding molecule is an agonist, is provided.In aspects of the present invention, an anti-FGFR2b antigen-binding molecule described herein does not substantially bind to mutated FGFR2, such as FGFR2 fusion proteins, or FGFR2 oncogenic isoforms.In yet further embodiments, the RTK protein is FGFR2b.The terms "FGFR2b" and "FGFR2IIIb", as used herein, refer to the amino acid sequence as set forth in SEQ ID NO: 5, and / or having the amino acid sequence as set forth in NCBI accession No. NP_075259.4, and is encoded by the FGFR2 gene residing on chromosome 10. The epithelial splicing regulatory protein 1 (ESRP1) isoform is responsible for the FGFR2 splicing and consequent expression of the epithelial FGFR2b isoform.An exemplary amino acid sequence of FGFR2b (FGFR2IIIb) is provided as UniProtKB P21802-3, which is reproduced as SEQ ID NO: 5 shown below.MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKHSGINSSNAEVLALFNVTEADAGEYICKVSNYIGQANQSAWLTVLPKQQAPGREKEITASPDYLEIAIYCIGVFLIACMVVTVILCRMKNTTKKPDFSSQPAVHKLTKRIPLRRQVTVSAESSSSMNSNTPLVRITTRLSSTADTPMLAGVSEYELPEDPKWEFPRDKLTLGKPLGEGCFGQVVMAEAVGIDKDKPKEAVTVAVKMLKDDATEKDLSDLVSEMEMMKMIGKHKNIINLLGACTQDGPLYVIVEYASKGNLREYLRARRPPGMEYSYDINRVPEEQMTFKDLVSCTYQLARGMEYLASQKCIHRDLAARNVLVTENNVMKIADFGLARDINNIDYYKKTTNGRLPVKWMAPEALFDRVYTHQSDVWSFGVLMWEIFTLGGSPYPGIPVEELFKLLKEGHRMDKPANCTNELYMMMRDCWHAVPSQRPTFKQLVEDLDRILTLTTNEEYLDLSQPLEQYSPSYPDTRSSCSSGDDSVFSPDPMPYEPCLPQYPHINGSVKT (SEQ ID NO: 5)The terms "FGFR2c" and "FGFR2IIIc", as used herein, refer to the epithelial FGFR2c isoform, and refer to the amino acid sequence as set forth in SEQ ID NO: 6, and / or having the amino acid sequence as set forth in NCBI accession No. NP_000132.3.In the present disclosure, an anti-FGFR2b antigen binding molecule comprising a first antigen-binding domain and a second antigen-binding domain, and wherein the molecule is an agonist is provided.The present invention therefore provides an agonistic antigen-binding molecule that binds to a human FGFR2 protein, wherein the molecule comprises a first antigen-binding domain that binds a first epitope of an extracellular domain (ECD) of a first FGFR2 protein and a second antigen-binding domain that binds a second epitope of an extracellular domain (ECD) of the first or a second FGFR2 protein, wherein the first epitope and the second epitope are different from each other.The present invention therefore provides an agonistic antigen-binding molecule that binds to a human FGFR2 protein, wherein the molecule comprises a first means for binding a first epitope of an extracellular domain (ECD) of a first FGFR2 protein and a second means for binding a second epitope of an extracellular domain (ECD) of the first or a second FGFR2 protein, wherein the first epitope and the second epitope are different from each other.According to one aspect, the first antigen-binding domain or the first means binds a first FGFR2 protein and the second antigen-binding domain or the second means binds a second FGFR2 protein.According to one aspect, the agonistic antigen-binding molecule of the present invention is a biparatopic antigen-binding molecule.According to one aspect, the human FGFR2 protein is human FGFR2b protein.According to one aspect, each of the extracellular domains is independently selected from an Immunoglobulin (Ig)-like domain of the FGFR2 protein.According to one aspect of the agonistic antigen-binding molecule of the present invention, wherein the first antigen-binding domain or the first means binds to a first domain of the FGFR2 protein and the second antigen-binding domain or the second means binds to a second domain of the FGFR2 protein, the first domain and the second domain is the same.According to one aspect of the agonistic antigen-binding molecule of the present invention, the agonistic antigen-binding molecule is biparatopic, and wherein the first antigen-binding domain or the first means binds to a first epitope in a first domain of the FGFR2 protein and the second antigen-binding domain or the second means binds to a second epitope in a second domain of the FGFR2 protein, and the first domain and the second domain is the same, but the first epitope and the second epitopes are different. In a further aspect, the first epitope and the second epitope are unique, non-overlapping epitopes.According to another aspect of the agonistic antigen-binding molecule of the present invention, wherein the agonistic antigen-binding molecule is biparatopic, and wherein the first antigen-binding domain or the first means binds to a first domain of the FGFR2 protein and the second antigen-binding domain or the second means binds to a second domain of the FGFR2 protein, and the second domain is different from the first domain.According to one aspect of the agonistic antigen-binding molecule of the present invention, the first antigen-binding domain and the second antigen-binding domain or the first means and the second means, independently of each other, bind an Ig-like domain of the FGFR2 protein, selected from the group consisting of IgI, IgII, IgIII, IgIIIb and IgIIIc of FGFR2.According to one aspect of the agonistic antigen-binding molecule of the present invention, the first antigen-binding domain and the second antigen-bindi...

Claims

1. An agonistic antigen-binding molecule that binds to a receptor tyrosine kinase (RTK) protein, and wherein the molecule is an agonist of the RTK protein, wherein the molecule comprises a first antigen-binding domain that binds a first epitope of a first RTK protein and a second antigen-binding domain that binds a second epitope of the first or a second RTK protein, wherein the first epitope resides in a first domain of the RTK protein, and the second epitope resides in a second domain of the RTK protein.

2. The agonistic antigen-binding molecule of claim 1, wherein the RTK protein isa human Fibroblast growth factor receptor 2 (FGFR2) protein, wherein the molecule comprises a first antigen-binding domain that binds a first epitope of an extracellular domain (ECD) of a first FGFR2 protein and a second antigen-binding domain that binds a second epitope of an extracellular domain (ECD) of the first or a second FGFR2 protein, wherein the first epitope and the second epitope are different from each other.

3. The molecule of claim 2, wherein the first antigen-binding domain binds a first FGFR2 protein and the second antigen-binding domain binds a second FGFR2 protein.

4. The molecule of claims 2 or 3, which is a biparatopic antigen-binding molecule.

5. The molecule of any one of claims 2 to 4, wherein the human FGFR2 protein is human FGFR2b protein.

6. The molecule of any one of claims 2 to 5, wherein each of the extracellular domains is independently selected from an Immunoglobulin (Ig)-like domain of the FGFR2 protein.

7. The molecule of any one of claims 2 to 6, wherein the first antigen-binding domain binds to a first domain of the FGFR2 protein and the second antigen-binding domain binds to a second domain of the FGFR2 protein, wherein the first domain and the second domain is the same.

8. The molecule of any one of claims 2 to 6, wherein the first antigen-binding domain binds to a first domain of the FGFR2 protein and the second antigen-binding domain binds to a second domain of the FGFR2 protein, wherein the second domain is different from the first domain.

9. The molecule of any one of claims 2 to 8, wherein the first antigen-binding domain and the second antigen-binding domain, independently of each other, bind an Ig-like domain of the FGFR2 protein, selected from the group consisting of IgI, IgII, IgIII, IgIIIb and IgIIIc of FGFR2.

10. The molecule of any one of claims 6 to 9, wherein the first antigen-binding domain and the second antigen-binding domain, independently of each other, binds an Ig-like domain of the FGFR2 in the following combinations selected from the group consisting of: (i) wherein the first antigen-binding domain and the second antigen-binding domain, independently of each other, bind the IgIIIb and IgIIIb domain of FGFR2; (ii) wherein the first antigen-binding domain and the second antigen-binding domain, independently of each other, bind the IgIIIb and IgIII domain of FGFR2; (iii) wherein the first antigen-binding domain and the second antigen-binding domain, independently of each other, bind the IgIIIb and IgII domain of FGFR2; and (iv) wherein the first antigen-binding domain and the second antigen-binding domain, independently of each other, bind the IgIIIb and IgI domain of FGFR2.

11. The molecule of any one of claims 6 to 10, wherein (i) the first antigen-binding domain binds the IgIIIb domain of FGFR2, or wherein (ii) the first antigen-binding domain binds specifically to IgIIIb of FGFR2 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgIIIc of FGFR2 and shows less than 10%, or less than 5%, or 0% cross-reactivity with IgI and IgII of FGFR2.

12. The molecule of any one of claims 4 to 11, wherein binding of the first antigen-binding domain and the second antigen-binding domain to FGFR2b protein leads to agonist activity as follows: (i) wherein binding of the molecule to FGFR2b protein via a cell-surface expressed FGFR2b in a target cell activates signaling in the target cell, thereby exhibiting agonist activity, and wherein the activated signal in the target cell is measured by an increase in expression of an intracellular protein downstream of FGFR2b by at least 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or more compared to the expression of said intracellular protein prior to binding of the molecule to the cell-surface expressed FGFR2b protein in the target cell, in particular wherein the intracellular protein downstream of FGFR2b is selected from the group consisting of: pAKT, pPLCG1, pFRS2, pPAK4, pRAS, pMAPK1 / pERK2, and pMAPK3 / pERK1; or (ii) wherein binding of the molecule to FGFR2b protein via a cell-surface expressed FGFR2b in a target cell induces proliferation of the target cell, thereby exhibiting agonist activity, wherein the induction in proliferation of the target cell is measured by an increase in ATP expression by at least 1.5-fold, or 2-fold, or 2.5-fold or more, in the target cell in the presence of the molecule compared to in the target cell in the absence of the molecule, wherein the ATP expression is directly proportional to the concentration of viable target cells, in particular wherein the target cell is a lung epithelial cell, optionally wherein the lung epithelial cell is selected from alveolar type II (AT2) cells; or (iii) wherein receptor dimerization is detected in the presence of the molecule in an in vitro cell assay, wherein receptor dimerization is indicative of agonist activity; or (iv) wherein phosphorylation of the FGFR2b protein is detected in the presence of the molecule in an in vitro cell assay, wherein FGFR2b protein phosphorylation is indicative of agonist activity.

13. The agonistic antigen-binding molecule of claim 1, wherein the RTK protein is a human Fibroblast growth factor receptor 1 (FGFR1) protein, wherein the molecule comprises a first antigen-binding domain that binds a first epitope of an extracellular domain (ECD) of a first FGFR1 protein and a second antigen-binding domain that binds a second epitope of an extracellular domain (ECD) of the first or a second FGFR1 protein, wherein the first epitope and the second epitope are different from each other.

14. The agonistic antigen-binding molecule of claim 1, wherein the RTK protein is a human Discoidin Domain receptor 1 (DDR1) protein, wherein the molecule comprises a first antigen-binding domain that binds a first epitope of an extracellular domain (ECD) of a first DDR1 protein and a second antigen-binding domain that binds a second epitope of an extracellular domain (ECD) of the first or a second DDR1 protein, wherein the first epitope and the second epitope are different from each other.

15. The molecule of any one of claims 1 to 14, wherein the first antigen-binding domain and the second antigen-binding domain are each independently selected from a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody, or wherein the first antigen-binding domain and the second antigen-binding domain are each a Fab, Fab’, F(ab)’2, scFab, scFv, Fv, VHH or single-domain antibody which are linked by at least one disulfide bond.

16. The molecule of any one of claims 1 to 15, wherein the first antigen-binding domain and the second antigen-binding domain are characterized by having at least one disulfide bond formed between amino acid residues which are not in a hinge region.

17. The molecule of claim 16, wherein the at least one disulfide bond is an engineered disulfide bond which is not present in a wild type IgG, optionally wherein said at least one disulfide bond is formed between a CH1 region, a CL region, a VH or VHH region, or a VL region of the first antigen-binding domain and a CH1 region, a CL region, a VH or VHH region, or a VL region of the second antigen-binding domain, in particular wherein said at least one disulfide bond is formed between the group selected from the following: [i] an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CH1 region of a second antigen-binding domain; [ii] an amino acid residue in a CL region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain; [iii] an amino acid residue in a CH1 region of a first antigen-binding domain and an amino acid residue in a CL region of a second antigen-binding domain; [iv] an amino acid residue in a VH or VHH region of a first antigen-binding domain and an amino acid residue in a VH or VHH region of a second antigen-binding domain; [v] an amino acid residue in a VL region of a first antigen-binding domain and an amino acid residue in a VL region of a second antigen-binding domain; and [vi] an amino acid residue in a VH or VHH region of a first antigen-binding domain and an amino acid residue in a VL region of a second antigen-binding domain.

18. The molecule of any one of claims 1 to 17, wherein the molecule comprises an antibody constant region, in particular (i) wherein the antibody constant region is a human antibody constant region, or (ii) wherein the antibody constant region is selected from a human IgG1, IgG2, IgG3 or IgG4 constant regions.

19. The molecule of any one of claim 1 to 18, wherein the molecule is characterized by two antigen-binding domains, or wherein the molecule is a bivalent molecule, or wherein the first antigen-binding domain and second antigen-binding domain are each a monovalent Fab or a monovalent VHH, or are each a monovalent scFab.

20. The molecule of any one of claims 1 to 19, wherein the molecule comprises more than two antigen-binding domains, or wherein the molecule is tri-valent, tetra-valent, or multivalent molecule, optionally wherein the molecule comprises a third antigen-binding domain, the third antigen-binding domain binds the same epitope on the same domain as the first or the second antigen-binding domain.

21. The molecule of claim 20, wherein the molecule comprises a fourth antigen-binding domain, the fourth antigen-binding domain binds the same epitope on the same domain as the first or the second antigen-binding domain but not the same epitope as the third antigen-binding domain, optionally wherein the molecule comprises a third and a fourth antigen-binding domain, wherein the third antigen-binding domain binds the same epitope on the same domain as the first antigen-binding domain, and the fourth antigen-binding domain binds the same epitope on the same domain as the second antigen-binding domain.

22. A pharmaceutical composition comprising the molecule of any one of claims 1 to 21, and a pharmaceutically acceptable carrier.

23. An immunoconjugate protein comprising the molecule of any one of claims 1 to 21.

24. The molecule of any one of claims 1 to 21 or the pharmaceutical composition of claim 22 or the immunoconjugate of claim 23 for use in the treatment or prevention of a disease, disorder, or condition related to injury of lung epithelial cells in an individual in need thereof.

25. The molecule or pharmaceutical composition or immunoconjugate for the use of claim 24, wherein the condition related to the injury of lung epithelial cells in an individual is selected from the group consisting of fibrosis of the lungs, inflammation of the lungs, senescence-related fibrosis of the lungs, asthma, a condition associated with exposure to environmental toxins, a condition associated with exposure to bacteria, a condition associated with exposure to a virus, cystic fibrosis, a pneumonectomy, a condition associated with exposure to radiation, a condition associated with exposure to tobacco smoke or chemicals, and bleomycin mediated epithelial injury.

26. The molecule of any one of claims 1 to 21 or the pharmaceutical composition of claim 22 or the immunoconjugate of claim 23 for use in the treatment of any disease, disorder, or condition susceptible of being improved or prevented by one of the following selected from the group consisting of: (i) an increase or enhancement in FGFR2b signaling; (ii) an increase in the proliferation of lung epithelial cells; and (iii) an increase in the proliferation alveolar type II (AT2) progenitor cells or alveolar type II (AT2) cells.

27. The molecule of any one of claims 1 to 21 or the pharmaceutical composition of claim 22 or the immunoconjugate of claim 23 for use in the treatment or prevention of fibrosis or inflammation in an individual in need thereof.

28. The molecule or pharmaceutical composition or immunoconjugate for the use of claim 27, wherein the fibrosis or inflammation is selected from fibrosis or inflammation of lung, heart, blood vessel, liver, bile duct, small intestine, large intestine, pancreas, kidney, eye, brain, skin, oral mucosa, thymus, bone marrow, or muscle tissue.

29. The molecule or pharmaceutical composition or immunoconjugate for the use of claim 28, wherein (i) the fibrosis or inflammation of lung is selected from the group consisting of pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis, scleroderma, chronic obstructive pulmonary disease (COPD), obstructive bronchitis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS associated pulmonary hypertension, sarcoidosis, interstitial lung tumor, and asthma; (ii) the fibrosis or inflammation of liver or bile duct is selected from the group consisting of non-alcoholic steatohepatitis, or alcoholic steatohepatitis, or cholangitis, or Alagille syndrome; (iii) the fibrosis or inflammation of pancreas is pancreatitis; (iv) the fibrosis or inflammation of kidney is selected from the group consisting of chronic kidney disease or acute kidney disease; (v) the fibrosis or inflammation of the oral mucosal is oral mucositis; (vi) the fibrosis or inflammation of the skin is diabetic foot ulcer or epidermolysis bullosa; (vii) the fibrosis or inflammation of the thymus is graft-versus-host disease (GvHD); and (viii) the fibrosis or inflammation of the small or large intestine is an inflammatory bowel disease (IBD), optionally wherein the IBD is ulcerative colitis (UC) or Crohn’s disease.

30. Use of molecule of any one of claims 1 to 21 or the pharmaceutical composition of claim 22 or the immunoconjugate of claim 23, in the manufacture of a medicament for the treatment or prevention of a disease, or disorder, or condition related to injury of lung epithelial cells in an individual in need thereof.

31. A method of treating a disease, or disorder, or condition related to injury of lung epithelial cells in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of the molecule of any one of claims 1 to 21, or the pharmaceutical composition of claim 22, or the immunoconjugate of claim 23.

32. The use of claim 30, or the method of claim 31, wherein the condition related to the injury of lung epithelial cells in an individual is selected from the group consisting of fibrosis of the lungs, inflammation of the lungs, senescence-related fibrosis of the lungs, asthma, a condition associated with exposure to environmental toxins, a condition associated with exposure to bacteria, a condition associated with exposure to a virus, cystic fibrosis, a pneumonectomy, a condition associated with exposure to radiation, a condition associated with exposure to tobacco smoke or chemicals, and bleomycin mediated epithelial injury.

33. The use of claim 30, or the method of claim 31, wherein the condition related to the injury of lung epithelial cells in an individual is one susceptible of being improved or prevented by one of the following selected from the group consisting of: (i) an increase or enhancement in FGFR2b signaling; (ii) an increase in the proliferation of lung epithelial cells; and (iii) an increase in the proliferation of alveolar type II (AT2) progenitor cells or alveolar type II (AT2) cells.

34. Use of the molecule of any one of claims 1 to 21 or the pharmaceutical composition of claim 22 or the immunoconjugate of claim 23 in the manufacture of a medicament for the treatment or prevention of fibrosis or inflammation in an individual in need thereof.

35. A method of treating fibrosis or inflammation in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of the molecule of any one of claims 1 to 21 or the pharmaceutical composition of claim 22 or the immunoconjugate of claim 23.

36. The use of claim 34, or the method of claim 35, wherein the fibrosis or inflammation is selected from fibrosis or inflammation of lung, heart, blood vessel, liver, bile duct, small intestine, large intestine, pancreas, kidney, eye, brain, skin, oral mucosa, thymus, bone marrow, or muscle tissue.

37. The use of claim 34, or the method of claim 35, wherein (i) the fibrosis or inflammation of lung is selected from the group consisting of pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis, scleroderma, chronic obstructive pulmonary disease (COPD), obstructive bronchitis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS associated pulmonary hypertension, sarcoidosis, interstitial lung tumor, and asthma; (ii) the fibrosis or inflammation of liver or bile duct is selected from the group consisting of non-alcoholic steatohepatitis, or alcoholic steatohepatitis, or cholangitis, or Alagille syndrome; (iii) the fibrosis or inflammation of pancreas is pancreatitis; (iv) the fibrosis or inflammation of kidney is selected from the group consisting of chronic kidney disease or acute kidney disease; (v) the fibrosis or inflammation of the oral mucosal is oral mucositis; (vi) the fibrosis or inflammation of the skin is diabetic foot ulcer or epidermolysis bullosa; (vii) the fibrosis or inflammation of the thymus is graft-versus-host disease (GvHD); and (viii) the fibrosis or inflammation of the small or large intestine is an inflammatory bowel disease (IBD), optionally wherein the IBD is ulcerative colitis (UC) or Crohn’s disease.

38. An isolated nucleic acid encoding the molecule of any one of claims 1 to 21 or a plurality of isolated nucleic acids encoding the molecule of any one of claims 1 to 21.

39. A host cell comprising the nucleic acid or the plurality of nucleic acids of claim 38.

40. A method of producing the molecule, or a process for producing the molecule comprising the following steps (a) culturing the host cell of claim 39, and (b) recovering the molecule that is produced in step (a).

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