CN116829594A - Antibody specifically recognizing FasL and application thereof - Google Patents

Antibody specifically recognizing FasL and application thereof Download PDF

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CN116829594A
CN116829594A CN202380009454.2A CN202380009454A CN116829594A CN 116829594 A CN116829594 A CN 116829594A CN 202380009454 A CN202380009454 A CN 202380009454A CN 116829594 A CN116829594 A CN 116829594A
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王广菲
任晓叶
李忠
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Beijing Solobio Genetechnology Co Ltd
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Abstract

Antibodies or antigen binding fragments that specifically recognize FasL, methods of making and uses thereof are disclosed.

Description

Antibody specifically recognizing FasL and application thereof
Cross Reference to Related Applications
The present application claims priority to chinese patent application No. 202210069822.X, filing date 2022.01.21, entitled "antibody specifically recognizing FasL and use thereof", and the entire contents of this application are incorporated herein by reference.
Reference to an electronic sequence Listing
The contents of the electronic sequence Listing (text name: CN_202201070662_SEQLIST. Xml, recording date: 2022.08.03, size: 137 KB) are incorporated herein by reference in their entirety.
Technical Field
The present application relates to antibodies or antigen binding fragments that specifically recognize FasL, and methods of making and using the same.
Background
FasL (CD 95L) is one of the transmembrane proteins and pro-apoptotic members of the Tumor Necrosis Factor (TNF) superfamily. The extracellular domain of FasL comprises a ligand dimer and a receptor binding domain (TNF homology domain, THD), whereas the intracellular domain of FasL is involved in various signaling pathways, especially as a T cell receptor costimulatory molecule during T cell activation
calcon-Hamat, flavia et al Cytokine vol.75,2 (2015): 228-33.). The intracellular portion of FasL contains an extended polyproline region capable of interacting with proteins having a proline binding motif, such as Src homology 3 (SH 3) and WW domains (Wenzel, J et al FEBS letters vol.509,2 (2001): 255-62.; blott, E J et al journal of cell science vol.114, pt 13 (2001): 2405-16.). In addition, there are several tyrosine phosphorylation sites and a "double" casein kinase phosphorylation motif. The FasL protein has two forms, a membrane-bound protein and a soluble protein. The soluble form is produced by alternative splicing or proteolytic hydrolysis of the membrane bound form. Under physiological conditions, fasL expression in cells of the innate and adaptive immune system and immune privileged sites, such as the eye, placenta or testis, is severely controlled and restricted (Stenqvist, ann-Christin et al journal of immunology (Baltimore, md.: 1950) vol.191,11 (2013): 5515-23.). FasL is expressed on the surface of two major immune effector cells, namely activated T cells and Natural Killer (NK) cells, but also on macrophages, neutrophils and dendritic cells (Kiener, P.A. et al Journal of experimental medicine vol.185,8 (1997): 1511-6.; lie, W.C. et al Journal of experimental medicine vol.184,2 (1996): 429-40.Doi: 10.1084/jem.184.2.429.). FasL expression can be induced by TCR (T cell receptor) activation, or can be regulated by transcription after cytokine stimulation, in particular Interferon (INF) stimulation (Tsutsui, H et al journal of immunology (Baltimore, md.: 1950) vol.157,9 (1996): 3967-73).
The Fas receptor (CD 95/APO-1) is one of the members of the TNF receptor superfamily. Fas protein has two forms, membrane-bound protein and soluble protein, and Fas exists mainly in membrane-bound form. Whereas soluble Fas protein, due to the lack of transmembrane domains, cannot interact with FasL to induce apoptosis, and therefore it plays a regulatory role in apoptosis, such as inhibiting membrane-bound Fas (mFas) -induced apoptosis (Jee, youngheun et al. Journal of veterinary science vol.11,2 (2010): 115-9.). The extracellular domain of the mFas protein comprises three cysteine-rich domains (CRDs), which are structural features of the TNF receptor family (Zhang, gongyi. Current opinion in structural biology vol.14,2 (2004): 154-60.). The C-terminus of the intracellular domain of the Fas protein contains the Death Domain (DD), which is essential for the induction of apoptosis and is also characteristic of this subset of death receptors (Chan, F K et al science (New York, N.Y.) vol.288,5475 (2000): 2351-4.). Fas is expressed in multiple organ tissues, especially in peripheral blood T and B lymphocytes, NK cells, monocyte cells, fibroblasts, endothelial cells, epithelial cells, etc. (Wang, mei, and Ping Su. Systems biology in reproductive medicine vol.64,2 (2018): 93-102.).
In the Fas-mediated apoptotic pathway, binding of FasL drives Fas aggregation and binding of Fas to Fas binding protein (FADD). FADD recruits caspase-8 and caspase-10 to form Death Inducing Signal Complexes (DISC) (Wilson, nicholas S et al nature immunology vol.10,4 (2009): 348-55.). DISC is activated by specific post-translational modifications of the Death Receptor (DR) such as palmitoylation and O-linked glycosylation (muppi, jagan R, and Richard M siegel. Nature immunology vol.5,2 (2004): 182-9.; wagner, klaus W et al nature media vol.13,9 (2007): 1070-7). DISC mediates autocatalytic treatment and activation of caspase-8 and caspase-10, which amplify death signals by proteolytic action of caspases such as caspase-3, caspase-6 and caspase-7. In type I cells (e.g., thymocytes), the action of cysteine proteases is sufficient to induce apoptosis. In contrast, in type II cells (e.g., B cells), apoptosis requires cysteine protease-8 mediated cleavage of BH 3-interacting domain death agonists (Bid), a BH 3-only protein that increases the permeability of the mitochondrial outer membrane and release of cytochrome c. Cytochrome c, upon release from mitochondria, can be involved as a cofactor in the assembly of a cytosolic caspase-activating complex called an apoptotic body that amplifies caspase cascade activation (Wagner, klaus W et al nature media vol.13,9 (2007): 1070-7).
Cell death is not the only cellular response caused by Fas activation. Fas is also able to induce NF- κB signaling. Downstream of the cellular caspase-8 like inhibitor protein (cFLIP) and TRAF2 acting in the Fas signaling pathway, T cell proliferation can be induced by NF-. Kappa.B activation (Kataoka, takao, and Murg Tschopp.molecular and cellular biology vol.24,7 (2004): 2627-36.). The N-terminal cleavage products p43FLIP and p22FLIP induced NF-. Kappa.B activation by binding to the IKK complex (Golks, alexander et al, the Journal of experimental medicine vol.203,5 (2006): 1295-305.; krammer, peter H et al Nature reviews.immunology vol.7,7 (2007): 532-42.). In addition, overexpression of cFLIP inhibits Fas-induced apoptosis of activated T cells (Van Parijs, L et al, "Autoimmunity as a consequence of retrovirus-mediated expression of C-FLIP in antibodies," Immunity vol.11,6 (1999): 763-70.; kirchhoff, S et al journal of immunology (Baltimore, md.: 1950) vol.165,11 (2000): 6293-300.). In addition, fas signaling regulates peripheral T cell homeostasis by regulating the balance between proliferation and cell death, for example, in primitive and memory T cell subsets (Jaleco, sara et al journal of immunology (Baltimore, md.: 1950) vol.171,1 (2003): 61-8.). Thus, homeostasis of peripheral T cells may be maintained by the dual effects of FasL/Fas signaling.
The Fas-FasL signaling pathway is associated with the development and progression of a variety of diseases, including autoimmune diseases, graft rejection, spinal cord injury, sepsis, and the like. Therefore, the development of inhibitors against the FasL target is of great importance.
Currently, there have been reports on FasL inhibitors, for example, in chinese patent CN1283662C, which disclose antagonistic anti-hFAS ligand antibodies and their use; chinese patent CN108290950B discloses an anti-FasL antibody 119-4A (as a control antibody in the examples section of the present application) and its use; chinese patent CN104662039B discloses Fas-Fc fusion protein APG101 (as a control in the examples section of the present application) and its use. There remains a need in the art for high affinity, high bioactivity anti-FasL antibodies.
The disclosures of all publications, patents, patent applications, and published patent applications mentioned herein are incorporated by reference in their entirety.
Summary of the application
In some embodiments, an isolated anti-FasL antibody is provided comprising: (i) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO 99 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:127 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (ii) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO:100 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 128 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (iii) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO:101 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:129 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (iv) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO:102 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:130 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (v) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO:103 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO. 131 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (vi) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO 104 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising, for exampleV shown in amino acid sequence SEQ ID NO. 132 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (vii) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO 105 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:133 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (viii) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO:106 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 134 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (ix) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO:107 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:135 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (x) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 108 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:136 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xi) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 109 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 137 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xii) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 110 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:138 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xiii) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO:111 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 139 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xiv) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO 112 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:140 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xv)V H Comprising V as shown in amino acid sequence SEQ ID NO:113 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:141 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xvi) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO:114 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:142 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xvii) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO 115 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:143 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xviii) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO:116 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO. 144 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xix) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 117 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in the amino acid sequence SEQ ID NO:145 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xx) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO:118 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 146 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xxi) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO:119 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:147 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xxii) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO:120 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:148 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xxiii) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO:121 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:149 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xxiv) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 122 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:150 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xxv) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 123 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:151 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xxvi) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO 124 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 152 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xxvii) V (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 125 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 153 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; or (xxviii) V H Comprising V as shown in amino acid sequence SEQ ID NO:126 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 154 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, an isolated anti-FasL antibody is provided comprising: (i) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:67, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:77; (ii) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, andHC-CDR3 comprising the amino acid sequence SEQ ID NO 32; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:78; (iii) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:51, LC-CDR2 comprising amino acid sequence SEQ ID NO:67, and LC-CDR3 comprising amino acid sequence SEQ ID NO:79; (iv) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:33; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:80; (v) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:34; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:81; (vi) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO 53, LC-CDR2 comprising amino acid sequence SEQ ID NO 69, and LC-CDR3 comprising amino acid sequence SEQ ID NO 82; (vii) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 21, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 36; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO. 54, LC-CDR2 comprising amino acid sequence SEQ ID NO. 70, and LC-CDR3 comprising amino acid sequence SEQ ID NO. 83; (viii) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:84; (ix) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:85; (x) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:85; (xi) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:85; (xii) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising an amino groupAn acid sequence SEQ ID NO. 55, an LC-CDR2 comprising an amino acid sequence SEQ ID NO. 72, and an LC-CDR3 comprising an amino acid sequence SEQ ID NO. 85; (xiii) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:85; (xiv) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:56, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:85; (xv) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:86; (xvi) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 9, HC-CDR2 comprising the amino acid sequence SEQ ID NO 26, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO 57, LC-CDR2 comprising amino acid sequence SEQ ID NO 73, and LC-CDR3 comprising amino acid sequence SEQ ID NO 87; (xvii) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 27, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 40; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 58, LC-CDR2 comprising the amino acid sequence73, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 88; (xviii) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 10, HC-CDR2 comprising the amino acid sequence SEQ ID NO 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 41; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO 59, LC-CDR2 comprising amino acid sequence SEQ ID NO 68, and LC-CDR3 comprising amino acid sequence SEQ ID NO 89; (xix) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:90; (xx) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 42; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 60, LC-CDR2 comprising the amino acid sequence SEQ ID NO 74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 91; (xxi) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 29, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 43; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:61, LC-CDR2 comprising amino acid sequence SEQ ID NO:75, and LC-CDR3 comprising amino acid sequence SEQ ID NO:92; (xxii) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 29, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 44; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO. 62, LC-CDR2 comprising the amino acid sequence SEQ ID NO. 75, and LC-CDR3 comprising the amino acid sequenceSEQ ID NO:93；(xxiii)V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 13, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 30, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 45; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO. 63, LC-CDR2 comprising amino acid sequence SEQ ID NO. 73, and LC-CDR3 comprising amino acid sequence SEQ ID NO. 94; (xxiv) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 14, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 46; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:95; (xxv) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 15, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 47; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO. 64, LC-CDR2 comprising the amino acid sequence SEQ ID NO. 68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO. 96; (xxvi) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 16, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 31, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 48; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:65, LC-CDR2 comprising amino acid sequence SEQ ID NO:76, and LC-CDR3 comprising amino acid sequence SEQ ID NO:97; (xxvii) V (V) H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 17, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 49; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO 66, LC-CDR2 comprising amino acid sequence SEQ ID NO 74, and LC-CDR3 comprising amino acid sequence SEQ ID NO 98; or (xxviii) V H The saidV H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 17, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 50; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:60, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:91.
In some embodiments, any of the isolated anti-FasL antibodies described above, comprising: v (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 99 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 99; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 127 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 127; (ii) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 100 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 100; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 128 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 128; (iii) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 101 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 101; v (V) L Comprising the amino acid sequence shown in SEQ ID NO. 129 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 129; (iv) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 102 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 102; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 130 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 130; (v) V (V) H Comprising the amino acid sequence shown in SEQ ID NO. 103 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 103; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 131 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 131; (vi) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 104 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 104; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 132 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 132; (vii) V (V) H Comprising the amino acid sequence shown in SEQ ID NO. 105 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 105; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 133 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 133; (viii) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 106 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 106; v (V) L Comprising the amino acid sequence shown in SEQ ID NO. 134 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 134; (ix) V (V) H Comprising the amino acid sequence shown in SEQ ID NO. 107 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 107; v (V) L Comprising the amino acid sequence shown in SEQ ID NO. 135 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 135; (x) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 108 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 108; v (V) L Comprising the amino acid sequence shown in SEQ ID NO. 136 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 136; (xi) V (V) H Comprising the amino acid sequence shown in SEQ ID NO. 109 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 109The method comprises the steps of carrying out a first treatment on the surface of the V (V) L Comprising the amino acid sequence shown in SEQ ID NO. 137 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 137; (xii) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 110 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 110; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 138 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 138; (xiii) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 111 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 111; v (V) L Comprising the amino acid sequence shown as SEQ ID NO. 139 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 139; (xiv) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 112 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 112; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 140 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 140; (xv) V (V) H Comprising the amino acid sequence shown in SEQ ID NO. 113 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 113; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 141 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 141; (xvi) V (V) H Comprising the amino acid sequence shown in SEQ ID NO. 114 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 114; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 142 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 142; (xvii) V (V) H Comprising the amino acid sequence shown as SEQ ID NO. 115 or a variant thereof having at least the amino acid sequence shown as SEQ ID NO. 115About 80% sequence identity; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 143 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 143; (xviii) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 116 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 116; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 144 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 144; (xix) V (V) H Comprising the amino acid sequence shown as SEQ ID NO. 117 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 117; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 145 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 145; (xx) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 118 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 118; v (V) L Comprising the amino acid sequence shown as SEQ ID NO. 146 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 146; (xxi) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 119 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 119; v (V) L Comprising the amino acid sequence shown in SEQ ID NO. 147 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 147; (xxii) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 120 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 120; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 148 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 148; (xxiii) V (V) H Comprising the amino acid sequence shown in SEQ ID NO. 121 or a variant thereof, which variant is identical to the amino acid sequence shown in SEQ ID NO. 121 The base acid sequences have at least about 80% sequence identity; v (V) L Comprising the amino acid sequence shown as SEQ ID NO. 149 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 149; (xxiv) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 122 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 122; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 150 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 150; (xxv) V (V) H Comprising the amino acid sequence shown in SEQ ID NO. 123 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 123; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 151 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 151; (xxvi) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 124 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 124; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 152 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 152; (xxvii) V (V) H Comprising the amino acid sequence set forth in SEQ ID NO. 125 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 125; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 153 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 153; or (xxviii) V H Comprising the amino acid sequence set forth in SEQ ID NO. 126 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 126; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 154 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 154.
In some embodiments, an isolated anti-FasL antibody is provided that competes with any of the isolated anti-FasL antibodies described above for specific binding to FasL. In some embodiments, an isolated anti-FasL antibody is provided that specifically binds to the same epitope as any of the isolated anti-FasL antibodies described above.
In some embodiments, any of the isolated anti-FasL antibodies described above comprises an Fc fragment. In some embodiments, the isolated anti-FasL antibody is a full-length IgG antibody. In some embodiments, the isolated anti-FasL antibody is a full length IgG1 or IgG4 antibody. In some embodiments, the isolated anti-FasL antibody is a chimeric, fully human or humanized antibody. In some embodiments, the isolated anti-FasL antibody is an antigen binding fragment selected from the group consisting of Fab, fab ', F (ab)' 2 Fab' -SH, single chain Fv (scFv), fv fragments, dabs, fd, nanobodies (nanobodies), diabodies (diabodies) and linear antibodies.
In some embodiments, an isolated nucleic acid molecule is provided that encodes any of the anti-FasL antibodies described above. In some embodiments, a vector is provided, the vector comprising any one of the nucleic acid molecules described above. In some embodiments, a host cell is provided that comprises any of the anti-FasL antibodies described above, any of the nucleic acid molecules described above, or any of the vectors described above. In some embodiments, a method of making an anti-FasL antibody is provided comprising: a) Culturing any of the above host cells under conditions effective to express an anti-FasL antibody; and b) obtaining the expressed anti-FasL antibody from the host cell.
In some embodiments, there is provided a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of any one of the anti-FasL antibodies as described above. In some embodiments, there is provided the use of any one of the anti-FasL antibodies described above in the manufacture of a pharmaceutical composition for treating a disease or disorder in a subject in need thereof. In some embodiments, there is provided the use of any one of the anti-FasL antibodies or a pharmaceutical composition comprising an anti-FasL antibody as described above in the manufacture of a medicament for treating a disease or disorder. In some embodiments, the disease or disorder is associated with the FasL-Fas signaling pathway, including inflammatory diseases, cancer, or autoimmune diseases or disorders. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer.
Also provided are pharmaceutical compositions, kits and articles of manufacture comprising any of the anti-FasL antibodies described above.
Detailed description of the application
In one aspect, the application provides anti-FasL antibody molecules. Through natural scFv phage library screening, a combination of appropriately designed biochemical and biological experiments, and antibody humanization, highly potent antibody molecules have been identified that are capable of binding to human FasL and inhibiting the action of human FasL on its receptor. The results presented herein demonstrate that the antibodies of the present application have better biological activity than known anti-FasL antibodies.
anti-FasL antibodies provided herein include, for example, full-length anti-FasL antibodies, anti-FasL single chain antibodies (scFvs), anti-FasL Fc fusion proteins, multispecific (e.g., bispecific) anti-FasL antibodies, anti-FasL immunoconjugates, and the like.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO 99 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising, for example, amino acidsV shown in SEQ ID NO. 127 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:100 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 128 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:101 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:129 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:102 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:130 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:103 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO. 131 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO 104 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO. 132 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO 105 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:133 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:106 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 134 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:107 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:135 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 108 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:136 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 109 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 137 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 110 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:138 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising an amino acid sequence as set forth in SEQ ID NO. 111V shown H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 139 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO 112 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:140 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:113 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:141 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:114 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:142 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO 115 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:143 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:116 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO. 144 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 117 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in the amino acid sequence SEQ ID NO:145 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:118 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 146 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:119 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:147 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:120 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:148 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:121 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:149 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 122 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:150 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the present applicationProviding an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 123 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:151 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO 124 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 152 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO. 125 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 153 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In another aspect, the application provides an anti-FasL antibody comprising: v (V) H Comprising V as shown in amino acid sequence SEQ ID NO:126 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 154 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
Also provided are nucleic acids encoding anti-FasL antibodies, compositions comprising anti-FasL antibodies, and methods of making and using anti-FasL antibodies.
Definition of the definition
As used herein, a "treatment" or "treatment" is a method of achieving a beneficial or desired result, including clinical results. In view of the objects of the present application, such beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms caused by the disease, alleviating the extent of the disease, stabilizing the disease (e.g., preventing or delaying exacerbation of the disease), preventing or delaying the spread of the disease (e.g., metastasis), preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, alleviating the disease (partially or wholly), reducing the dosage of one or more other drugs required to treat the disease, delaying the progression of the disease, improving or enhancing quality of life, increasing weight, and/or prolonging survival. Meanwhile, "treatment" also includes reduction of disease pathology results (e.g., tumor volume for cancer). The methods of the present application contemplate any one or more aspects of these treatments.
The term "antibody" includes full length antibodies and antigen binding fragments thereof. Full length antibodies include two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen binding. The variable region in both chains typically comprises 3 hypervariable loops, known as Complementarity Determining Regions (CDRs) (light chain (LC) CDRs comprise LC-CDR1, LC-CDR2 and LC-CDR3, and Heavy Chain (HC) CDRs comprise HC-CDR1, HC-CDR2 and HC-CDR 3). CDR boundaries of the antibodies or antigen binding fragments disclosed herein may be defined or recognized by Kabat, chothia or Al-Lazikani conventions (Al-Lazikani 1997;Chothia 1985;Chothia 1987;Chothia 1989;Kabat 1987;Kabat 1991). The 3 CDR regions of the heavy or light chain are inserted between flanking segments called Framework Regions (FRs) which are more conserved than the CDR regions and form a scaffold supporting the hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen binding, but exhibit multiple effector functions. Antibodies are classified based on the amino acid sequence of their heavy chain constant regions. The five main classes or isotypes of antibodies are IgA, igD, igE, igG and IgM, which are characterized by having heavy chains of the alpha, delta, epsilon, gamma and mu types, respectively. Several major antibody classes are classified into subclasses, such as IgG1 (gamma 1 heavy chain), igG2 (gamma 2 heavy chain), igG3 (gamma 3 heavy chain), igG4 (gamma 4 heavy chain), igA1 (alpha 1 heavy chain), or IgA2 (alpha 2 heavy chain).
As used herein, the term "antigen-binding fragment" includes antibody fragments, e.g., diabodies (diabodies), fab ', F (ab') 2 Fv fragment, disulfide stabilized Fv fragment (dsFv), (dsFv) 2 Bispecific dsFv (dsFv-dsFv'), disulfide stabilized diabodies (ds diabodies), single chain Fv (scFv), scFv dimers (diabodies), multi-t consisting of antibody fragments comprising one or more CDRsA specific antibody, a single domain antibody, a nanobody (nanobody), a domain antibody, a bivalent domain antibody, or any other antibody fragment capable of binding an antigen but not comprising the complete antibody structure. The antigen binding fragment is capable of binding the same antigen as the parent antibody or parent antibody fragment (e.g., parent scFv). Antigen binding fragments also include fusion proteins comprising the above antibody fragments. In some embodiments, an antigen binding fragment may include one or more CDRs from a particular human antibody grafted to a framework region from one or more different human antibodies.
As used herein, the term "epitope" refers to a specific group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. If two antibodies or antibody portions exhibit competitive binding to an antigen, they may bind to the same epitope on the antigen.
As used herein, a first antibody "competes" with a second antibody for binding to a FasL target when the second antibody inhibits binding to the FasL target by at least 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) at an equimolar concentration, and vice versa. PCT publication WO 03/48731 describes a high throughput antibody "epitope categorization" method based on cross-competition.
As used herein, the term "specifically binds," "specifically recognizes," or "specific for," refers to a measurable and reproducible interaction, e.g., binding of an antibody to a target can determine the presence of the target in a heterogeneous population of molecules, including biomolecules. For example, an antibody being able to specifically recognize a target (which may be an epitope) means that the antibody binds to the target with a higher affinity, avidity, easier and/or longer lasting than other targets. In some embodiments, an antibody that specifically recognizes an antigen reacts with one or more antigenic determinants of the antigen with a binding affinity that is at least 10-fold greater than its binding affinity to other targets.
As used herein, an "isolated" anti-FasL antibody refers to an anti-FasL antibody that (1) is independent of naturally occurring proteins, (2) does not contain other proteins of the same origin, (3) is expressed by cells of different species, or (4) does not occur in nature.
As used herein, the term "isolated nucleic acid" refers to nucleic acids of genomic, cDNA, or synthetic origin, or a combination thereof. According to its origin, the term "isolated nucleic acid" means (1) not related to all or part of the polynucleotide found in nature in "isolated nucleic acid" (2) operably linked to a polynucleotide not linked thereto in nature, or (3) not present in nature as part of a longer sequence.
As used herein, the term "CDR" or "complementarity determining region" means a discontinuous antigen binding site found within the variable domains of heavy and light chain polypeptides. J.biol.chem.252:6609-6616 (1977); kabat et al, U.S. Dept. Of Health and Human Services, "Sequences of proteins of immunological interest" (1991); chothia et al, J.mol.biol.196:901-917 (1987); al-Lazikani B.et Al, J.mol.biol.,273:927-948 (1997); macCallum et al, J.mol. Biol.262:732-745 (1996); abhinandan and Martin, mol. Immunol.,45:3832-3839 (2008); lefranc M.P.et al, dev.Comp.Immunol.,27:55-77 (2003); and honeygger and Pluckthun, J.mol.biol.,309:657-670 (2001), wherein these definitions include the coincidence or subset of amino acid residues when compared to each other. However, any definition of a CDR for an antibody or grafted antibody or variant thereof is intended to be included within the terms defined and used herein. The positions of the amino acid residues comprised by the CDRs defined by the various references cited above are listed in table 1 to illustrate the comparison. Algorithms and binding interfaces for CDR prediction are known in the art, including, for example, abhinandan and Martin, mol.immunol.,45:3832-3839 (2008); ehrenmann F.et al, nucleic Acids Res.,38:D301-D307 (2010); and Adolf-Bryfogle J.et al, nucleic Acids Res.,43:D432-D438 (2015). The content of the references cited in this paragraph is hereby incorporated by reference in its entirety for the purposes of the present application and possibly in one or more of the claims contained herein.
TABLE 1 CDR determinationMeaning of 1 Amino acid residue numbering refers to the nomenclature used in Kabat et al, supra 2 Amino acid residue numbering refers to the nomenclature used in Chothia et al, supra 3 Amino acid residue numbering refers to the nomenclature used in MacCallum et al, supra 4 Amino acid residue numbering refers to the nomenclature used in the above-mentioned Lefranc et al 5 Amino acid residue numbering refers to the naming method in Honygger and Pluckthun, supra
The term "chimeric antibody" refers to an antibody in which a portion of the heavy and/or light chain is identical or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they possess the biological activity of the application (see U.S. patent No.4,816,567; and Morrison et al, proc.Natl. Acad. Sci. USA,81:6851-6855 (1984)).
"Fv" is the smallest antibody fragment that contains the complete antigen recognition and binding site. The fragment is a dimer formed by a tight non-covalent linkage of one heavy chain variable domain and one light chain variable domain. By folding of these two domains, 6 hypervariable loops (3 loops in each of the light and heavy chains) were derived, which Gao Bianhuan provided the amino acid residues for the antibody to bind antigen and confer specificity to the antibody for binding to antigen. However, even a single variable domain (or half of an Fv fragment, which contains only 3 CDRs specific for an antigen) has the ability to recognize and bind antigen, although with less affinity than the complete binding site.
"Single chain Fv", also abbreviated "sFv" or "scFv", is a polypeptide comprising V linked as a single polypeptide chain H And V L Antibody fragments of the antibody domains. In some embodiments of the present invention, in some embodiments,the scFv polypeptide further comprises V H And V L A linker polypeptide between the domains, which allows the scFv to form the desired structure for antigen binding. For a summary of scFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol.113, rosenburg and Moore eds., springer-Verlag, new York, pp.269-315 (1994).
The term "diabody" is in V H And V L A small antibody fragment prepared from scFv fragments (see above) is constructed using short linkers (e.g., 5-10 residues) between the domains, which allows the variable domains to pair between the chains rather than within the chains, resulting in a bivalent fragment, i.e., a fragment having two antigen binding sites. Bispecific diabodies are heterodimers of two "cross" scFv fragments, wherein V of both antibodies H And V L Domains are located on different polypeptide chains. In EP 404,097; WO 93/11161; diabodies are described fully in Hollinger et al, proc.Natl.Acad.Sci.USA,90:6444-6448 (1993).
The "humanized" form of a non-human (e.g., rodent) antibody is a chimeric antibody that includes minimal sequences from the non-human antibody. In most cases, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (HVR) of the recipient antibody are replaced by residues from a hypervariable region of a non-human species, such as mouse, rat, rabbit or non-human mammal, having the desired antibody specificity, affinity and properties (donor antibody). In some cases, residues in the framework region of the human immunoglobulin are replaced with corresponding non-human residues. In addition, humanized antibodies may include residues that are not present in either the recipient antibody or the donor antibody. These modifications can further improve the performance of the antibody. Typically, a humanized antibody will comprise substantially all, at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are human immunoglobulin sequences. The human antibody optionally also includes at least a portion of an immunoglobulin constant region (Fc), typically a constant region of a human immunoglobulin. For specific details, reference may be made to Jones et al, nature 321:522-525 (1986); riechmann et al, nature 332:323-329 (1988); and Presta, curr.Op.struct.biol.2:593-596 (1992).
The "percent (%) amino acid sequence identity" or "homology" of the polypeptide and antibody sequences identified herein is defined as: sequence comparison is performed where conservative substitutions are considered to be part of the sequence identity, the percentage of amino acid residues in the candidate sequence that are identical to the polypeptide sequence to be compared. The percentage of amino acid sequence identity may be determined by a variety of alignment methods within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, megalign (DNASTAR), or MUSCLE software. One skilled in the art can determine suitable parameters for measuring the alignment, including any algorithms needed to achieve maximum alignment over the full length of the compared sequences. However, for purposes herein, the percent amino acid sequence identity values were generated using the sequence alignment computer program MUSCLE (Edgar, R.C., nucleic Acids Research (5): 1792-1797,2004; edgar, R.C., BMC Bioinformatics (1): 113,2004).
The term "Fc receptor" or "FcR" is used to describe a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR of the application is one that binds an IgG antibody (a gamma receptor), including receptors of the fcyri, fcyrii, and fcyriii subclasses, including allelic variants and alternatively spliced forms of these receptors. Fcyrii receptors include fcyriia ("activating receptor") and fcyriib ("inhibiting receptor"), which have similar amino acid sequences, differing primarily in the cytoplasmic domain. The cytoplasmic domain of the activating receptor fcyriia contains an immune receptor tyrosine activation motif (ITAM). The cytoplasmic domain of the inhibition receptor fcyriib contains the Immunoreceptor Tyrosine Inhibitory Motif (ITIM) (see m.in Annu.Rev.Immunol.15:203-234 (1997)). The term also includes allotypes, such as fcyriiia allotypes: fcgammaRIIIA-Phe 158, fcgammaRIIIA-Val 158, fcgammaRIIA-R131 and/or FcgammaRIIA-H131. In Ravetch and Kinet, annu.Rev.Immunol 9:457-92 (1991) and Capel et al, immunomets 4:25-34 (1994); fcRs are described in de Haas et al, J.Lab.Clin.Med.126:330-41 (1995). The term FcR in the present application encompasses other types of FcRs, including FcRs identified in the future. The term FcR also includes the neonatal receptor FcRn, which is responsible for transferring the parent IgGs to the neonate (Guyer et al, J.Immunol.117:587 (1976) and Kim et al, J.Immunol.24:249 (1994)).
The term "FcRn" refers to neonatal Fc receptor (FcRn). FcRn is structurally similar to the Major Histocompatibility Complex (MHC), consisting of non-covalent binding of the alpha chain to beta 2 microglobulin. The various functions of the neonatal Fc receptor FcRn are reviewed in Ghetie and Ward (2000) Annu. Rev. Immunol.18,739-766. FcRn plays an important role in the passive transport of immunoglobulin IgGs from the mother to neonates and in the regulation of serum IgG levels. FcRn acts as a salvage receptor that can bind and transport endocytosed IgG in intact form within and between cells and protect them from the default degradation pathway.
The "CH1 domain" of the human IgG heavy chain constant region typically extends from amino acid 118 to amino acid 215 (EU numbering system).
The "hinge region" is generally defined as extending from Glu at position 216 to Pro at position 230 of human IgG1 (Burton, molecular immunol.22:161-206 (1985)). The hinge regions of other IgG isotypes can be aligned with the IgG1 sequence by placing the first and last cysteine residues that form the inter-heavy chain disulfide bond in the same position as IgG 1.
The "CH2 domain" of the human IgG Fc region typically extends from amino acid 231 to amino acid 340. The CH2 domain is unique in that it does not mate tightly with another region, but rather inserts two N-terminally linked branched carbohydrate chains between the two CH2 domains of the intact native IgG molecule. It is speculated that carbohydrates may serve as a surrogate for domain-to-domain pairing, helping to keep the CH2 domain stable. Burton, molecular. Immunol.22:161-206 (1985).
The "CH3" domain includes the extension from the C-terminal residue to the CH2 domain (from amino acid 341 to the C-terminal end of the antibody sequence, typically amino acid 446 or 447 of IgG) within the Fc region.
The "functional Fc fragment" has the "effector function" possessed by the native Fc region sequence. Exemplary "effector functions" include C1q binding; complement Dependent Cytotoxicity (CDC); fc receptor binding; antibody dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down-regulation of cell surface receptors (e.g., B cell receptors; BCR), and the like. Such effector functions typically require that the Fc region bind to a binding domain (e.g., an antibody variable region) and can be assessed using a variety of experimental methods well known in the art.
Antibodies to IgG Fc variants having "altered" FcR binding affinity or ADCC activity have increased or decreased FcR binding activity and/or ADCC activity compared to the parent polypeptide or polypeptide comprising the native Fc sequence. Fc variants exhibiting "enhanced binding" to FcR have a higher binding affinity (e.g., lower apparent Kd or IC) to at least one FcR than the parent polypeptide or polypeptide comprising the native IgG Fc sequence 50 Values). In some embodiments, the binding capacity is increased by a factor of 3, e.g., 5, 10, 25, 50, 60, 100, 150, 200, even up to a factor of 500 or the binding capacity is increased by a factor of 25% to 1000% as compared to the parent polypeptide. Fc variants exhibiting "reduced binding" to FcR, which have lower affinity (e.g., higher apparent Kd or IC) for at least one FcR than the parent polypeptide 50 Values). Its binding capacity is reduced by 40% or more compared to the parent polypeptide.
"antibody-dependent cell-mediated cytotoxicity" or "ADCC" is a form of cytotoxicity that refers to the binding of secreted Ig to Fc receptors (FcRs) present on certain cytotoxic cells, such as natural killer cells (NK), neutrophils, and macrophages, enabling these cytotoxic effector cells to specifically bind antigen-bearing target cells, followed by killing of the target cells with cytotoxins. Antibodies "arm" cytotoxic cells and are necessary for such killing. In the major cell types mediating ADCC NK cells express fcyriii only, whereas monocytes express fcyri, fcyrii and fcyriii. FcR expression on hematopoietic cells is summarized in Table 3 at page 464 of Ravetch and Kinet, annu.Rev.Immunol 9:457-92 (1991). The ADCC activity of the target molecule is assessed and an in vitro ADCC assay may be performed and is described in U.S. patent nos. 5,500,362 or 5,821,337. Effector cells suitable for such experiments include Peripheral Blood Mononuclear Cells (PBMC) and natural killer cells (NK). Alternatively, or in addition, ADCC activity of the target molecule may also be assessed in vivo, for example as described in an animal model as disclosed in Clynes et al PNAS (USA) 95:652-656 (1998).
Polypeptides comprising an Fc region variant that are experimentally substantially the same in number as wild-type IgG Fc polypeptides (or parent polypeptides) are more effective in mediating ADCC in vitro or in vivo when they exhibit "enhanced ADCC activity" or are capable of mediating ADCC effects more effectively in the presence of human effector cells than wild-type IgG Fc polypeptides or parent polypeptides. Such variants are typically identified using any in vitro ADCC assay known in the art, such as assays or methods for identifying ADCC activity, e.g., in animal models, etc. In some embodiments, such variants mediate ADCC with a 5 to 100 fold, e.g., 25 to 50 fold increase in efficiency compared to the wild-type Fc (or parent polypeptide).
"complement dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by binding of the first component of the complement system (C1 q) to antibodies (subclasses of appropriate structure) that bind to cognate antigens. To assess complement activation, CDC experiments can be performed as described in Gazzano-Santoro et al, J.Immunol. Methods 202:163 (1996). Polypeptide variants having altered amino acid sequences of the Fc region and increased or decreased C1q binding capacity are described in U.S. Pat. No.6,194,551B1 and WO 99/51642. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogie et al J.Immunol.164:4178-4184 (2000).
Unless otherwise indicated, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate versions of each other and encode the same amino acid sequence. The nucleotide sequence encoding a protein or RNA may also include introns, e.g., the nucleotide sequence encoding a protein may in some forms comprise introns.
The term "operably linked" refers to a functional linkage between a regulatory sequence and a heterologous nucleotide sequence such that the latter is expressed. For example, a first nucleotide sequence is operably linked to a second nucleotide sequence when the first nucleotide sequence is in a functional relationship with the second nucleotide sequence. For example, a promoter is operably linked to a coding sequence if it affects the transcription or expression of the coding sequence. Typically, operably linked DNA sequences are contiguous and, if necessary, two protein coding regions can be linked in the same reading frame.
"homology" refers to sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. If the same position of two compared sequences is the same base or amino acid monomer subunit, for example, the same position of both DNA molecules is adenine, then both DNA molecules are homologous at that position. The percentage of homology between two sequences refers to the function of the ratio of the number of matching or homologous positions to the total number of positions shared by the two sequences multiplied by 100. For example, if 6 of the 10 positions in two sequences are matched or homologous, the two sequences are 60% homologous. For example, the DNA sequences ATTGCC and TATGGC have 50% homology. In general, when two sequences are aligned, alignment is performed with the aim of obtaining maximum homology.
An "effective amount" of an anti-FasL antibody or composition as disclosed herein refers to an amount sufficient to achieve a particular purpose. The "effective amount" may be determined empirically and by methods known in connection with the purpose.
The term "therapeutically effective amount" refers to an amount of an anti-FasL antibody or composition thereof disclosed herein that is effective to treat a disease or condition in an individual, i.e., an amount sufficient to reduce or ameliorate the severity and/or duration of the disease or one or more symptoms thereof; preventing disease progression, causing regression of the condition, preventing recurrence, development, onset, or progression of one or more symptoms associated with the disease, detecting the disease, or enhancing/improving the prophylactic or therapeutic effect of another therapy (e.g., a prophylactic or therapeutic agent). For example, in the case of cancer, a therapeutically effective amount of an anti-FasL antibody or composition thereof refers to an amount capable of reducing the number of cancer cells; reducing the size or weight of the tumor; inhibit (i.e., slow or preferably stop to some extent) infiltration of peripheral organs by tumor cells; inhibit (i.e., slow or preferably stop to some extent) tumor metastasis; inhibit to some extent the growth of tumors, and/or alleviate to some extent one or more symptoms associated with cancer. The anti-FasL antibodies or compositions thereof disclosed herein are capable of preventing or inhibiting to some extent the binding of FasL to its receptor Fas, in addition to an apoptosis signaling pathway, fas-mediated non-apoptotic signals (such as NF-kB, MAPK or PI 3K) that promote inflammation, contribute to canceration, and regulate immunological parameters (e.g., tumor infiltrating T cell populations). All of these activities may be inhibited by the antibodies described herein.
As used herein, "pharmaceutically acceptable" or "pharmacologically compatible" refers to materials that are not biologically active or otherwise undesirable, e.g., that can be added to a pharmaceutical composition administered to a patient without causing significant adverse biological reactions or interacting in a deleterious manner with any of the other components of the composition in which they are contained. The pharmaceutically acceptable carrier or excipient preferably meets the desired criteria for toxicology or manufacturing testing and/or is contained in inactive ingredient guidelines established by the U.S. food and drug administration.
The embodiments of the application described herein should be understood to include embodiments consisting of … … and/or consisting essentially of … ….
Reference herein to "about" is a numerical value or parameter, including (and describing) variations on the value or parameter itself. For example, a description relating to "about X" includes a description of "X".
As used herein, reference to a value or parameter that is "not (not)" generally means and describes "other than (other than)" a value or parameter. For example, the method cannot be used to treat type X cancers, meaning that the method is generally used to treat other types of cancers in addition to type X cancers.
As used herein and in the claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
anti-FasL antibodies
In one aspect, the application provides anti-FasL antibodies that specifically bind human FasL. Such anti-FasL antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibodies, human antibodies, and antibody molecules comprising heavy and/or light chain CDRs as described herein. In one aspect, the application provides isolated antibodies that bind to FasL. Contemplated anti-FasL antibodies include, for example, full-length anti-FasL antibodies (e.g., full-length IgG1 or IgG 4), anti-FasL single-chain antibodies, anti-FasL Fc fusion proteins, multispecific (e.g., bispecific) anti-FasL antibodies, anti-FasL immunoconjugates, and the like. In some embodiments, the anti-FasL antibody is a full length antibody (e.g., full length IgG1 or IgG 4) or an antigen-binding fragment thereof, which specifically binds to FasL. In some embodiments, the anti-FasL antibody is a Fab, fab ', F (ab)' 2 Fab' -SH, single chain Fv (scFv), fv fragment, dAb, fd, nanobody (nanobody), diabody (diabody), or linear antibody. In some embodiments, an antibody that specifically binds FasL means that the antibody binds FasL with an affinity that is at least 10 times greater than the affinity of the binding affinity of the antibody to the non-target (including, for example, 10 2 、10 3 、10 4 、10 5 、10 6 Or 10 7 Multiple). In some embodiments, non-target refers to an antigen that is not FasL. Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence Activated Cell Sorting (FACS) analysis, or Radioimmunoassay (RIA). Kd values can be determined by methods known in the art, such as Surface Plasmon Resonance (SPR) techniques or Biological Layer Interferometry (BLI).
While anti-FasL antibodies comprising human sequences (e.g., human heavy and light chain variable domains comprising human CDR sequences) are discussed extensively herein, non-human anti-FasL antibodies are also contemplated. In some embodiments, the non-human anti-FasL antibody comprises the human CDR sequences and non-human framework region sequences of the anti-FasL antibodies described herein, and in some embodiments, the non-human framework region sequences comprise any sequences for producing heavy and/or light chain variable domains using one or more human CDR sequences as described herein, including, for example, mammals, such as mice, rats, rabbits, pigs, cattle (e.g., cattle, bulls, buffalo), deer, sheep, goats, chickens, cats, dogs, ferrets, primates (e.g., apes, macaques), and the like. In some embodiments, the non-human anti-FasL antibody comprises an anti-FasL antibody produced by grafting one or more human CDR sequences described herein into a non-human framework region (e.g., a murine or chicken framework region sequence).
An exemplary human FasL comprises the complete amino acid sequence of SEQ ID NO:159 or an amino acid sequence set forth in SEQ ID NO: 159. An exemplary human FasL extracellular region amino acid sequence comprises SEQ ID NO:160 or an amino acid sequence set forth in SEQ ID NO:160, and a polypeptide having the amino acid sequence shown in seq id no.
In some embodiments, the anti-FasL antibodies described herein specifically recognize an epitope in human FasL. In some embodiments, the anti-FasL antibody cross-reacts with FasL of a species other than human. In some embodiments, the anti-FasL antibody is completely specific for human FasL and does not cross-react with other non-human species.
In some embodiments, the anti-FasL antibody cross-reacts with at least one allelic variant of the FasL protein (or fragment thereof). In some embodiments, an allelic variant has up to 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30) amino acid substitutions (e.g., conservative substitutions) compared to a naturally occurring FasL protein (or fragment thereof). In some embodiments, the anti-FasL antibody does not cross-react with any allelic variants of the FasL protein (or fragment thereof).
In some embodiments, the anti-FasL antibody cross-reacts with at least one intervarietal variant of FasL protein. In some embodiments, for example, the FasL protein (or fragment thereof) is human FasL, and the intervarietal variant of the FasL protein (or fragment thereof) is a variant in cynomolgus monkey. In some embodiments, the anti-FasL antibody does not cross-react with any of the inter-variants of the FasL protein.
In some embodiments, any of the anti-FasL antibodies as described herein comprises an antibody heavy chain constant region and an antibody light chain constant region. In some embodiments, the anti-FasL antibody comprises an IgG1 type heavy chain constant region. In some embodiments, the anti-FasL antibody comprises an IgG2 type heavy chain constant region. In some embodiments, the anti-FasL antibody comprises an IgG3 type heavy chain constant region. In some embodiments, the anti-FasL antibody comprises an IgG4 type heavy chain constant region. In some embodiments, the heavy chain constant region comprises (including consisting of … or consisting essentially of …) the amino acid sequence SEQ ID NO 155. In some embodiments, the heavy chain constant region comprises (including consisting of … or consisting essentially of …) the amino acid sequence SEQ ID NO 156. In some embodiments, the anti-FasL antibody comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises (including consisting of … or consisting essentially of …) the amino acid sequence SEQ ID NO. 157. In some embodiments, the anti-FasL antibody comprises a lambda light chain constant region. In some embodiments, the light chain constant region comprises (including consisting of … or consisting essentially of …) the amino acid sequence SEQ ID NO 158. In some embodiments, the anti-FasL antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, HC-CDR3 comprising the amino acid sequence SEQ ID NO:32, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:67, LC-CDR3 comprising the amino acid sequence SEQ ID NO:77, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasLThe body contains V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:67, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:77.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO 99 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:127 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising an amino acid sequence of SEQ ID NO 99 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO 99; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 127 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 127. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO 99 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 127.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:19, HC-CDR3 comprising the amino acid sequence SEQ ID NO:32, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, LC-CDR3 comprising the amino acid sequence SEQ IDNO: 78, or the V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:78.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:100 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 128 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 100 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 100; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 128 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 128. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 100 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 128.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, HC-CDR3 comprising the amino acid sequence SEQ ID NO:32, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:67, LC-CDR3 comprising the amino acid sequence SEQ ID NO:79, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:67, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:79.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:101 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:129 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 101 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 101; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 129 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 129. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO 101 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 129.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2, which comprisesComprising the amino acid sequence SEQ ID NO. 20, HC-CDR3 comprising the amino acid sequence SEQ ID NO. 33, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, LC-CDR3 comprising the amino acid sequence SEQ ID NO:80, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:33; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:80.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:102 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:130 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 102 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 102; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 130 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 130. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 102 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 130.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, HC-CDR3 comprising the amino acid sequence SEQ ID NO:34, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, LC-CDR3 comprising the amino acid sequence SEQ ID NO:81, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:34; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:81.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:103 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO. 131 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 103 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO. 103; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 131 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO. 131. In some embodiments, the anti-cancer agentFasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO 103 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 131.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:4, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, HC-CDR3 comprising the amino acid sequence SEQ ID NO:35, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, LC-CDR2 comprising the amino acid sequence SEQ ID NO:69, LC-CDR3 comprising the amino acid sequence SEQ ID NO:82, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, LC-CDR2 comprising the amino acid sequence SEQ ID NO:69, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:82.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO 104 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO. 132 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 104 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 104; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 132 or a variant thereof The body has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO. 132. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO 104 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 132.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:5, HC-CDR2 comprising the amino acid sequence SEQ ID NO:21, HC-CDR3 comprising the amino acid sequence SEQ ID NO:36, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:54, LC-CDR2 comprising the amino acid sequence SEQ ID NO:70, LC-CDR3 comprising the amino acid sequence SEQ ID NO:83, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 21, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 36; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:54, LC-CDR2 comprising the amino acid sequence SEQ ID NO:70, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:83.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO 105 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:133 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 105 or a variant thereof having at least about 80% (e.g. at least) with the amino acid sequence SEQ ID NO. 10580%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 133 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO. 133. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO 105 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 133.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, LC-CDR3 comprising the amino acid sequence SEQ ID NO:84, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:84.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:106 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 134 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-cancer agentThe FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 106 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 106; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 134 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 134. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO 106 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 134.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:7, HC-CDR2 comprising the amino acid sequence SEQ ID NO:23, HC-CDR3 comprising the amino acid sequence SEQ ID NO:38, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, LC-CDR3 comprising the amino acid sequence SEQ ID NO:85, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:107 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:135 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 107 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 107; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 135 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 135. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO 107 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 135.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, LC-CDR3 comprising the amino acid sequence SEQ ID NO:85, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO. 108 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:136 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 108 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 108; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 136 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 136. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 108 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 136.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, LC-CDR3 comprising the amino acid sequence SEQ ID NO:85, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1, comprising amino acid sequence SEQ ID NO:55, LC-CDR2, comprising amino acid sequence SEQ ID NO:71, and LC-CDR3, comprising amino acid sequence SEQ ID NO:85.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO. 109 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 137 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 109 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 109; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 137 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 137. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 109 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 137.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:72, LC-CDR3 comprising the amino acid sequence SEQ ID NO:85, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising an amino groupAcid sequence SEQ ID NO. 7, HC-CDR2 comprising amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:72, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO. 110 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:138 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 110 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 110; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 138 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 138. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 110 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 138.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, LC-CDR3 comprising the amino acid sequence SEQ ID NO:85, or said V L Variants of (2) comprising up to aboutSubstitutions of 5 amino acids.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:111 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 139 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 111 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 111; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 139 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 139. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO 111 and V L The V is L Comprising the amino acid sequence SEQ ID NO 139.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising an amino acid sequenceSEQ ID NO. 56, LC-CDR2 comprising the amino acid sequence SEQ ID NO. 71, LC-CDR3 comprising the amino acid sequence SEQ ID NO. 85, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:56, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO 112 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:140 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO 112 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO 112; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 140 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 140. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO 112 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 140.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, HC-CDR3 comprising the amino acid sequence SEQ ID NO 38, or the V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, LC-CDR3 comprising the amino acid sequence SEQ ID NO:86, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:86.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:113 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:141 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 113 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 113; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 141 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO. 141. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO:113 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 141.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:9, HC-CDR2 comprising the amino acid sequence SEQ ID NO:26, HC-CDR3 comprising the amino acid sequence SEQ ID NO:39, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:57, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, LC-CDR3 comprising the amino acid sequence SEQ ID NO:87, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 9, HC-CDR2 comprising the amino acid sequence SEQ ID NO 26, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:57, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:87.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:114 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:142 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 114 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 114; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO:142 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 142. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 114, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 142.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:27, HC-CDR3 comprising the amino acid sequence SEQ ID NO:40, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:58, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, LC-CDR3 comprising the amino acid sequence SEQ ID NO:88, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 27, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 40; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:58, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:88.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO 115 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:143 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 115 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 115; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO:143 or a variant thereof having at least about 80% (e.g., at least 80%),85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 115 and V L The V is L Comprising the amino acid sequence SEQ ID NO:143.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 10, HC-CDR2 comprising the amino acid sequence SEQ ID NO 20, HC-CDR3 comprising the amino acid sequence SEQ ID NO 41, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 59, LC-CDR2 comprising the amino acid sequence SEQ ID NO 68, LC-CDR3 comprising the amino acid sequence SEQ ID NO 89, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 10, HC-CDR2 comprising the amino acid sequence SEQ ID NO 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 41; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 59, LC-
CDR2 comprising the amino acid sequence SEQ ID NO. 68 and LC-CDR3 comprising the amino acid sequence SEQ ID NO. 89.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:116 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO. 144 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 116 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%) with the amino acid sequence SEQ ID NO. 11697%, 98%, or 99%) sequence identity; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 144 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 144. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 116 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 144.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, LC-CDR3 comprising the amino acid sequence SEQ ID NO:90, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:90.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO. 117 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in the amino acid sequence SEQ ID NO:145 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The sum ofThe V is H Comprising the amino acid sequence SEQ ID NO. 117 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 117; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO:145 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 145. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 117 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 145.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:11, HC-CDR2 comprising the amino acid sequence SEQ ID NO:28, HC-CDR3 comprising the amino acid sequence SEQ ID NO:42, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:60, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, LC-CDR3 comprising the amino acid sequence SEQ ID NO:91, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 42; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:60, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:91.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:118 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising, for example, an amino acid sequenceV shown in SEQ ID NO. 146 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 118 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 118; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 146 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 146. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO 118 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 146.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:12, HC-CDR2 comprising the amino acid sequence SEQ ID NO:29, HC-CDR3 comprising the amino acid sequence SEQ ID NO:43, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence SEQ ID NO:75, LC-CDR3 comprising the amino acid sequence SEQ ID NO:92, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 29, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 43; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence SEQ ID NO:75, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:92.
In some embodiments, the anti-cancer agentFasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:119 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:147 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 119 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 119; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 147 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 147. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO:119 and V L The V is L Comprising the amino acid sequence SEQ ID NO 147.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:12, HC-CDR2 comprising the amino acid sequence SEQ ID NO:29, HC-CDR3 comprising the amino acid sequence SEQ ID NO:44, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:62, LC-CDR2 comprising the amino acid sequence SEQ ID NO:75, LC-CDR3 comprising the amino acid sequence SEQ ID NO:93, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 29, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 44; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQID No. 62, LC-CDR2 comprising the amino acid sequence SEQ ID No. 75, and LC-CDR3 comprising the amino acid sequence SEQ ID No. 93.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:120 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:148 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 120 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 120; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 148 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence SEQ ID NO. 148. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 120 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 148.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 13, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 30, HC-CDR3 comprising the amino acid sequence SEQ ID NO. 45, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:63, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, LC-CDR3 comprising the amino acid sequence SEQ ID NO:94, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 13, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 30, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 45; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:63, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:94.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:121 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:149 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising amino acid sequence SEQ ID NO. 121 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to amino acid sequence SEQ ID NO. 121; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO:149 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:149. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO 121 and V L The V is L Comprising the amino acid sequence SEQ ID NO:149.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 14, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, HC-CDR3 comprising the amino acid sequence SEQ ID NO. 46, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, LC-CDR3 comprising the amino acid sequence SEQ ID NO:95, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 14, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 46; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:95.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO. 122 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:150 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 122 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 122; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 150 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 150. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 122 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 150.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 15, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, HC-CDR3 comprising the amino acid sequence SEQ ID NO. 47, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:64, LC-CDR2,comprising the amino acid sequence SEQ ID NO. 68, LC-CDR3 comprising the amino acid sequence SEQ ID NO. 96, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 15, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 47; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO. 64, LC-CDR2 comprising the amino acid sequence SEQ ID NO. 68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO. 96.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO. 123 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:151 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 123 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 123; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 151 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 151. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 123 and V L The V is L Comprises an amino acid sequence SEQ ID NO. 151.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 16, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 31, HC-CDR3 comprising the amino acid sequence SEQ ID NO. 48, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:65, LC-CDR2 comprising the amino acid sequence SEQ ID NO:76, LC-CDR3 comprising the amino acid sequence SEQ ID NO:97, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 16, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 31, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 48; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:65, LC-CDR2 comprising the amino acid sequence SEQ ID NO:76, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:97.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO 124 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 152 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 124 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 124; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 152 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 152. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO 124 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 152.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:17, HC-CDR2 comprising the amino acid sequence SEQ ID NO:28, HC-CDR3 comprising the amino acid sequence SEQ ID NO:49, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:66, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, LC-CDR3 comprising the amino acid sequence SEQ ID NO:98, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 17, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 49; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:66, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:98.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO. 125 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 153 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 125 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 125; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO 153 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO 153. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 125, andV L the V is L Comprising the amino acid sequence SEQ ID NO 153.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:17, HC-CDR2 comprising the amino acid sequence SEQ ID NO:28, HC-CDR3 comprising the amino acid sequence SEQ ID NO:50, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:60, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, LC-CDR3 comprising the amino acid sequence SEQ ID NO:91, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 17, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 50; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:60, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:91.
In some embodiments, the anti-FasL antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:126 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 154 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-FasL antibody comprises: v (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 126 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO. 126; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 154 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 9) of the amino acid sequence SEQ ID NO. 154 5%, 96%, 97%, 98% or 99%) sequence identity. In some embodiments, the anti-FasL antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 126 and V L The V is L Comprising the amino acid sequence SEQ ID NO. 154.
In some embodiments, the amino acid substitutions described above are limited to the "exemplary substitutions" shown in table 4 herein. In some embodiments, amino acid substitutions are limited to the "preferred substitutions" shown in table 4 herein.
In some embodiments, the functional epitope can be resolved by combining alanine scanning methods. In this process, combinatorial alanine scanning techniques can be used to identify amino acids in the FasL protein that are necessary for interaction with anti-FasL antibodies. In some embodiments, the epitope is conformational, while the crystal structure of an anti-FasL antibody that binds to FasL protein may be employed to identify the epitope.
In some embodiments, the application provides antibodies that competitively bind to FasL with any of the anti-FasL antibodies described herein. In some embodiments, antibodies are provided that are capable of competitively binding to an epitope on FasL with any of the anti-FasL antibodies described herein. In some embodiments, anti-FasL antibodies are provided that are associated with a polypeptide comprising V H And V L The anti-FasL antibody molecules of (2) bind to the same epitope, wherein said V H Comprising the amino acid sequence shown in any one of SEQ ID NOs 99-126 and V L Comprising the amino acid sequence shown in any one of SEQ ID NOs 127-154. In some embodiments, anti-FasL antibodies are provided that are associated with a polypeptide comprising V H And V L Is capable of competitively binding to FasL, wherein said V H Comprising the amino acid sequence shown in any one of SEQ ID NOs 99-126 and V L Comprising the amino acid sequence shown in any one of SEQ ID NOs 127-154.
In some embodiments, competition experiments can be used to identify monoclonal antibodies that competitively bind to FasL with the anti-FasL antibodies described herein. Competition experiments can determine whether two antibodies bind to the same epitope by recognizing the same or spatially overlapping epitopes or by one antibody competitively inhibiting the binding of the other antibody to the antigen. In certain embodiments, such a competing antibody binds to the same epitope as the antibodies described herein. Some exemplary competition experiments include, but are not limited to, routine experiments as mentioned in Harlow and Lane (1988) Antibodies A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, cold Spring Harbor, N.Y.). A detailed exemplary method for resolving epitopes bound by antibodies is described in Morris (1996), "Epitope Mapping Protocols," in Methods in Molecular Biology vol.66 (Humana Press, totowa, N.J.). In some embodiments, each antibody is said to bind to the same epitope if it blocks 50% or more of the binding of the other antibody. In some embodiments, the antibody that competes with the anti-FasL antibodies described herein is a chimeric, humanized, or fully human antibody.
Exemplary anti-FasL antibody sequences are shown in tables 2 and 3, wherein CDR numbering is performed according to the Chothia definition. Those skilled in the art will recognize that there are a variety of known algorithms (Chothia definition) to predict the position of CDRs and define the antibody light and heavy chain variable regions. Comprising CDRs of an antibody as described herein, V H And/or V L Sequences, but based on predictive algorithms other than the antibodies exemplified in the tables below are also within the scope of the application.
TABLE 2 exemplary anti-FasL antibody CDR sequences
Table 3 exemplary sequences
Full-length anti-FasL antibodies
In some embodiments, the anti-FasL antibody is a full-length anti-FasL antibody. In some embodiments, the full-length anti-FasL antibody is IgA, igD, igE, igG or IgM. In some embodiments, the full-length anti-FasL antibody comprises an IgG constant region, e.g., a constant region of IgG1, igG2, igG3, igG4, or a variant thereof. In some embodiments, the full length anti-FasL antibody comprises a lambda light chain constant region. In some embodiments, the full length anti-FasL antibody comprises a kappa light chain constant region. In some embodiments, the full length anti-FasL antibody is a full length human anti-FasL antibody. In some embodiments, the full-length anti-FasL antibody comprises a mouse immunoglobulin Fc sequence. In some embodiments, the full-length anti-FasL antibody comprises an Fc sequence that has been altered or otherwise altered such that it has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) effector functions.
Thus, for example, in some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided that specifically binds to FasL. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG2 constant region that specifically binds to FasL is provided. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG3 constant region is provided that specifically binds to FasL. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region that specifically binds to FasL is provided. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs 1-17, HC-CDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs 18-31, and HC-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs 32-50, or a variant of said heavy chain variable domain comprising up to about 5 (e.g., 1, 2, 3, 4 or 5) amino acid substitutions in the HC-CDR sequence; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs 51 to 66, LC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs 67 to 76, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs 77 to 98, or a variant of said light chain variable domain comprising up to about 5 (e.g. 1, 2, 3, 4 or 5) amino acid substitutions in the LC-CDR sequence. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs 1-17, HC-CDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs 18-31, and HC-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs 32-50, or a variant of said heavy chain variable domain comprising up to about 5 (e.g., 1, 2, 3, 4 or 5) amino acid substitutions in the HC-CDR sequence; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs 51 to 66, LC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs 67 to 76, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs 77 to 98, or a variant of said light chain variable domain comprising up to about 5 (e.g. 1, 2, 3, 4 or 5) amino acid substitutions in the LC-CDR sequence. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs 1-17, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs 18-31, and HC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs 32-50; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs:51-66, LC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:67-76, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 77-98. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs 1-17, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs 18-31, and HC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs 32-50; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs:51-66, LC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:67-76, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 77-98. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:67, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:77. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:78. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:67, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:79. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:33; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:80. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:34; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:81. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, LC-CDR2 comprising the amino acid sequence SEQ ID NO:69, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:82. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 21, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 36; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:54, LC-CDR2 comprising the amino acid sequence SEQ ID NO:70, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:83. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:84. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:72, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:56, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:86. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 9, HC-CDR2 comprising the amino acid sequence SEQ ID NO 26, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:57, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:87. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 27, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 40; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:58, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:88. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 10, HC-CDR2 comprising the amino acid sequence SEQ ID NO 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 41; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 59, LC-CDR2 comprising the amino acid sequence SEQ ID NO 68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 89. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:90. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 42; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:60, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:91. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 29, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 43; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence SEQ ID NO:75, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:92. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 29, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 44; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:62, LC-CDR2 comprising the amino acid sequence SEQ ID NO:75, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:93. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 13, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 30, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 45; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:63, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:94. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 14, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 46; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:95. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 15, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 47; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO. 64, LC-CDR2 comprising the amino acid sequence SEQ ID NO. 68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO. 96. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 16, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 31, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 48; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:65, LC-CDR2 comprising the amino acid sequence SEQ ID NO:76, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:97. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 17, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 49; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:66, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:98. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 17, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 50; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:60, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:91. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:67, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:77. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:78. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:67, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:79. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:33; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:80. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:34; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:81. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, LC-CDR2 comprising the amino acid sequence SEQ ID NO:69, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:82. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 21, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 36; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:54, LC-CDR2 comprising the amino acid sequence SEQ ID NO:70, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:83. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:84. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:72, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:56, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:86. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 9, HC-CDR2 comprising the amino acid sequence SEQ ID NO 26, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:57, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:87. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 27, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 40; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:58, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:88. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 10, HC-CDR2 comprising the amino acid sequence SEQ ID NO 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 41; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 59, LC-CDR2 comprising the amino acid sequence SEQ ID NO 68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 89. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:90. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 42; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:60, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:91. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 29, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 43; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence SEQ ID NO:75, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:92. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 29, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 44; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:62, LC-CDR2 comprising the amino acid sequence SEQ ID NO:75, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:93. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 13, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 30, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 45; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:63, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:94. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 14, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 46; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:95. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 15, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 47; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO. 64, LC-CDR2 comprising the amino acid sequence SEQ ID NO. 68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO. 96. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 16, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 31, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 48; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:65, LC-CDR2 comprising the amino acid sequence SEQ ID NO:76, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:97. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 17, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 49; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:66, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:98. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 17, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 50; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:60, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:91. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: heavy chain variable domain (V H ) The V is H Comprising an amino acid sequence set forth in any one of SEQ ID NOs 99-126, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs 99-126; light chain variable domains (V L ) The V is L Comprising an amino acid sequence as set forth in any one of SEQ ID NOs 127-154 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence as set forth in any one of SEQ ID NOs 127-154. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises Or consists of the amino acid sequence SEQ ID NO. 155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG2 constant region is provided, wherein the anti-FasL antibody comprises: heavy chain variable domain (V H ) The V is H Comprising an amino acid sequence set forth in any one of SEQ ID NOs 99-126, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs 99-126; light chain variable domains (V L ) The V is L Comprising an amino acid sequence as set forth in any one of SEQ ID NOs 127-154 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence as set forth in any one of SEQ ID NOs 127-154. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG3 constant region is provided, wherein the anti-FasL antibody comprises: heavy chain variable domain (V H ) The V is H Comprising an amino acid sequence set forth in any one of SEQ ID NOs 99-126, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs 99-126; light chain variable domains (V L ) The V is L Comprising an amino acid sequence as set forth in any one of SEQ ID NOs 127-154 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence as set forth in any one of SEQ ID NOs 127-154. In some embodiments of the present invention, in some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises orConsists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: heavy chain variable domain (V H ) The V is H Comprising an amino acid sequence set forth in any one of SEQ ID NOs 99-126, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs 99-126; light chain variable domains (V L ) The V is L Comprising an amino acid sequence as set forth in any one of SEQ ID NOs 127-154 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence as set forth in any one of SEQ ID NOs 127-154. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: heavy chain variable domain (V H ) Said (V) H ) Comprising the amino acid sequence shown in any one of SEQ ID NOs 99-126 and a light chain variable domain (V L ) Said (V) L ) Comprising the amino acid sequence shown in any one of SEQ ID NOs 127-154. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some casesIn embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: heavy chain variable domain (V H ) The V is H Comprising the amino acid sequence shown in any one of SEQ ID NOs 99-126 and a light chain variable domain (V L ) The V is L Comprising the amino acid sequence shown in any one of SEQ ID NOs 127-154. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 99 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99; v (V) L Comprising the amino acid sequence SEQ ID NO. 127 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 127. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 100 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 100; v (V) L Comprising the amino acid sequence SEQ ID NO. 128 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 128. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 101 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 101; v (V) L Comprising the amino acid sequence SEQ ID NO. 129 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 129. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 102 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 102; v (V) L Comprising the amino acid sequence SEQ ID NO. 130 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 130. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 103 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 103; v (V) L Comprising the amino acid sequence SEQ ID NO. 131 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 131. In some embodiments, whatThe IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 104 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 104; v (V) L Comprising the amino acid sequence SEQ ID NO. 132 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 132. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 105 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 105; v (V) L Comprising the amino acid sequence SEQ ID NO. 133 or a variant thereof, said variant being compatible with ammoniaThe base acid sequence SEQ ID NO. 133 has at least about 80% sequence identity. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 106 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 106; v (V) L Comprising the amino acid sequence SEQ ID NO. 134 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 134. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 107 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 107; to be used for V (V) L Comprising the amino acid sequence SEQ ID NO. 135 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 135. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 108 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 108; v (V) L Comprising the amino acid sequence SEQ ID NO. 136 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 136. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 109 or a variant thereofA variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO. 109; v (V) L Comprising the amino acid sequence SEQ ID NO. 137 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 137. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 110 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 110; v (V) L Comprising the amino acid sequence SEQ ID NO. 138 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 138. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided,wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 111 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 111; v (V) L Comprising the amino acid sequence SEQ ID NO. 139 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 139. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 112 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 112; v (V) L Comprising the amino acid sequence SEQ ID NO. 140 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 140. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 113 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 113; v (V) L Comprising the amino acid sequence SEQ ID NO. 141 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 141. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 114 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 114; v (V) L Comprising the amino acid sequence SEQ ID NO. 142 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 142. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 andthe light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 115 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 115; v (V) L Comprising the amino acid sequence SEQ ID NO. 143 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 143. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 116 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 116; v (V) L Comprising the amino acid sequence SEQ ID NO. 144 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 144. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. At the position of In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 117 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 117; v (V) L Comprising the amino acid sequence SEQ ID NO. 145 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 145. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 118 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 118; v (V) L Comprising the amino acid sequence SEQ ID NO. 146 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 146. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 119 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 119; v (V) L Comprising the amino acid sequence SEQ ID NO. 147 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 147. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 120 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 120; v (V) L Comprising the amino acid sequence SEQ ID NO. 148 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO. 148. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of an amino acid sequenceSEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 121 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 121; v (V) L Comprising the amino acid sequence SEQ ID NO. 149 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 149. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 122 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 122; v (V) L Comprising the amino acid sequence SEQ ID NO. 150 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 150. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of an amino acid sequenceSEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 123 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 123; v (V) L Comprising the amino acid sequence SEQ ID NO. 151 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 151. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 124 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 124; v (V) L Comprising the amino acid sequence SEQ ID NO. 152 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 152. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of an amino acid sequenceSEQ ID NO. 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 125 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 125; v (V) L Comprising the amino acid sequence SEQ ID NO. 153 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 153. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG1 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 126 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 126; v (V) L Comprising the amino acid sequence SEQ ID NO. 154 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 154. In some embodiments of the present invention, in some embodiments,the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:155 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 99 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99; v (V) L Comprising the amino acid sequence SEQ ID NO. 127 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 127. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 100 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 100; v (V) L Comprising the amino acid sequence SEQ ID NO. 128 or a variant thereof, said variant being compatible with ammoniaThe nucleotide sequence SEQ ID NO. 128 has at least about 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 101 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 101; v (V) L Comprising the amino acid sequence SEQ ID NO. 129 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 129. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 102 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 102; to be used forV (V) L Comprising the amino acid sequence SEQ ID NO. 130 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 130. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 103 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 103; v (V) L Comprising the amino acid sequence SEQ ID NO. 131 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 131. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO 104 or a variant thereof A variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 104; v (V) L Comprising the amino acid sequence SEQ ID NO. 132 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 132. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 105 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 105; v (V) L Comprising the amino acid sequence SEQ ID NO. 133 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 133. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided,wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 106 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 106; v (V) L Comprising the amino acid sequence SEQ ID NO. 134 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 134. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 107 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 107; v (V) L Comprising the amino acid sequence SEQ ID NO. 135 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 135. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 108 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 108; v (V) L Comprising the amino acid sequence SEQ ID NO. 136 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 136. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 109 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 109; v (V) L Comprising the amino acid sequence SEQ ID NO. 137 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 137. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 andthe light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 110 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 110; v (V) L Comprising the amino acid sequence SEQ ID NO. 138 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 138. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 111 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 111; v (V) L Comprising the amino acid sequence SEQ ID NO. 139 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 139. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. At the position ofIn some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 112 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 112; v (V) L Comprising the amino acid sequence SEQ ID NO. 140 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 140. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 113 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 113; v (V) L Comprising the amino acid sequence SEQ ID NO. 141 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 141. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 114 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 114; v (V) L Comprising the amino acid sequence SEQ ID NO. 142 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 142. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 115 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 115; v (V) L Comprising the amino acid sequence SEQ ID NO. 143 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 143. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of an amino acid sequenceSEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 116 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 116; v (V) L Comprising the amino acid sequence SEQ ID NO. 144 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 144. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 117 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 117; v (V) L Comprising the amino acid sequence SEQ ID NO. 145 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 145. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of an amino acid sequenceSEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 118 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 118; v (V) L Comprising the amino acid sequence SEQ ID NO. 146 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 146. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 119 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 119; v (V) L Comprising the amino acid sequence SEQ ID NO. 147 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 147. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of an amino acid sequenceSEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 120 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 120; v (V) L Comprising the amino acid sequence SEQ ID NO. 148 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO. 148. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 121 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 121; v (V) L Comprising the amino acid sequence SEQ ID NO. 149 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 149. In some embodiments of the present invention, in some embodiments,the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 122 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 122; v (V) L Comprising the amino acid sequence SEQ ID NO. 150 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 150. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 123 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 123; v (V) L Comprising the amino acid sequence SEQ ID NO. 151 or a variant thereof, said variant being identical toThe amino acid sequence SEQ ID NO. 151 has at least about 80% sequence identity. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 124 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 124; v (V) L Comprising the amino acid sequence SEQ ID NO. 152 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 152. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 125 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 125; V (V) L Comprising the amino acid sequence SEQ ID NO. 153 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 153. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, a full length anti-FasL antibody comprising an IgG4 constant region is provided, wherein the anti-FasL antibody comprises: v (V) H Comprising the amino acid sequence SEQ ID NO. 126 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 126; v (V) L Comprising the amino acid sequence SEQ ID NO. 154 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 154. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
Binding affinity
Binding affinity is expressed in terms of Kd, koff, kon or Ka. As used herein, the term Koff refers to the rate constant of dissociation of an antibody from an antigen/antibody complex, as determined by a kinetic selection device. The term Kon refers to the binding rate constant of an antibody to an antigen to form an antigen/antibody complex. The equilibrium dissociation constant Kd as used herein refers to the dissociation constant at which a particular antibody antigen interacts, meaning that in a solution of an antibody molecule, the antigen occupies half of all antibody binding sites and the concentration of antigen required to reach equilibrium is equal to Koff/Kon. Determination of Kd assumes that all binding molecules are in solution. In the case of antibody attachment to the cell wall, for example in yeast expression systems, the corresponding equilibrium dissociation rate constant is expressed as EC50, which is a good approximation of Kd. The affinity binding constant Ka is the inverse of the dissociation constant Kd.
The dissociation constant (Kd) can be used as an indicator of the affinity of the reactive antibody moiety for the antigen. For example, the interactions between biomolecules can be analyzed by Scatchard method using antibodies labeled with various markers, and Biacore instrument (manufactured by Amersham Biosciences) by surface plasmon resonance according to a user manual or an attached kit. The Kd values obtained using these methods are expressed in units M. Antibodies that specifically bind to the target may have, for example, 10 +. -7 M、≤10 -8 M、≤10 -9 M、≤10 -10 M、≤10 -11 M、≤10 -12 M or less than or equal to 10 -13 Kd value of M.
The binding specificity of an antibody can be determined experimentally by methods known in the art. These methods include, but are not limited to, western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIAcore assays, peptide scans, and the like.
In some embodiments, the anti-FasL antibody specifically binds to the FasL target with a Kd value of 10 -7 M to 10 -13 M (e.g. 10 -7 M to 10 -13 M、10 -8 M to 10 -13 M、10 -9 M to 10 -13 M or 10 -10 M to 10 -12 M). Thus, in some embodiments, the Kd value of the binding between the anti-FasL antibody and FasL is 10 -7 M to 10 -13 M、1×10 -7 M to 5X 10 -13 M、10 - 7 M to 10 -12 M、10 -7 M to 10 -11 M、10 -7 M to 10 -10 M、10 -7 M to 10 -9 M、10 -8 M to 10 -13 M、1×10 - 8 M to 5X 10 -13 M、10 -8 M to 10 -12 M、10 -8 M to 10 -11 M、10 -8 M to 10 -10 M、10 -8 M to 10 -9 M、5×10 - 9 M to 1X 10 -13 M、5×10 -9 M to 1X 10 -12 M、5×10 -9 M to 1X 10 -11 M、5×10 -9 M to 1X 10 -10 M、10 -9 M to 10 -13 M、10 -9 M to 10 -12 M、10 -9 M to 10 -11 M、10 -9 M to 10 -10 M、5×10 -10 M to 1X 10 -13 M、5×10 - 10 M to 1X 10 -12 M、5×10 -10 M to 1X 10 -11 M、10 -10 M to 10 -13 M、1×10 -10 M to 5X 10 -13 M、1×10 -10 M to 1X 10 -12 M、1×10 -10 M to 5X 10 -12 M、1×10 -10 M to 1X 10 -11 M、10 -11 M to 10 -13 M、1×10 -11 M to 5X 10 -13 M、10 -11 M to 10 -12 M、10 -12 M to 10 -13 M. In some embodiments, the Kd value of the binding between the anti-FasL antibody and FasL is 10 -7 M to 10 -13 M。
In some embodiments, the Kd value of the binding between the anti-FasL antibody and the non-target is higher than the Kd value of the anti-FasL antibody and the target, and in some embodiments cited herein, the binding affinity of the anti-FasL antibody to the target (e.g., fasL) is higher than the binding affinity of the anti-FasL antibody to the non-target. In some embodiments, the non-target is an antigen other than FasL. In some embodiments, the anti-FasL antibodies (directed against FasL) differ by at least a factor of 10, e.g., 10-100, 100-1000, 10, between the Kd values bound to non-FasL targets 3 -10 4 Multiple of 10 4 -10 5 Multiple of 10 5 -10 6 Multiple of 10 6 -10 7 Multiple of 10 7 -10 8 Multiple of 10 8 -10 9 Multiple of 10 9 -10 10 Multiple of 10 10 -10 11 Multiple of 10 11 -10 12 Multiple times.
In some embodiments, the anti-FasL antibody binds to a non-target with a Kd value of 10 -1 M to 10 -6 M (e.g. 10 -1 M to 10 -6 M、10 -1 M to 10 -5 M、10 -2 M to 10 -4 M). In some embodiments, the non-target refers to an antigen other than FasL. Thus, in some embodiments, the Kd value of binding between the anti-FasL antibody and the non-FasL target is 10 -1 M to 10 -6 M、1×10 -1 M to 5X 10 -6 M、10 -1 M to 10 -5 M、1×10 -1 M to 5X 10 -5 M、10 -1 M to 10 -4 M、1×10 -1 M to 5X 10 -4 M、10 -1 M to 10 -3 M、1×10 -1 M to 5X 10 -3 M、10 -1 M to 10 -2 M、10 -2 M to 10 -6 M、1×10 -2 M to 5X 10 -6 M、10 -2 M to 10 -5 M、1×10 -2 M to 5X 10 -5 M、10 -2 M to 10 -4 M、1×10 -2 M to 5X 10 -4 M、10 -2 M to 10 -3 M、10 -3 M to 10 -6 M、1×10 -3 M to 5X 10 -6 M、10 -3 M to 10 -5 M、1×10 -3 M to 5X 10 -5 M、10 -3 M to 10 -4 M、10 -4 M to 10 -6 M、1×10 -4 M to 5X 10 -6 M、10 -4 M to 10 -5 M、10 -5 M to 10 -6 M。
In some embodiments, when referring to an anti-FasL antibody specifically recognizing a FasL target with high binding affinity and binding to a non-target with low binding affinity, the anti-FasL antibody binds to the FasL target with a Kd value of 10 -7 M to 10 -13 M (e.g. 10 -7 M to 10 -13 M、10 -8 M to 10 -13 M、10 -9 M to 10 -13 M、10 -10 M to 10 -12 M), and Kd value of 10 for non-target binding -1 M to 10 -6 M (e.g. 10 -1 M to 10 -6 M、10 -1 M to 10 -5 M、10 -2 M to 10 -4 M)。
In some embodiments, when reference is made to an anti-FasL antibody specifically recognizing FasL, the binding affinity of the anti-FasL antibody is compared to the binding affinity of a control anti-FasL antibody (e.g., 119-4A or APG101or MAB126-100). In some embodiments, the Kd value of the binding between the control anti-FasL antibody and FasL may be at least 2-fold, e.g., 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 100-fold, 1000-fold, 10-fold, the Kd value of the binding between the anti-FasL antibody and FasL described herein 3 -10 4 Multiple times.
Nucleic acid
Nucleic acid molecules encoding anti-FasL antibodies are also contemplated. In some embodiments, a nucleic acid (or set of nucleic acids) encoding a full-length anti-FasL antibody is provided, including any of the full-length anti-FasL antibodies described herein. In some embodiments, a nucleic acid (or set of nucleic acids) of an anti-FasL antibody described herein can also include a nucleic acid sequence encoding a polypeptide tag (e.g., a protein purification tag, his tag, HA tag).
Also contemplated herein are isolated host cells comprising an anti-FasL antibody, isolated nucleic acids encoding an anti-FasL antibody polypeptide component, or vectors comprising nucleic acids encoding an anti-FasL antibody polypeptide component described herein.
The application also includes variants of these nucleic acid sequences. For example, variants include nucleotide sequences that hybridize under at least moderately stringent hybridization conditions to nucleic acid sequences encoding anti-FasL antibodies of the application.
The application also provides vectors into which the nucleic acid sequences of the application can be inserted.
Briefly, an anti-FasL antibody (e.g., a full-length anti-FasL antibody) can be expressed by inserting a natural or synthetic nucleic acid encoding the anti-FasL antibody into a suitable expression vector such that the nucleic acid is operably linked to 5' and 3' regulatory elements, including, for example, promoters (e.g., lymphocyte-specific promoters) and 3' untranslated regions (UTRs). The vectors may be suitable for replication and integration in eukaryotic host cells. Typical cloning and expression vectors contain transcriptional and translational terminators, initiation sequences, and promoters that regulate the expression of a nucleic acid sequence of interest.
The nucleic acids of the application can also be used for nucleic acid immunization and gene therapy by using standard gene delivery protocols. Nucleic acid delivery methods are known in the art. See, for example, U.S. Pat. nos.5,399,346, 5,580,859, 5,589,466, the entire contents of which are incorporated herein by reference. In some embodiments, the application also provides gene therapy vectors.
Nucleic acids can be cloned into many types of vectors. For example, the nucleic acid may be cloned into vectors including, but not limited to, plasmids, phagemids, phage derivatives, animal viruses and cosmids. Vectors of particular interest include expression vectors, replication vectors, probe-generating vectors and sequencing vectors.
In addition, the expression vector may be provided to the cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Green and Sambrook (2013,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,New York), as well as in other virology or molecular biology manuals. Viruses that may be used as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses. In general, suitable vectors include an origin of replication, promoter sequences, convenient restriction enzyme sites, and one or more selectable markers that function in at least one organism (see, e.g., WO 01/96584; WO 01/29058; and U.S. Pat.No.6,326,193).
Many virus-based systems have been developed for transferring genes into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. The selected gene may be inserted into a vector and packaged into retroviral particles using techniques known in the art. The recombinant virus is then isolated and delivered to cells of the subject in vivo or in vitro. Many retroviral systems are known in the art. In some embodiments, an adenovirus vector is used. Many adenoviral vectors are known in the art. In some embodiments, lentiviral vectors are used. Retroviral-derived vectors, such as lentiviruses, are suitable tools for achieving long-term gene transfer, as they allow for long-term stable integration of the transgene and propagation in daughter cells. Lentiviral vectors have additional advantages over retroviruses derived from tumors, such as the mouse leukemia virus, in that they can transduce non-dividing cells, such as hepatocytes. At the same time, it has the additional advantage of low immunogenicity.
Other promoter elements, e.g., enhancers, regulate the transcription initiation frequency. Typically they are located 30-110bp upstream of the start site, although many promoters have recently been found to contain functional elements downstream of the start site as well. The spacing between promoter elements is generally flexible so that the function of the promoter is maintained when the elements are interchanged or moved in position relative to each other. In the thymidine kinase (tk) promoter, the increase in the spacing between promoter elements to 50bp activity begins to decrease.
One example of a suitable promoter is the immediate early Cytomegalovirus (CMV) promoter sequence. The promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operably linked thereto. Another example of a suitable promoter is the elongation factor 1 alpha (EF-1 alpha) promoter. However, other constitutive promoters may also be used, including but not limited to simian virus 40 (SV 40) early promoter, mouse Mammary Tumor Virus (MMTV), human immunodeficiency virus long terminal repeat (HIV-LTR) promoter, moMuLV promoter, avian leukemia virus promoter, epstein-Barr virus immediate early promoter, rous sarcoma virus promoter, and human gene promoters including, for example, but not limited to, actin promoter, myosin promoter, hemoglobin promoter, and creatine kinase promoter. Furthermore, the application should not be limited to the use of constitutive promoters alone, and inducible promoters are also contemplated by the application. The use of an inducible promoter provides a molecular switch that enables expression of the polynucleotide sequence to which it is operably linked when such expression is desired and turns off expression when not desired. Inducible promoters include, but are not limited to, metallothionein promoters, glucocorticoid promoters, progesterone promoters, and tetracycline promoters.
In some embodiments, expression of the anti-FasL antibody is inducible. In some embodiments, the nucleic acid sequence encoding an anti-FasL antibody is operably linked to an inducible promoter, including any of the inducible promoters described herein.
Inducible promoter
The use of an inducible promoter provides a molecular switch that can initiate expression of a polynucleotide sequence operably linked thereto when expression is desired and which can shut down expression when expression is not desired. Exemplary inducible promoters suitable for use in eukaryotic cells include, but are not limited to, hormone-modulating elements (see, e.g., mader, S.and White, J.H. (1993) Proc.Natl. Acad. Sci. USA 90:5603-5607), synthetic ligand-modulating elements (see Spencer, D.M.et al (1993) Science 262:1019-1024), and ionizing radiation-modulating elements (see Manome, Y.et al (1993) Biochemistry 32:10607-10613;Datta,R.et al) (1992) Proc.Natl. Acad. Sci. USA 89:1014-10153). Other exemplary inducible promoters suitable for use in mammalian systems in vivo or in vitro are described in Gingrich et al (1998) Annual Rev. Neurosci 21:377-405. In some embodiments, the inducible promoter system for expression of the anti-FasL antibody is the Tet system. In some embodiments, the inducible promoter system for expression of the anti-FasL antibody is the E.coli lac suppression system.
One exemplary inducible promoter system employed in the present application is the Tet system. The system is based on the Tet system described by golden et al (1993). In one exemplary embodiment, the target polynucleotide is controlled by a promoter comprising one or more Tet operator (TetO) sites. In the inactive state, the Tet repressor (TetR) binds to the TetO site and inhibits transcription of the promoter. In the activated state, for example, in the presence of an inducer such as tetracycline (Tc), anhydrous tetracycline, doxycycline (Dox), or an active analog thereof, the inducer will release TetR from TetO, resulting in transcription. Doxycycline is a member of the tetracycline antibiotic family under the chemical name 1-dimethylamino-2, 4a,5, 7-pentahydroxy-11-methyl-4, 6-dioxo-1, 4a,11 a,12 a-hexahydrotetraene-3-carboxamide.
In one embodiment, tetR is codon optimized for expression in mammalian cells, such as mouse or human cells. Because of the degeneracy of the genetic code, most amino acids are encoded by more than one codon, such that the sequence of a given nucleic acid has a large number of variants without any change in the amino acid sequence encoded thereby. However, many organisms differ in codon usage, also known as "codon preference" (i.e., the preference of a given amino acid to use a particular codon). Codon preference is generally related to the presence of dominant tRNA species for a particular codon, which in turn increases the efficiency of mRNA translation. Coding sequences derived from a particular species (e.g., prokaryotes) can thus be tailored by codon optimization to enhance their expression in a different species (e.g., eukaryotes).
Other specific variations of the Tet system include the following "Tet-Off" and "Tet-On" systems. In the Tet-off system, transcription is inactive in the presence of Tc or Dox. In this system, the tetracycline-regulated transcriptional activator protein (tTA), consisting of TetR fused to the strong transcriptional activation domain of the herpes simplex virus VP16, regulates expression of the target nucleic acid under the transcriptional control of the tetracycline responsive promoter element (TRE). The TRE element consists of a TetO sequence tandem fused to a promoter (typically the smallest promoter sequence derived from the human cytomegalovirus immediate early promoter). In the absence of Tc or Dox, tTA binds to TRE and activates transcription of the target gene. In the presence of Tc or Dox, tTA cannot bind to TRE and the target gene cannot be expressed.
In contrast, in the Tet-On system, transcription is active in the presence of Tc or Dox. The Tet-On system is based On the reverse tetracycline regulated transcriptional activator rtTA. Like tTA, rtTA is a fusion protein consisting of the TetR repressor and VP16 transcriptional activation domain. However, a 4 amino acid change in the DNA binding region of TetR alters the binding properties of rtTA such that it recognizes only the tetO sequence on the target transgenic TRE in the presence of Dox. Therefore in the Tet-On system rtTA activates the transcription of the target gene regulated by TRE only in the presence of Dox.
Another inducible promoter system is the E.coli lac repressor system (see Brown et al, cell 49:603-612 (1987)). The Lac repressor system functions by regulating transcription of a polynucleotide of interest operably linked to a promoter comprising the Lac operator (lacO). Lac repressors (lacR) bind to LacO and thereby prevent transcription of the target polynucleotide. Expression of the polynucleotide of interest is induced by a suitable inducer, for example isopropyl- β -D thiogalactopyranoside (IPTG).
To assess the expression of the polypeptide or portion thereof, the expression vector to be introduced into the cell may further comprise a selectable marker gene or a reporter gene or both to facilitate identification and selection of the expressing cell from a population of cells transfected or infected with the viral vector. In other aspects, the selectable marker may be carried on separate DNA fragments and used in a co-transfection experiment. Either the selectable marker gene or the reporter gene may be flanked by appropriate regulatory sequences to enable expression in the host cell. Useful selectable markers include, for example, antibiotic resistance genes, such as neo and the like.
Reporter genes can be used to identify potentially transfected cells and evaluate the function of regulatory sequences. Typically, a reporter gene is a gene that is not present in or expressed by a recipient organism or tissue, and encodes a polypeptide whose expression is manifested by some readily detectable property, such as enzymatic activity. After the DNA is introduced into the recipient cell, the expression of the reporter gene is detected at an appropriate time. Suitable reporter genes may include genes encoding luciferases, beta-galactosidases, chloramphenicol acetyl transferase, secreted alkaline phosphatase, or green fluorescent protein (see Ui-Tel et al 2000FEBS Letters 479:79-82). Suitable expression systems are well known and may be prepared by known techniques or obtained commercially. In general, constructs that display the smallest 5' flanking region of the highest expression level of the reporter gene are considered promoters. Such promoter regions may be linked to reporter genes and used to assess the ability of certain substances to regulate promoter-driven transcription.
In some embodiments, nucleic acids encoding any of the full-length anti-FasL antibodies described herein are provided. In some embodiments, the nucleic acid comprises one or more nucleic acid sequences encoding the full length anti-FasL antibody heavy and light chains. In some embodiments, each of the one or more nucleic acid sequences is contained in a separate vector. In some embodiments, at least some of the nucleic acid sequences are contained in the same vector. In some embodiments, all nucleic acid sequences are contained in the same vector. The vector may be selected from, for example, mammalian expression vectors and viral vectors (such as vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpesviruses and lentiviruses).
Methods for introducing and expressing genes into cells are known in the art. In the context of expression vectors, the vector may be readily introduced into a host cell, such as a mammalian cell, bacterial, yeast or insect cell, by any method known in the art. For example, the expression vector may be introduced into the host cell by physical, chemical or biological means.
Physical methods for introducing polynucleotides into host cells include calcium phosphate precipitation, lipofection, gene gun methods, microinjection, electroporation, and the like. Methods for preparing cells comprising vectors and/or exogenous nucleic acids are well known in the art. See, e.g., green and Sambrook (2013,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,New York). In some embodiments, the polynucleotide is introduced into the host cell by calcium phosphate transfection.
Biological methods for introducing polynucleotides of interest into host cells include the use of DNA and RNA vectors. Viral vectors, particularly retroviral vectors, have become the most widely used method for inserting genes into mammalian cells, such as human cells. Other viral vectors may be derived from lentiviruses, poxviruses, herpes simplex virus type 1, adenoviruses, adeno-associated viruses, and the like. See, e.g., U.S. Pat. nos.5,350,674 and 5,585,362.
Chemical methods for introducing polynucleotides into host cells include colloidal dispersion systems, such as macromolecular complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system used as a delivery vehicle in vivo and in vitro is a liposome (e.g., an artificial membrane vesicle).
In the case of non-viral delivery systems, an exemplary delivery vehicle is a liposome. The use of lipid formulations to introduce nucleic acids into host cells (in vitro, ex vivo or in vivo) is contemplated. In another aspect, the nucleic acid may be conjugated to a lipid. The lipid-bound nucleic acid may be entrapped within the aqueous interior of the liposome, dispersed within the lipid bilayer of the liposome, linked to the liposome by a linking molecule that binds to the liposome and the oligonucleotide, entrapped in the liposome, formed a complex with the liposome, dispersed in a solution containing the lipid, mixed with the lipid, bound to the lipid, suspended in the lipid, contained in or mixed with the micelle, or otherwise bound to the lipid. The lipid, lipid/DNA or lipid/expression vector-related composition is not limited to any particular structure in solution. For example, they may exist in a bilayer structure, in micelles, or in a "collapsed" structure. They may also be simply dispersed in solution, possibly forming aggregates of non-uniform size or shape. Lipids are fatty substances, which may be naturally occurring or synthetic. For example, lipids include fat droplets naturally occurring in the cytoplasm, as well as a class of compounds containing long chain aliphatic hydrocarbons and derivatives thereof, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.
Regardless of the method used to introduce exogenous nucleic acid into a host cell or otherwise expose the cell to the inhibitors of the application, various experiments can be performed in order to confirm the presence of the recombinant DNA sequence in the host cell. Such assays include, for example, "molecular biology" assays well known to those of skill in the art. Such as Southern and Northern blotting, RT-PCR and PCR; "biochemical" assays, such as detecting the presence or absence of a particular polypeptide, such as by immunological methods (ELISAs and Western blots) or by the assays described herein, fall within the scope of the application.
Preparation of anti-FasL antibodies
In some embodiments, the anti-FasL antibody is a monoclonal antibody or is derived from a monoclonal antibody. In some embodiments, the anti-FasL antibody comprises V from a monoclonal antibody H And V L Or a variant thereof. In some embodiments, the anti-FasL antibody further comprises CH1 and CL regions from a monoclonal antibody, or a variant thereof. Monoclonal antibodies can be prepared using methods known in the art, including hybridoma cell methods, phage display methods, or using recombinant DNA methods, for example. Furthermore, exemplary phage display methods are described herein and in the examples below.
In hybridoma cell methods, hamsters, mice, or other suitable host animals are typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, lymphocytes may be immunized in vitro. The immunizing agent may include a polypeptide or fusion protein of the protein of interest. Typically, peripheral Blood Lymphocytes (PBLs) are used if human cells are desired, whereas spleen cells or lymph node cells are used if non-human mammalian cells are desired. Lymphocytes are fused with an immortalized cell line, such as polyethylene glycol, using an appropriate fusion agent to form a hybridoma cell. Immortalized cell lines are typically transformed mammalian cells, especially myeloma cells of rodent, bovine and human origin. Rat or mouse myeloma cell lines are typically employed. The hybridoma cells may be cultured in a suitable medium, which preferably contains one or more substances that inhibit the growth or survival of the unfused immortalized cells. For example, if the parent cell lacks hypoxanthine-guanine phosphoribosyl transferase (HGPRT or HPRT), the hybridoma cell culture medium typically includes hypoxanthine, aminopterin, and thymidine (HAT medium), which prevents HGPRT-deficient cells from growing.
In some embodiments, the immortalized cell lines fuse efficiently, ensure high levels of stable expression of antibodies by the antibody-producing cell of choice, and are sensitive to certain media, such as HAT media. In some embodiments, the immortal cell line is a mouse myeloma cell line, available from, for example, the sork cell collection in san diego, california and the american type culture collection in ma, virginia. Human myeloma and murine-human hybrid myeloma cell lines are also described for use in the production of humanized monoclonal antibodies.
The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the polypeptide. The binding specificity of monoclonal antibodies produced by hybridoma cells can be determined by immunoprecipitation or in vitro binding assays, such as Radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques or analytical methods are known in the art. The binding affinity of a monoclonal antibody can be determined by, for example, the Scatchard (Scatchard) assay described in Munson and Pollard, anal. Biochem.,107:220 (1980).
After the desired hybridoma cells are identified, the target clone may be subcloned by limiting dilution and cultured by standard methods. Suitable media for this purpose include, for example, modified Eagle Medium (DMEM) and RPMI-1640 medium. Alternatively, the hybridoma cells may be grown as ascites in a mammalian body.
Monoclonal antibodies secreted by subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification methods, such as protein A-sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
In some embodiments, according to any of the anti-FasL antibodies described herein, the anti-FasL antibody comprises a sequence selected from the group consisting of clones of an antibody library (e.g., a phage library displaying scFv or Fab fragments). The clones may be identified by screening combinatorial libraries of antibody fragments having the desired activity. For example, a variety of methods are known in the art for generating phage display libraries and screening these libraries to obtain antibodies of the desired binding characteristics. These methods are reviewed in, for example, hoogenboom et al, methods in Molecular Biology 178:178:1-37 (O' Brien et al, ed., human Press, totowa, N.J., 2001), and in, for example, mcCafferty et al, nature 348:552-554; clackson et al, nature 352:624-628 (1991); marks et al, J.mol. Biol.222:581-597 (1992); marks and Bradbury, methods in Molecular Biology 248:161-175 (Lo, ed., human Press, totowa, n.j., 2003); sidhu et al, J.mol. Biol.338 (2): 299-310 (2004); lee et al, J.mol.biol.340 (5): 1073-1093 (2004); felloose, proc. Natl. Acad. Sci. USA 101 (34): 12467-12472 (2004); and Lee et al, J.Immunol. Methods 284 (1-2): 119-132 (2004).
In some phage display methods, V is cloned separately by Polymerase Chain Reaction (PCR) H And V L All components of the gene are randomly recombined in a phage library and then screened for phages capable of binding antigen as described in Winter et al, ann.rev.immunol.,12:433-455 (1994). Phage typically display antibody fragments as scFv fragments or as Fab fragments. The immune-derived library phage provides high affinity antibodies to the immunogen without the need to construct hybridoma cells. Alternatively, natural libraries (e.g., from humans) can be cloned to provide a single antibody source against multiple non-self and self-antigens without any immunization, as described in Griffiths et al, EMBO J,12:725-734 (1993). Finally, natural libraries can also be prepared by cloning non-rearranged V-gene fragments from stem cells and encoding CDR3 hypervariable regions using PCR primers comprising random sequences and completing the rearrangement in vitro, as described in Hoogenboom and Winter, J.mol.biol.,227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example, U.S. Pat. nos. 5,750,373 and US Patent Publication nos. 2005/007974, 2005/019455, 2005/0266000, 2007/017126, 2007/0160598, 2007/0237764, 2007/0292936 and 2009/0002360.
The anti-FasL antibodies are prepared by phage display screening of the portions of the library of anti-FasL antibodies that specifically bind to the target FasL. The library may be a human scFv phage display library having at least 1X 10 9 (e.g. at least 1X 10) 9 、2.5×10 9 、5×10 9 、7.5×10 9 、1×10 10 、2.5×10 10 、5×10 10 、7.5×10 10 Or 1X 10 11 ) A diverse variety of unique human antibody fragments. In some embodiments, the library is a human natural library constructed from DNA extracted from PMBCs and spleen of healthy subjects, comprising all human heavy and light chain subfamilies. In some embodiments, the library is a human natural library constructed from DNA extracted from PMBCs isolated from patients with various diseases, such as patients with autoimmune diseases, cancer patients, and patients with infectious diseases. In some embodiments, the library is a semi-synthetic human library in which the heavy chain CDR3 is entirely random, with all amino acids (except cysteine) present at any given position with the same probability. (see, e.g., hoet, R.M. et al, nat. Biotechnol.23 (3): 344-348, 2005). In some embodiments, the heavy chain CDR3 of the semi-synthetic human library is between 5 and 24 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24) amino acids in length. In some embodiments, the library is a fully synthetic phage display library. In some embodiments, the library is a non-human phage display library.
Phage clones with high affinity for target FasL can be screened by iterative binding of phage to target FasL, which is bound to a solid support (e.g., beads for solution panning or mammalian cells for cell panning), followed by removal of unbound phage and elution of specifically bound phage. The bound phage clones are then eluted and used to infect appropriate host cells, e.g., E.coli XL1-Blue, for expression and purification. Phage clones that specifically bind to FasL can be enriched by multiple rounds of panning (e.g., 2, 3, 4, 5, 6 or more rounds), such as solution panning, cell panning, or both. Specific binding of the enriched phage clones to the target FasL can be detected by any method known in the art, including, for example, ELISA and FACS.
Another method of screening antibody libraries is to display proteins on the surface of yeast cells. Wittrup et al (U.S. Pat. Nos. 6,699,658 and 6,696,251) developed a method for displaying libraries of yeast cells. In this yeast display system, one component comprises a yeast lectin protein (Aga 1) anchored to the yeast cell wall, and the other component comprises a second subunit of lectin protein Aga2, which subunit can bind to the Aga1 protein via disulfide bonds and thus be displayed on the yeast cell surface. The Aga1 protein is expressed by integrating the Aga1 gene into the yeast chromosome. A library of single-chain variable fragments (scFv) was fused to the Aga2 gene in a yeast display plasmid, and after transformation, the library was retained in the yeast due to the presence of additional nutritional markers. Both the Aga1 and Aga2 proteins are expressed under the control of a galactose-inducible promoter.
Human antibody V gene bank (V) H And V K Fragments) were obtained by PCR methods using a set of degenerate primers (Sblatttero, D.and Bradbury, A.Immunotechnology 3,271-278 1998). PCR templates were derived from commercially available RNA or cDNA, including PBMC, spleen, lymph nodes, bone marrow and tonsils. Will be independent V H And V K After PCR library pooling, they were assembled into scFv forms by overlap extension PCR (Sheets, M.D.et al, proc.Natl. Acad.Sci.USA 95,6157-6162 1998). To construct a yeast scFv display library, the resulting scFv PCR product was cloned into a yeast display plasmid in yeast by homologous recombination. (Chao, G, et al, nat Protoc.2006;1 (2): 755-68.Miller KD,et al.Current Protocols in Cytometry 4.7.1-4.7.30,2008).
anti-FasL antibodies can be screened using a mammalian cell display system in which the antibody is partially displayed on the cell surface and antibodies specifically targeting FasL are isolated by antigen-directed screening methods (as described in U.S. patent No.7,732,195B2). A Chinese Hamster Ovary (CHO) cell library displaying a large number of human IgG antibody genes can be established and used to discover clones expressing high affinity antibody genes. Another display system has been developed that allows the same protein to be displayed and secreted simultaneously on the cell surface by alternative splicing, wherein the displayed protein phenotype remains genotype-dependent, allowing the secreted soluble antibody to be characterized simultaneously in biophysical and cell function-based assays. This method overcomes many of the limitations previously exhibited by mammalian cells and enables direct screening and maturation of antibodies in the form of full-length, glycosylated IgGs (Peter M.Bowers, et al Methods 2014, 65:44-56). Transient expression systems are suitable for single round antigen selection prior to antibody gene recovery and are therefore most useful for selecting antibodies from smaller libraries. Stable exon vectors offer an attractive option. The exon vectors can be transfected efficiently and stably maintained at low copy numbers, allowing multiple rounds of panning and resolution of more complex antibody libraries.
The IgG library was constructed based on ligation of germline sequence V gene segments isolated from a population of human donors with rearranged (D) J regions. Reverse transcription of RNA collected from 2000 human blood samples into cDNA using V H And V K Specific primer amplification V H And V K Fragments were purified by gel extraction. Will V H And V K Fragments were subcloned into display vectors containing the IgG1 or K constant regions, respectively, and then 293T was electroporated or transduced into cells to prepare IgG libraries. To prepare scFv antibody display libraries, ligation V H And V K To generate scfvs, which are then subcloned into display vectors and electroporated or transduced into 293T cells. It is well known that IgG libraries are constructed based on germline sequence V gene segments and rearranged (D) J regions isolated from a population of donors, which may be mice, rats, rabbits or monkeys.
Monoclonal antibodies can also be prepared by recombinant DNA methods, for example as described in U.S. patent No.4,816,567. The DNA encoding the monoclonal antibodies of the application can be readily isolated and sequenced by conventional methods, such as by oligonucleotide probes that specifically bind to the light and heavy chain genes encoding murine antibodies. The hybridoma cells described above or the FasL-specific phage clones of the application can serve as a source of such DNA. After isolation, the DNA may be placed in an expression vector, which is then transfected into a host cell, such as simian COS cells, chinese hamster ovary Cancer (CHO) cells, or myeloma cells that do not produce immunoglobulins, to obtain monoclonal antibodies synthesized in the recombinant host cell. The DNA may also be modified, for example by replacing the human heavy and light chain constant regions with coding sequences and/or by replacing homologous non-human sequences with framework regions (U.S. patent No.4,816,567; morrison et al, supra), or by covalently joining all or part of the coding sequence of an immunoglobulin to the coding sequence of a non-immunoglobulin polypeptide. Such non-immunoglobulin polypeptides may replace the constant regions of the antibodies of the application, or may replace an antigen binding site in the variable domains of the antibodies of the application, to form chimeric bivalent antibodies.
The antibody may be a monovalent antibody. Methods of making monovalent antibodies are known in the art. For example, a recombinant expression method involving an immunoglobulin light chain and a modified heavy chain. Heavy chains are typically truncated at any position in the Fc region to prevent heavy chains from cross-linking with each other. Alternatively, the relevant cysteine residues are substituted with other amino acid residues or deleted to prevent cross-linking.
In vitro methods are also suitable for the preparation of monovalent antibodies. Digestion of antibodies to produce antibody fragments, particularly Fab fragments, may be accomplished using any method known in the art.
The antibody variable domain having the desired binding specificity (antibody-antigen binding site) may be fused to an immunoglobulin constant region. Preferably fusion with an immunoglobulin heavy chain constant region, which comprises at least part of the hinge, CH2 and CH3 regions. In some embodiments, the first heavy chain constant region (CH 1) comprising the necessary site for light chain binding is present in at least one fusion. The DNA encoding the immunoglobulin heavy chain fusion, and if desired, the immunoglobulin light chain, is inserted into a separate expression vector and co-transfected into a suitable host organism.
Fully human and humanized antibodies
The anti-FasL antibody (e.g., full length anti-FasL antibody) may be a fully human antibody or a humanized antibody. Humanized forms of non-human (e.g., mouse) antibody portions are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (e.g., fv, fab, fab ', F (ab') 2 Other antigen binding subsequences of scFv or antibodies), which typically include minimal sequences derived from non-human immunoglobulins. Humanized antibodies include human immunoglobulins, immunoglobulin chains or fragments thereof (recipient antibodies) in which residues from the recipient CDR are assigned the desired specificity, affinity andnon-human (donor antibody) CDR residues of performance are substituted, e.g., mouse, rat or rabbit CDRs. In some embodiments, the human immunoglobulin Fv framework region residues are replaced by corresponding non-human residues. Humanized antibodies may also comprise amino acid residues that are neither of the recipient antibody nor in the introduced CDR or framework sequences. Typically, a humanized antibody comprises at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are human immunoglobulin consensus sequences.
Typically, humanized antibodies contain one or more amino acid residues introduced from a non-human source. Those non-human amino acid residues are often referred to as "import" residues, typically from "import" variable domains. According to some embodiments, humanization may be performed essentially as described below by Winter and colleagues (Jones et al, nature,321:522-525 (1986); riechmann et al, nature,332:323-327 (1988); verhoeyen et al, science,239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Thus, this "humanized" antibody portion (U.S. patent No.4,816,567), which is substantially less than a fully human antibody, has its variable domains replaced by corresponding sequences from a non-human source. In practice, humanized antibody portions are typical human antibody portions in which some CDR residues and possibly some framework region residues are replaced with residues from similar sites in rodent antibodies.
Fully human antibodies are an alternative to humanization. For example, transgenic animals (e.g., mice) that are capable of producing a complete fully human antibody library after immunization without endogenous immunoglobulin production can now be prepared. For example, homozygous deletion of the antibody heavy chain Junction (JH) gene in chimeric and germ-line mutant mice has been reported to completely suppress endogenous antibody production. Transferring an array of human germline immunoglobulin genes into such germline mutant mice, human antibodies can be produced under antigen stimulation, see, e.g., akobovits et al, PNAS USA,90:2551 (1993); jakobovits et al, nature,362:255-258 (1993); bruggemann et al, year in immunol.,7:33 (1993); U.S. patent nos.5,545,806,5,569,825,5,591,669,5,545,807; and WO 97/17852. Alternatively, fully human antibodies can be prepared by introducing a human immunoglobulin locus into a transgenic animal (e.g., a mouse in which endogenous immunoglobulin genes have been partially or fully silenced). Upon antigen stimulation, the production of fully human antibodies can be found to be very similar in all respects to their production in humans, including gene rearrangement, assembly and antibody libraries. Such methods are described, for example, in U.S. patent nos.5,545,807;5,545,806;5,569,825;5,625,126;5,633,425; and 5,661,016,and Marks et al, bio/Technology,10:779-783 (1992); lonberg et al, nature,368:856-859 (1994); morrison, nature,368:812-813 (1994); fishwild et al Nature Biotechnology,14:845-851 (1996); neuberger, nature Biotechnology,14:826 (1996); lonberg and Huszar, international.Rev.Immunol., 13:65-93 (1995).
Fully human antibodies are also produced by in vitro activation of B cells (see U.S. patents 5,567,610and 5,229,275) or by using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J.mol.biol.,227:381 (1991); the techniques of Marks et al, J.mol.biol.,222:581 (1991), cole et al, and Boerner et al can also be used to prepare fully human monoclonal antibodies. See Cole et al, monoclonal Antibodies and Cancer Therapy, alan R.Lists, p.77 (1985) and Boerner et al, J.Immunol.,147 (1): 86-95 (1991).
anti-FasL antibody variants
In some embodiments, the amino acid sequences of anti-FasL antibody variants provided herein (e.g., full length anti-FasL antibodies) are also contemplated. For example, it may be desirable to improve the binding affinity and/or other biological activity of antibodies. The amino acid sequence of an antibody variant may be prepared by introducing appropriate modifications in the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues in the amino acid sequence of the antibody. The final construction can be accomplished by any combination of amino acid residue deletions, insertions, and substitutions to impart the desired characteristics. For example, antigen binding.
In some embodiments, anti-FasL antibody variants having one or more amino acid substitutions are provided. Target sites for substitution mutations include hypervariable regions (HVRs) and Framework Regions (FRs). Amino acid substitutions may be introduced into the antibody of interest to screen for products of a desired activity, e.g., improved biological activity, retention/improvement of antigen binding capacity, reduced immunogenicity, or improved ADCC or CDC.
Conservative substitutions are shown in table 4 below.
TABLE 4 conservative substitutions
Amino acids are classified into different classes according to the nature of the side chain:
a. hydrophobic amino acid: norleucine, methionine Met, alanine Ala, valine Val, leucine Leu, isoleucine Ile;
b. neutral hydrophilic amino acid: cysteine Cys, serine Ser, threonine Thr, asparagine Asn, glutamine Gln;
c. acidic amino acid: aspartic acid Asp, glutamic acid Glu;
d. basic amino acid: histidine His, lysine Lys, arginine Arg;
e. contains amino acids affecting the chain direction: glycine Gly, proline Pro;
f. aromatic amino acid: tryptophan Trp, tyrosine Tyr, phenylalanine Phe.
Substitutions of non-conservative amino acids include substitution of one of the above classes into another class.
One exemplary substitution variant is an affinity matured antibody, conveniently produced using, for example, phage display-based affinity maturation techniques. Briefly, one or more CDR residues are mutated, the variant antibody portion is displayed on a phage, and variants are screened for a particular biological activity (e.g., activity to inhibit apoptosis or increased antibody affinity). Alterations (e.g., substitutions) may be made in the HVRs regions to obtain improved antibody affinity or biological activity. Can be used forThe resulting variants V were detected with a codon-encoded residue that was altered in the "hot spot" of the HVR, i.e., mutated at high frequencies during somatic maturation (see, e.g., chordhury, methods mol. Biol.207:179-196 (2008)), and/or at Specific Determinant Residues (SDRs) H And V L Is used for the binding affinity of (a) to the substrate. Methods of constructing and reselecting affinity maturation from secondary libraries have been described in several documents, for example, hoogenboom et al in Methods in Molecular Biology 178:1-37 (O' Brien et al ed., human Press, totowa, N.J. (2001)).
In some affinity maturation embodiments, diversity is introduced into the selected variable genes for affinity maturation by any of a variety of methods (e.g., error-prone PCR, strand shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is screened to identify antibody variants with the desired affinity. Another approach to introducing diversity involves HVR-mediated approaches in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding are specifically recognized, for example, using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 regions are generally particularly important targets.
In some embodiments, substitutions, insertions, or deletions may occur within one or more HVRs, provided that such changes do not substantially reduce the ability of the antibody to bind to an antigen. For example, conservative changes (e.g., conservative substitutions provided herein) may be made in HVRs that do not substantially reduce binding affinity. These changes may occur outside the HVR "hot spot" or SDRs region. Variant V provided above in some embodiments H And V L The sequence, each HVR is either unchanged or contains no more than 1, 2, or 3 amino acid substitutions.
One useful method by which amino acid residues or regions of an antibody can be identified that can be targeted for mutation is termed "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244:1081-1085. In this method, one or a group of target residues (e.g., charged residues such as arginine, aspartic acid, histidine, lysine, and glutamic acid) are substituted with neutral or negatively charged amino acids (e.g., alanine or glutamic acid) to determine whether the interaction of the antibody with the antigen is affected. Substitutions may be further introduced at the amino acid position to demonstrate functional sensitivity of the position to the initial substitution. Alternatively or additionally, the contact site between the antibody and the antigen is identified by the crystal structure of the antigen-antibody complex. These contact site residues and adjacent residues may be targeted or eliminated as substitution candidates. Variants are screened to determine if they have the desired properties.
Insertion of amino acid sequences, including fusion at the amino and/or carboxy terminus, ranges in length from 1 residue to polypeptides comprising 100 or more residues, and also includes insertion of 1 or more amino acid residues within the sequence. Examples of terminal insertions include antibodies having a methionyl residue at the N-terminus. Other insertional variants of antibody molecules include polypeptides that fuse an enzyme (e.g., ADEPT) or increase the serum half-life of an antibody at the N-or C-terminus of the antibody molecule.
Variant Fc region
In some embodiments, one or more amino acid modifications are introduced into the Fc region of an antibody described herein (e.g., a full length anti-FasL antibody or an anti-FasL antibody fusion protein), thereby producing an Fc region variant. In some embodiments, the Fc region variant has enhanced ADCC potency, typically associated with Fc-binding receptors (FcRs). In some embodiments, the Fc region variant has reduced ADCC potency. There are many examples of alterations or mutations in Fc sequences affecting their potency, for example, WO 00/42072 and Shields et al J biol. Chem.9 (2): 6591-6604 (2001) describe antibody variants with increased or decreased binding to FcRs. The contents of these publications are incorporated herein by reference.
Antibody-dependent cell-mediated cytotoxicity (ADCC) is the mechanism of action of therapeutic antibodies against tumor cells. ADCC is a cell-mediated immune defense in which effector cells of the immune system actively lyse target cells (e.g., cancer cells) when antigens on the surface of the target cell membrane are bound by specific antibodies (e.g., anti-FasL antibodies). Typically ADCC effects involve NK cells activated by antibodies. NK cells express the Fc receptor CD16. The receptor recognizes and binds to the Fc portion of an antibody molecule that binds to the surface of a target cell. The most common Fc receptor on the surface of NK cells is CD16 or fcyriii. Binding of the Fc receptor to the Fc region of the antibody results in activation of NK cells, releasing the cell lysis particles, followed by apoptosis of the target cells. The killing of tumor cells by ADCC can be determined by experiments specific for NK-92 cells transfected with high affinity FcR. The results were compared with wild-type NK-92 which did not express FcR.
In some embodiments, the application also provides anti-FasL antibody variants (e.g., full length anti-FasL antibody variants) comprising an Fc region having a portion, but not all, of effector function such that it has an extended half-life in vivo, whereas specific effector functions (e.g., CDC or ADCC) are not necessary or detrimental, which anti-FasL antibodies are desirable candidates for the application. Reduction/elimination of CDC and/or ADCC activity is confirmed by cytotoxicity assays in vitro and/or in vivo. For example, antibodies were confirmed to lack fcγr binding capacity (and thus potentially ADCC activity) by an Fc receptor (FcR) binding assay but still retain FcRn binding capacity. Among the major cells mediating ADCC, NK cells express fcyriii only, whereas monocytes express fcyri, fcyrii and fcyriii. The expression of FcR on hematopoietic cells is summarized in Table 3 at page 464 of Ravetch and Kinet Annu.Rev.Immunol.9:457-492 (1991). Non-limiting examples of in vitro evaluation of ADCC activity of a target molecule are described in U.S. Pat. No.5,500,362 (see, e.g., hellstrom, I.et al Proc.Nat 'l Acad.Sci.USA 83:7059-7063 (1986) and Hellstrom, I.et al., proc.Nat' l Acad.Sci.USA 82:1499-1502 (1985); U.S. Pat. No.5,821,337 (see, e.g., buggemann, M.et., J.exp.Med.166:1351-1361 (1987)) or non-radioactive detection methods may be employed (see, e.g., ACTI) TM Flow cytometry non-radioactive cytotoxicity assays (CellTechnology, inc.Mountain View, calif.) and CYTOTOX 96 TM Nonradioactive cytotoxicity assay (Promega, madison, wis.). Effector cells employed in such assay experiments include Peripheral Blood Mononuclear Cells (PBMCs) and natural killer cells (NK). Alternatively, or in addition, ADCC activity of the target molecule is detected in vivo, e.g., in an animal model, such as ClyAs described in nes et al Proc. Nat' l Acad. Sci. USA 95:652-656 (1998). Also, a C1q binding assay may be performed to confirm that the antibody is unable to bind to C1q, thereby lacking CDC activity. See, e.g., C1q and C3C binding ELISA in WO 2006/029879 and WO 2005/100402. To assess complement activation, CDC assays can be performed (see, e.g., gazzano-Santoro et al, J.Immunol. Methods 202:163 (1996); cragg, M.S. et al, blood 101:1045-1052 (2003); and Cragg, M.S. and M.J. Glennie, blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life are determined using methods known in the art (see, e.g., petkova, s.b. et al, int' l.immunol.18 (12): 1759-1769 (2006)).
Antibodies with reduced effector function comprising substitution of one or more residues at residues 238, 265, 269, 270, 297, 327 and 329 of the Fc region (u.s.pat.no. 6,737,056). These Fc variants include Fc variants with substitution of two or more residues at positions 265, 269, 270, 297 and 327, including Fc variants known as "DANA" with substitution of alanine at residues 265 and 297 (u.s.pat. No.7,332, 581).
Such antibody variants with increased or decreased binding to FcRs have been described (see, e.g., U.S. Pat.No.6,737,056; WO2004/056312, and Shields et al, J.biol.chem.9 (2): 6591-6604 (2001)).
In some embodiments, an anti-FasL antibody (e.g., full length anti-FasL antibody) variant is provided that comprises an Fc region variant having one or more amino acid substitutions capable of enhancing ADCC effects. In some embodiments, the Fc region variant comprises one or more amino substitutions at positions 298, 333, and/or 334 (EU residue numbering) of the Fc region that are capable of enhancing ADCC effects. In some embodiments, the anti-FasL antibody (e.g., full length anti-FasL antibody) variant comprises amino acid substitutions at positions S298A, E333A, and K334A of the Fc region.
In some embodiments, the alteration of the Fc region results in an alteration (i.e., an increase or decrease) in C1q binding and/or Complement Dependent Cytotoxicity (CDC), as described in U.S.Pat.No.6,194,551, WO/51642, and Idusogie et al, J.Immunol.164:4178-4184 (2000).
In some embodiments, an anti-FasL antibody (e.g., full length anti-FasL antibody) variant is provided that comprises an Fc region variant having one or more amino acid substitutions that is capable of extending half-life or enhancing binding to an Fc receptor (FcRn). Antibodies with extended half-life and improved FcRn binding are described in US 2005/0014934A1 (hiton et al). These antibody Fc regions comprise one or more amino acid substitutions that enhance the binding of the Fc region to FcRn. These Fc variants comprise one or more substitutions in residues 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434 in the Fc region, for example a substitution in residue 434 in the Fc region (u.s.pat. No.7,371,826).
See also Duncan & Winter, nature 322:738-40 (1988); U.S. Pat. nos. 5,648,260; examples of other Fc region variants are provided in U.S. Pat. No.5,624,821 and WO 94/29351.
The application contemplates anti-FasL antibodies (e.g., full length anti-FasL antibodies) comprising any one or a combination of the Fc variants described herein.
Glycosylation variants
In some embodiments, an anti-FasL antibody provided herein (e.g., a full length anti-FasL antibody) is altered to increase or decrease the degree of glycosylation of the anti-NGF antibody. The addition or deletion of glycosylation sites on an anti-FasL antibody can be conveniently accomplished by altering the amino acid sequence of the anti-NGF antibody or polypeptide portion thereof to thereby add or remove one or more glycosylation sites.
Wherein the anti-FasL antibody comprises an Fc region to which a saccharide can be linked. Natural antibodies produced by mammalian cells typically comprise branched double-antennary oligosaccharides, which are typically linked to the Fc region CH2 domain Asn297 via an N-linkage, see, e.g., wright et al, TIBTECH 15:26-32 (1997). The oligosaccharides may comprise a variety of sugars, such as mannose, N-acetylglucosaminide (GlcNAc), galactose and sialic acid, as well as trehalose attached to the GlcNAc of the "stem" of the double-antennary oligosaccharide structure. In some embodiments, the anti-FasL antibodies of the present application can be oligosaccharide modified to produce anti-FasL antibody variants with certain improved properties.
N-glycans attached to the CH2 domain of the Fc region are heterogeneous. Antibodies or Fc fusion proteins produced in CHO cells are fucosylated by fucosyltransferase activity, see Shoji-Hosaka et al, J.biochem.2006,140:777-83. Typically, a small fraction of naturally occurring nonfucosylated IgGs can be detected in human serum. N-glycosylation of the Fc region is important for its binding to fcγr; whereas non-fucosylated N-glycans enhance the binding capacity of Fc to fcγriiia. Enhanced binding to FcRIIIa results in enhanced ADCC effect, which is advantageous in certain antibody therapeutic applications requiring cytotoxicity.
In some embodiments, enhanced effector function may be detrimental when Fc-mediated cellular cytotoxicity is not required. In some embodiments, the Fc fragment or CH2 domain is non-glycosylated. In some embodiments, glycosylation is prevented by mutating the N-glycosylation site in the CH2 domain.
In some embodiments, anti-FasL antibody (e.g., full length anti-FasL antibody) variants are provided that comprise an Fc region, wherein the saccharide structure linked to the Fc region has reduced fucose or lacks fucose, which may enhance ADCC function. In particular, provided herein are anti-FasL antibodies that have reduced fucose relative to the same anti-FasL antibodies produced by wild-type CHO cells. That is, they are characterized by having a smaller amount of fucose than antibodies produced by natural CHO cells (e.g., CHO cells producing a naturally glycosylated form, CHO cells containing the natural FUT8 gene). In some embodiments, the N-linked glycans of the anti-FasL antibody have less than 50%, 40%, 30%, 20%, 10% or 5% fucose. For example, the anti-FasL antibody may have a fucose content of 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. In some embodiments, the N-linked glycans of the anti-FasL antibody do not comprise fucose, i.e., wherein the anti-FasL antibody is completely free of fucose, or is free of fucose or is defucosylated. The fucose content is determined by calculating the average fucose content in the sugar chains attached to Asn297 relative to the total amount of all sugar structures attached to Asn297 (e.g. complex, hybrid or mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546. Asn297 refers to the asparagine residue at position 297 of the Fc region (EU Fc region residue numbering system). However, asn297 may also be located upstream or downstream of position 297 by ±3 amino acids, i.e. between positions 294 and 300, due to minor sequence variations of the antibody. These fucosylated variants may have enhanced ADCC function. See, for example, US Patent Publication nos. US 2003/0157108 (Presta, l.), US 2004/0093621 (Kyowa Hakko Kogyo co., ltd). Examples of publications related to antibody variants that are "defucosylated" or "lack of fucose" include US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/015614; US 2002/0164328; US 2004/0093621; US 2004/013321; US 2004/010704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO 2005/053742; WO 2002/031140; okazaki et al J.mol.biol.336:1239-1249 (2004); yamane-Ohnuki et al Biotech.Bioeng.87:614 (2004). Cell lines capable of producing defucosylated antibodies include Lec13CHO cells lacking the fucosylation function of the protein (Ripka et al, arch. Biochem. Biophysis. 249:533-545 (1986), US Pat Appl No US 2003/0157108a1, presta, l, and WO 2004/056312A1,Adams et al, especially example 11), and knockout cell lines such as alpha-1, 6-fucosyltransferase genes, FUT8 knockout CHO cells (see Yamane-Ohnuki et al, biotech. Bioeng.87:614 (2004), kanda, y. Et al, biotechnol. Bioeng.,94 (4): 680-688 (2006), and WO 2003/085107).
Variants of anti-FasL antibodies (e.g., full length anti-FasL antibodies) further provide bisecting oligosaccharides, e.g., wherein a double-antennary oligosaccharide linked to the Fc region of an anti-FasL antibody is bisected by GlcNAc. Such anti-FasL antibody (e.g., full length anti-FasL antibody) variants may have reduced fucosylation and/or enhanced ADCC function. Examples of such antibody variants are described in WO 2003/011878 (Jean-mair et al); U.S. Pat. No.6,602,684 (Umana et al); US 2005/0123946 (Umana et al), and Ferrara et al Biotechnology and Bioengineering,93 (5): 851-861 (2006). Also provided are variants of anti-FasL antibodies (e.g., full length anti-FasL antibodies) having at least one galactose residue in the oligosaccharide linked to the Fc region. Such anti-FasL antibody variants may have enhanced CDC function. Such variants are described, for example, in WO 1997/30087 (Patel et al); WO 1998/58964 (Raju, s.); and WO 1999/22764 (Raju, S.).
In some embodiments, the anti-FasL antibody (e.g., full length anti-FasL antibody) variant comprises an Fc region capable of binding to fcyriii. In some embodiments, the anti-FasL antibody (e.g., full length anti-FasL antibody) variant comprising an Fc region has ADCC activity in the presence of human effector cells (e.g., T cells) or has enhanced ADCC activity in the presence of human effector cells as compared to an otherwise identical anti-FasL antibody (e.g., full length anti-FasL antibody) having a human wild-type IgG1Fc region.
Cysteine engineered variants
In some embodiments, it is desirable to prepare a cysteine engineered anti-FasL antibody (e.g., a full length anti-FasL antibody) in which one or more amino acid residues are substituted with cysteine residues. In some embodiments, the substitution residue occurs at an accessible site of the anti-FasL antibody. By substituting those residues with cysteines, active sulfhydryl groups are located at accessible sites of anti-FasL antibodies that can be used to couple the anti-FasL antibodies with other moieties, such as drug moieties or linker-drug moieties, to prepare anti-FasL immunoconjugates as further described herein. Cysteine engineered anti-FasL antibodies (e.g., full length anti-FasL antibodies) can be prepared as described, for example, in U.S. Pat. No.7,521,541.
Derivatives and their use as inhibitors of viral infection
In some embodiments, the anti-FasL antibodies provided herein (e.g., full length anti-FasL antibodies) can be further modified to include other non-protein portions known and readily available in the art. Suitable moieties for derivatizing anti-FasL antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1, 3-dioxolane, poly-1, 3, 6-trioxane, ethylene/maleic anhydride copolymers, polyaminoacids (homo-or random copolymers), dextran or poly (n-vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymers, propylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde has advantages in manufacturing due to its stability in water. The polymer may have any molecular weight and may be branched or unbranched. The number of polymers attached to the anti-FasL antibody can vary, and if more than one polymer is attached, they can be the same or different molecules. In general, the amount and/or type of polymer used for derivatization can be determined based on considerations including, but not limited to, the need to improve the properties or function of the anti-FasL antibody, whether the anti-FasL antibody derivative is used for treatment under particular conditions, and the like.
Pharmaceutical composition
Also provided herein are compositions (e.g., pharmaceutical compositions, also referred to herein as formulations) comprising any one of the anti-FasL antibodies (e.g., full-length anti-FasL antibodies), nucleic acids encoding the antibodies, vectors comprising nucleic acids encoding the antibodies, or host cells comprising the nucleic acids or vectors described herein. In some embodiments, a pharmaceutical composition is provided comprising any of the anti-FasL antibodies described herein and a pharmaceutically acceptable carrier.
Suitable anti-FasL antibody formulations may be prepared in lyophilized or liquid formulation form by mixing anti-FasL antibody of the desired purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition,Osol,A.Ed. (1980)). Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at the dosages and concentrations employed, and include buffers such as: phosphates, citric acid, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g. octadecyldimethylbenzyl ammonium chloride, hexamethyl ammonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butanol or benzyl alcohol, alkyl p-hydroxybenzoates, such as methyl or propyl p-hydroxybenzoate, catechol, m-hydroxybenzoate A benzenediol; cyclohexanol; 3-pentanol and m-cresol); a low molecular weight (less than 10 residues) polypeptide; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., zinc-protein complexes); and/or nonionic surfactants such as TWEEN TM ，PLURONICS TM Or polyethylene glycol (PEG); exemplary formulations are as described in WO98/56418 and are expressly incorporated herein by reference. Lyophilized formulations suitable for subcutaneous administration are described in WO 97/04801. Such lyophilized formulations can be reconstituted into high protein concentration formulations by means of a suitable diluent and the reconstituted formulations can be administered to the individual to be treated herein by means of subcutaneous administration. Cationic liposomes or liposomes can be used to deliver the anti-FasL antibodies of the application to cells.
The formulations described herein may contain, in addition to an anti-FasL antibody (e.g., a full length anti-FasL antibody), one or more other active agents necessary to treat a particular disorder, preferably agents that are complementary in activity and do not adversely react with each other. For example, it may be desirable to further include an anti-tumor agent, growth inhibitor, cytotoxic agent, or chemotherapeutic agent in addition to the anti-FasL antibody. These molecules are present in combination in amounts effective for the intended purpose. The effective amount of the other substances depends on the amount of anti-FasL antibody in the formulation, the type of disease or disorder or treatment, and other factors as described above. These drugs are typically used at the same dosages and routes of administration as described herein, or at 1% to 99% of the presently employed dosages.
The anti-FasL antibodies (e.g., full length anti-FasL antibodies) can also be embedded in microcapsules prepared, for example, by coacervation techniques and interfacial polymerization, such as hydroxymethylcellulose or gelatin-microcapsules and poly (methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Can be prepared into sustained release preparation.
Sustained release formulations of anti-FasL antibodies (e.g., full length anti-FasL antibodies) can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody (or fragments thereof), which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl methacrylate) or poly (vinyl alcohol)), polylactic acid (U.S. Pat. No.3,773,919), L-glutamic acid and L-ethyl glutamate copolymers, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON deptatm (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprorelin acetate), and poly-D (-) -3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic-glycolic acid can allow release of molecules for more than 100 days, certain hydrogels can release proteins in a shorter time. When encapsulated antibodies stay in the body for a long period of time, they may denature or aggregate as a result of exposure to a humid environment at 37 ℃ and may result in loss of biological activity or altered immunogenicity. anti-FasL antibodies can be stabilized according to corresponding mechanisms, and rational strategies can be devised. For example, if the aggregation mechanism is found to be the formation of intermolecular S-S bonds through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing in acidic solutions, controlling water content, using appropriate additives, and developing specific polymer matrix compositions.
In some embodiments, the anti-FasL antibody (e.g., full length anti-FasL antibody) is formulated in a buffer containing citrate, sodium chloride, acetate, succinate, glycine, polysorbate 80 (tween 80), or any combination thereof.
Formulations for in vivo administration must be sterile. This can be easily achieved by, for example, filtration using sterile filtration membranes.
Therapeutic methods using anti-FasL antibodies
anti-FasL antibodies (e.g., full length anti-FasL antibodies) and/or compositions of the application can be administered to an individual (e.g., mammal, such as a human) to treat diseases and/or conditions (e.g., inflammatory diseases, autoimmune diseases or cancers) resulting from dysregulation of FasL-Fas signaling pathway, including but not limited to pemphigus, transplant rejection, graft versus host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, nonalcoholic steatohepatitis, liver cirrhosis, drug-induced liver injury/failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic nephropathy, cancer. In some embodiments, the cancer is a FasL positive cancer disease; in particular, fasL positive cancer diseases are characterized by FasL expressed on their cell surface. In some embodiments, a cancer may be considered positive for FasL if at least 1%, at least 2%, at least 5%, at least 10%, at least 20%, or at least 50% of the cells in the cancer sample express FasL. In some embodiments, the number of FasL positive cells can be detected by counting cells in a microtome. Accordingly, in some embodiments, the application provides a method of treating a disease and/or disorder resulting from dysregulation of FasL signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to an individual an effective amount of a composition (e.g., a pharmaceutical composition) comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), such as any of the anti-FasL antibodies described herein (e.g., a full-length anti-FasL antibody), in some embodiments, the individual is a human.
For example, in some embodiments, a method is provided for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a pharmaceutical composition comprising a FasL antibody that specifically binds to an epitope on human FasL (e.g., a full-length anti-FasL antibody), wherein the epitope comprises an amino acid residue at the position of human FasL. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease; in particular FasL-positive cancer diseases are characterized in that FasL is expressed on the cell surface. In some embodiments, a cancer may be considered positive for FasL if at least 1%, at least 2%, at least 5%, at least 10%, at least 20%, or at least 50% of the cells in the cancer sample express FasL. In some embodiments, the number of FasL positive cells can be detected by counting cells in a microtome. In some embodiments, the individual is a human.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC (liquid Crystal) device-CDR1 comprising the amino acid sequence SEQ ID No. 51, LC-CDR2 comprising the amino acid sequence SEQ ID No. 67, and LC-CDR3 comprising the amino acid sequence SEQ ID No. 77, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 99 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 99; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 127 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 127.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:19, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:78, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis B, acute viral hepatitis C, chronic hepatitis B, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug Physical liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, and cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 100 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 100; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 128 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 128.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32, or said V H Variants of (2), H thereofSubstitutions comprising up to about 5 amino acids in the C-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:67, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:79, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 101 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 101; v (V) L The V is L Comprising the amino acid sequence shown as SEQ ID NO. 129 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 129.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:33, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:80, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral infection Hepatitis B, acute viral hepatitis C, chronic hepatitis B, alcoholic hepatitis, nonalcoholic steatohepatitis, liver cirrhosis, drug induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, and cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 102 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 102; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 130 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 130.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2, which comprisesComprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 34, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:81, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 103 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 103; v (V) L The V is L Comprising the amino acid sequence shown as SEQ ID NO. 131 or a variant thereof which is identical to the amino acid sequence shown as SEQ ID NO. 131Has at least about 80% sequence identity to the amino acid sequence of (a).
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, LC-CDR2 comprising the amino acid sequence SEQ ID NO:69, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:82, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, inflammatory bowel disease, or a combination thereof, Ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis B, acute viral hepatitis C, chronic hepatitis B, alcoholic hepatitis, nonalcoholic steatohepatitis, liver cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, and cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 104 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 104; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 132 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 132.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, a method is provided for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or a cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), and administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibodyChain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 21, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 36, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:54, LC-CDR2 comprising the amino acid sequence SEQ ID NO:70, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:83, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 105 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 105; andV L the V is L Comprising the amino acid sequence set forth in SEQ ID NO. 133 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 133.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:84, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, pemphigus, transplant rejection, graft versus host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute Respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis B, acute viral hepatitis C, chronic hepatitis B, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 106 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 106; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 134 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 134.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, a method for treating a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) is providedA method of treating a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the sequence shown in SEQ ID NO. 107An amino acid sequence or variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID No. 107; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 135 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 135.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, Graft versus host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 108 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 108; v (V) L The V is L Comprising the amino acid sequence shown in SEQ ID NO. 136 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 136.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, the first and second processing elements,there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, a method is provided for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount ofA composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 109 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 109; v (V) L The V is L Comprising the amino acid sequence shown in SEQ ID NO. 137 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 137.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:72, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the wholeThe long anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 110 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 110; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 138 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 138.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, a therapeutic agent is provided for use in association with the FasL-Fas signaling pathwayA method of treating an individual for a disorder (e.g., an inflammatory disorder, an autoimmune disorder, or cancer) comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 111 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 111; v (V) L The V is L Comprising the amino acid sequence shown in SEQ ID NO. 139 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 139.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:56, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85, or said V L Variants of (2) comprising in the LC-CDRsSubstitutions of up to about 5 amino acids. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 112 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 112; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 140 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 140.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:86, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the The individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 113 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 113; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 141 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 141.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 9, HC-CDR2 comprising the amino acid sequence SEQ ID NO 26, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 57, LC-CDR2 comprising the amino acid sequenceThe sequence SEQ ID NO:73, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:87, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence shown in SEQ ID NO. 114 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 114; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 142 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 142.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:27, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:40, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:58, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:88, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis B, acute viral hepatitis C, chronic hepatitis B, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease Diabetic nephropathy, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 115 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 115; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 143 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 143.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 10, HC-CDR2 comprising the amino acid sequence SEQ ID NO 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 41, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable structureDomain (V) L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 59,
LC-CDR2 comprising the amino acid sequence SEQ ID NO. 68 and LC-CDR3 comprising the amino acid sequence SEQ ID NO. 89, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 116 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 116; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 144 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 144.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:90, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis B, acute viral hepatitis C, chronic Liver disease, chronic hepatitis B, alcoholic hepatitis, nonalcoholic steatohepatitis, liver cirrhosis, drug induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 117 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 117; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 145 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 145.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, andHC-CDR3 comprising the amino acid sequence SEQ ID NO. 42, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 60,
LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:91, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 118 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 118; v (V) L The V is L Comprising the amino acid sequence shown as SEQ ID NO. 146 or a variant thereof which is identical to the amino acid sequence shown as SEQ ID NO. 146Has at least about 80% sequence identity to the amino acid sequence of (a).
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 29, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 43, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence SEQ ID NO:75, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:92, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, inflammatory bowel disease, or a combination thereof, Ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis B, acute viral hepatitis C, chronic hepatitis B, alcoholic hepatitis, nonalcoholic steatohepatitis, liver cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, and cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 119 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 119; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 147 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 147.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, a method is provided for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or a cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), and administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibodyChain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 29, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 44, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:62, LC-CDR2 comprising the amino acid sequence SEQ ID NO:75, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:93, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 120 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 120; andV L the V is L Comprising the amino acid sequence set forth in SEQ ID NO. 148 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 148.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 13, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 30, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 45, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:63, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:94, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft versus host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury The present invention relates to a method for treating chronic respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis B, acute viral hepatitis C, chronic hepatitis B, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic nephropathy, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 121 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 121; v (V) L The V is L Comprising the amino acid sequence shown as SEQ ID NO. 149 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 149.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, a therapeutic agent for treating a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) is providedA method of treating a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 14, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 46, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:95, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising SEQ ID NO. 122An amino acid sequence as set forth or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 122; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 150 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 150.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 15, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 47, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO. 64, LC-CDR2 comprising the amino acid sequence SEQ ID NO. 68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO. 96, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplantation Rejection, graft versus host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence shown in SEQ ID NO. 123 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 123; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 151 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 151.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some implementationsIn one example, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 16, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 31, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 48, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:65, LC-CDR2 comprising the amino acid sequence SEQ ID NO:76, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:97, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, a method is provided for treating an individual for a disease associated with FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individualAn effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 124 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 124; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 152 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 152.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:17, HC-CDR2 comprising the amino acid sequence SEQ ID NO:28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:49, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:66, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:98, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodimentsThe full length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 125 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 125; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 153 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 153.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-FasL antibody (e.g., a full-length anti-FasL antibody), a heavy chain variable domain (V H ) The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 17, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 50, or said V H A variant of (2) comprising up to about 5 amino acid substitutions in the HC-CDRs; light chain variable domains (V L ) The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:60, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:91, or said V L Comprising up to about 5 amino acid substitutions in the LC-CDRs. In some embodiments, the anti-FasL antibody is a full-length antibody. In some embodiments, the full-length anti-FasL antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from, for example, pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer. In some embodiments, the cancer is a FasL positive cancer disease. In some embodiments, the individual is a human.
In some embodiments, a therapeutic agent for treating a cancer associated with FasL-FasA method of treating an individual for a number pathway-related disease (e.g., an inflammatory disease, an autoimmune disease, or cancer), comprising administering to the individual an effective amount of a composition comprising an anti-FasL antibody, wherein the antibody comprises: v (V) H The V is H Comprising the amino acid sequence set forth in SEQ ID NO. 126 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 126; v (V) L The V is L Comprising the amino acid sequence set forth in SEQ ID NO. 154 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 154.
In some embodiments, the anti-FasL antibodies described herein are full length anti-FasL antibodies comprising IgG1 or IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 155. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 156. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 157. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 158.
In some embodiments, the individual is a mammal (e.g., human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.). In some embodiments, the individual is a human. In some embodiments, the individual is a clinical patient, a clinical trial volunteer, a laboratory animal, or the like. In some embodiments, the individual is less than 60 years old (including, for example, less than 50, 40, 30, 25, 20, 15, or 10 years old). In some embodiments, the individual is older than 60 years (including, for example, older than 70, 80, 90, or 100 years). In some embodiments, the individual is diagnosed with or genetically predisposed to one or more of the diseases or disorders described herein (e.g., an inflammatory disease, an autoimmune disease, or cancer). In some embodiments, the individual has one or more risk factors associated with one or more diseases or disorders described herein.
In some embodiments, the application provides a method of delivering an anti-FasL antibody (e.g., any of the anti-FasL antibodies described herein, e.g., an isolated anti-FasL antibody) to a cell expressing FasL on its surface in an individual, the method comprising administering to the individual a composition comprising an anti-FasL antibody.
Many diagnostic methods for inflammatory diseases, autoimmune diseases or cancers or any other diseases that exhibit aberrant expression of FasL and clinical descriptions of these diseases are known in the art. Such methods include, but are not limited to, for example, immunohistochemistry, PCR, and Fluorescence In Situ Hybridization (FISH).
In some embodiments, the anti-FasL antibodies (e.g., full length anti-FasL antibodies) and/or compositions of the application are used in combination with a second, third, or fourth agent (including, e.g., an immunosuppressant, an anti-inflammatory agent, an antineoplastic agent, a growth inhibitor, a cytotoxic agent, a chemotherapeutic agent, or a vascular inhibitor) to treat a disease associated with the FasL-Fas signaling pathway.
Dosage and method of administration of anti-FasL antibodies
The dosage of an anti-FasL antibody (e.g., isolated anti-FasL antibody) composition administered to an individual (e.g., a human) may vary with the particular composition, the mode of administration, and the type of disease being treated. In some embodiments, the amount of a composition (e.g., a composition comprising an anti-FasL antibody) is effective to produce an objective response (e.g., a partial response or a complete response) in the treatment of an inflammatory disease, autoimmune disease, or cancer. In some embodiments, the amount of anti-FasL antibody composition is sufficient to produce a complete response in the individual. In some embodiments, the amount of anti-FasL antibody composition is sufficient to produce a partial response in the individual. In some embodiments, the dose of anti-FasL antibody composition administered (e.g., when administered alone) is sufficient to produce a total response rate of greater than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 80%, 85% or 90% in a population of individuals treated with the anti-FasL antibody composition.
In some embodiments, the amount of the composition (e.g., a composition comprising an isolated anti-FasL antibody) is sufficient to extend the progression-free survival of the individual. In some embodiments, the amount of the composition is sufficient to extend the overall survival of the individual. In some embodiments, the amount of the composition (e.g., when administered alone) is sufficient to produce a clinical benefit of greater than 50%, 60%, 70%, or 77% in a population of individuals treated with the anti-FasL antibody composition.
In some embodiments, the amount of a composition (e.g., a composition comprising an isolated anti-FasL antibody), alone or in combination with a second, third, and/or fourth agent, is an amount sufficient to control symptoms and reduce the risk of exacerbations prior to treatment or as compared to the corresponding activity in other subjects not receiving treatment. The magnitude of the therapeutic effect can be measured using standard methods, such as in vitro assays for purified enzymes, cell-based assays, animal models, or human trials.
In some embodiments, when the composition is administered to an individual, the amount of anti-FasL antibody (e.g., full length anti-FasL antibody) in the composition is below a level that causes a toxic effect (i.e., an effect above a clinically acceptable toxicity level) or at a level where potential side effects can be controlled or tolerated.
In some embodiments, the amount of the composition approaches the Maximum Tolerated Dose (MTD) of the composition following the same dosing regimen. In some embodiments, the amount of the composition is greater than 80%, 90%, 95% or 98% of the MTD.
In some embodiments, the amount of anti-FasL antibody (e.g., full length anti-FasL antibody) in the composition is in the range of 0.001 μg to 1000 μg.
In any of the embodiments described above, the effective amount of anti-FasL antibody (e.g., full length anti-FasL antibody) in the composition is in the range of 0.1 μg/kg to 100mg/kg as calculated at body weight.
The anti-FasL antibody composition can be administered to a subject (e.g., a human) by a variety of routes including, for example, intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, inhalational, intravascular, intramuscular, intratracheal, subcutaneous, intraocular, intrathecal, mucosal or transdermal. In some embodiments, a slow release formulation of the composition is used. In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered through an artery. In some embodiments, the composition is administered intraperitoneally. In some embodiments, the composition is administered intrahepatially. In some embodiments, the composition is administered by hepatic arterial infusion. In some embodiments, the composition is applied to a site remote from the first lesion.
Product and kit
In some embodiments of the application, an article of manufacture is provided that comprises a substance that can be used to treat a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, autoimmune disease, or cancer), or to deliver anti-FasL antibodies (e.g., a full-length anti-FasL antibody) to cells that surface express FasL. The article of manufacture may comprise a container and a label or package insert attached to or associated with the container. Suitable containers include, for example, bottles, vials, syringes, and the like. The container may be made of a variety of materials, such as glass or plastic. Typically, the container contains a composition effective to treat the diseases or conditions described herein and has a sterile port (e.g., the container may be an iv bag or a vial with a pierceable cap of a hypodermic injection needle). At least one active substance in the composition is the anti-FasL antibody. The label or package insert identifies the particular condition for which the composition may be used. The label or package insert further comprises instructions for administering the anti-FasL antibody composition to the patient. Articles of manufacture and kits comprising combination therapies are within the contemplation herein.
Package insert refers to instructions that are typically contained within the commercial package of therapeutic products, including indications, usage, dosage, administration, contraindications, and/or warning information regarding the use of such therapeutic products. In some embodiments, the package insert indicates that the composition can be used to treat a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer). In some embodiments, the package insert indicates that the composition may be used to treat a disease including pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, nonalcoholic steatohepatitis, cirrhosis, drug-induced liver injury/failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer.
In addition, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffer, grignard solution, or dextrose solution. Other materials may be included as desired from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.
Also, kits useful for various purposes, such as for treating diseases associated with the FasL-Fas signaling pathway (e.g., inflammatory diseases, autoimmune diseases, or cancers), or for delivering anti-FasL antibodies (e.g., full-length anti-FasL antibodies) to cells that express FasL on their surfaces, optionally in combination with a preparation. Kits of the application include one or more containers comprising an anti-FasL antibody composition (or single dose form and/or article of manufacture), and in some embodiments, further comprising another agent (e.g., an agent described herein) and/or instructions for use consistent with any of the methods described herein. The kit may further comprise a description of the selection of suitable individuals for treatment. The instructions for use attached to the kits of the application are typically written instructions on labels or packaging instructions (e.g., paper sheets contained within the kit), and machine-readable instructions (e.g., instructions on a magnetic or optical storage disc) are also acceptable.
For example, in some embodiments, the kit comprises a composition comprising an anti-FasL antibody (e.g., a full length anti-FasL antibody). In some embodiments, the kit comprises: a) A composition comprising any of the anti-FasL antibodies described herein, and b) at least one additional agent in an amount effective to enhance the effect (e.g., therapeutic effect, detection effect) of the anti-FasL antibody. In some embodiments, the kit comprises: a) A composition comprising any of the anti-FasL antibodies described herein, and b) instructions for administering the anti-FasL antibody composition to a subject for treating a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer). In some embodiments, the kit comprises: a) a composition comprising any of the anti-FasL antibodies described herein, and b) at least one additional agent in an amount effective to enhance the effect (e.g., therapeutic effect, detection effect) of the anti-FasL antibody, and c) instructions for administering the anti-FasL antibody composition and additional agents to an individual for treating a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, autoimmune disease, or cancer). The anti-FasL antibody and the other substance may be present in separate containers or in the same container. For example, the kit may comprise one specific composition or two or more compositions, wherein one composition comprises an anti-FasL antibody and the other composition comprises another agent.
In some embodiments, the kit comprises a nucleic acid (or a set of nucleic acids) encoding an anti-FasL antibody (e.g., a full-length anti-FasL antibody). In some embodiments, the kit comprises: a) A nucleic acid (or a set of nucleic acids) encoding an anti-FasL antibody (e.g., a full length anti-FasL antibody), and b) a host cell expressing the nucleic acid (or the set of nucleic acids). In some embodiments, the kit comprises: a) A nucleic acid (or set of nucleic acids) encoding an anti-FasL antibody (e.g., a full length anti-FasL antibody), and b) instructions for use, suitable for: i) Expressing an anti-FasL antibody in a host cell, ii) preparing a composition comprising an anti-FasL antibody, and iii) administering the composition comprising an anti-FasL antibody to an individual to treat a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer). In some embodiments, the kit comprises: a) a nucleic acid (or set of nucleic acids) encoding an anti-FasL antibody (e.g., a full length anti-FasL antibody), b) a host cell expressing the nucleic acid (or set of nucleic acids), and c) instructions for use, suitable for: i) Expressing an anti-FasL antibody in a host cell, ii) preparing a composition comprising an anti-FasL antibody, and iii) administering the composition comprising an anti-FasL antibody to an individual to treat a disease associated with the FasL-Fas signaling pathway (e.g., an inflammatory disease, an autoimmune disease, or cancer).
The kit of the application is packaged in a suitable form. Suitable packages include, but are not limited to, vials, bottles, jars, flexible packages (e.g., sealed mylar or plastic bags), and the like. The kit may optionally provide additional components, such as buffers and instructional information. Thus, the present application also provides articles, including vials, bottles, jars, flexible packages (e.g., sealed mylar or plastic bags), and the like.
Instructions for the use of anti-FasL antibody compositions typically include information such as dosage, period of administration, route of administration, and the like. The container may be unit dose, large package (e.g., multi-dose package) or subunit dose. For example, a kit comprising a sufficient dose of an anti-FasL antibody as described herein (e.g., full length anti-FasL antibody) is provided for long term effective treatment of an individual, e.g., one week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. The kit may also contain multiple unit doses of anti-FasL antibody, pharmaceutical compositions, and instructions for use, and be packaged in amounts sufficient for storage and use in a pharmacy, such as a hospital pharmacy and a compounding pharmacy.
Those skilled in the art will recognize several embodiments that are possible within the scope and spirit of the application. The application will now be described in more detail by reference to the following non-limiting examples. The following examples further illustrate the application but should not be construed as in any way limiting its scope.
Detailed Description
Example 1: preparation of antigens
Preparation of recombinant FasL/Fas proteins
cDNA (synthesized by Beijing Yiqiao Shenzhou technologies Co., ltd.) encoding the extracellular region of human FasL (human FasL, hFasL; genBank ID number: 356) was constructed into eukaryotic expression vectors by subcloning, respectively. A plasmid containing the human and monkey FasL extracellular domain coding sequence was constructed by adding His tag and/or human Fc tag and/or other tags commonly used by those skilled in the art to the end of cDNA encoding the above protein. The above plasmid is transfected into 293F cells for expression to produce fusion proteins containing the extracellular domain of FasL, such as His-hFasL, hFc-hFasL, wherein "His" represents a His tag and "hFc" represents a human Fc fragment.
In the same manner as described above, a vector containing the extracellular region coding sequence of human Fas (human Fas, hFas; genBank ID No.: 355) was constructed and 293F cells were transfected to express and produce a fusion protein containing the extracellular region of human Fas, such as His-hFas, wherein "His" represents a His tag.
The recombinant protein with His tag was purified by Immobilized Metal Affinity Chromatography (IMAC) using a nickel (Ni) column-HisCap Smart 6ff 5ml pre-packed column (san 036C15, ltd.) according to the manufacturer's instructions. The specific operation is as follows: first buffer A1 (50 mM Na 3 PO 4 The nickel column was equilibrated with 0.15M NaCl, pH7.2 at a flow rate of 150cm/h, and the pH of the solution containing the fusion protein (e.g., cell culture supernatant) was adjusted to 7.2, and the sample was loaded at room temperature at a flow rate of 150cm/h. Subsequently, the column was again equilibrated with 6 column volumes of A1 buffer at a flow rate of 150cm/h. Finally, elution was performed with 10 column volumes of 50mM PB solution (containing 0.15M NaCl and 0.2M imidazole, pH 7.2) and the eluate was collected. And (3) carrying out ultrafiltration liquid exchange on the eluent by adopting an ultrafiltration tube, and concentrating the eluent to a certain concentration.
The fusion protein with the Fc fragment was purified using a protein A column-MabCAP At 4FF 5ml pre-packed column (Hemsleyak and Biotechnology Co., ltd., SA023C 15). The specific operation is as follows: the protein A column was first equilibrated with 6 column volumes of PBS buffer (containing 50mM PBS and 0.15M NaCl, pH 7.2) at a flow rate of 5ml/min. The pH of the culture supernatant was adjusted to 7.2, and the sample was applied at room temperature at a flow rate of 5ml/min. Subsequently, the column was again equilibrated with 6-10 column volumes of PBS buffer at a flow rate of 5ml/min. After complete equilibration, the eluate (containing 0.1M Gly and 150mM NaCl, pH 3.2) was added for elution and the eluate was collected. And (3) carrying out ultrafiltration liquid exchange on the eluent by adopting an ultrafiltration tube, and concentrating the eluent to a certain concentration.
Example 2: screening for Single chain antibodies (scFv) against FasL
Construction of scFv antibody phage display library:
mice were immunized with an equal volume (v/v) of adjuvant using the human FasL extracellular domain as antigen. Serum from immunized mice was taken and ELISA was used to measure total IgG titer in serum from immunized mice. After several rounds of immunization, phage display libraries were established using the spleen of the mice. Briefly, the spleen of immunized mice was taken, RNA was extracted, cDNA was obtained by reverse transcription, and V was used H And V K Specific primer amplification V H And V K Fragment, after gel recovery and purification, is connected with V H And V K scFv were constructed and cloned into phage display plasmids, which were then electrotransferred into e.coli TG1, and phage infection of e.coli TG1 was used to obtain scFv antibody phage display libraries.
Screening for anti-FasL Single chain antibodies (scFv):
scFv that specifically binds hFasL were isolated and obtained from phage display libraries. Briefly, take 2X10 11 The phage scFv library of PFU was added to ELISA plates coated with His-hFasL antigen and incubated at 37℃for 2 hours. The phage bound to the hFasL antigen were captured by the FasL antigen coated on ELISA plates and unbound phage were washed away, using PBST solution for 8-15 washes (washing times increased with increasing number of screening rounds). Phage that specifically bound to hFasL antigen were eluted with 0.1M Glycine-HCl solution (pH 2.2). The phage was infected with TG1 cells in exponential growth phase, and after 1 hour of culture with ampicillin, helper phage was added thereto, and the culture was performed overnight at 28℃and 220rpm in a shaker. The culture solution is collected the next day, supernatant is obtained after centrifugation, and the next round of screening is performed. Positive scFv antibody libraries were obtained after multiple rounds of panning.
ELISA method for detecting anti-FasL single-chain antibody:
ELISA screening was performed on phages enriched after panning. Briefly, his-hFaThe sL antigen was dissolved in PBS solution and coated on 96-well plates at 0.1. Mu.g/well overnight at 4 ℃. After washing 1 time with PBST solution, 90 μl of PBS containing 4% nonfat dry milk was added to each well. Subsequently, 10. Mu.L of the supernatant of the phase-scFv culture was added to the corresponding wells and incubated at 37℃for 1-2 hours. After washing 8 times with PBST solution, 100. Mu.L/well of anti-M13-HRP antibody (Sino Biological,11973-MM 05T-H) was added at a 1:4000 dilution. Incubate at 37℃for 1h. After washing the plates 6 times with PBST, TMB color development solution was added, 100. Mu.L/well, and incubated at room temperature for 10min in the dark. By 2M H 2 SO 4 The chromogenic reaction was terminated and the absorbance at 450nm was read with a microplate reader. At the end of the screening process, a series of positive scFv antibodies were obtained and sequenced.
Example 3: preparation and characterization of full-Length anti-FasL chimeric antibodies
3.1 preparation of full Length anti-FasL chimeric antibodies
The obtained positive scFv antibody was reconstituted into a chimeric antibody having a human IgG1 or IgG4 heavy chain constant region and a human kappa (κ) light chain constant region. Amplification of V from phage display vectors L And V H Are constructed into eukaryotic expression vectors pTTa1-L (comprising human kappa constant region) and pTT5-H1 (comprising human IgG1 heavy chain constant region) or pTTa1-H4 (comprising human IgG4 heavy chain constant region), respectively. Cotransfection of a plasmid expressing the light chain and a plasmid expressing the heavy chain into 293F cells, 37℃and 5% CO 2 Culturing at 120rpm for 6 days, and purifying the culture solution by using a Protein A affinity chromatography column. The antibody purification method was the same as that of example 1 using a protein a column. After ultrafiltration concentration, the antibody concentration was determined and further biochemical and biological activity assays were performed.
3.2 determination of binding Capacity of anti-FasL antibody
Affinity of anti-FasL antibodies
The constructed full-length anti-FasL chimeric antibody (reconstituted into human IgG4 form) was subjected to a binding assay with human FasL to reflect the binding activity of the anti-FasL antibody to human FasL antigen. Briefly, human hFc-hFasL antigen was dissolved in PBS solution and coated in 96-well plates at 0.1. Mu.g/well overnight at 4 ℃. The mixture was blocked with 5% milk at 37℃for 1 hour and washed 6 times with PBST solution. Each antibody sample was first diluted to 66.67nM, followed by 1:4 ratio ofAnd (5) carrying out gradient dilution. Samples after gradient dilution were added to 96-well plates, 100. Mu.L per well, and incubated at 37℃for 1 hour. Followed by 6 washes with PBST solution. mu.L of anti-human kappa-HRP (southern Biotech, E1920-MJ11B,1:4000 dilution) was added to each well and incubated at 37℃for 1 hour. Wash 6 times with PBST solution. mu.L TMB was added to each well and incubated at 37℃for 10-20 min with 2. 2M H 2 SO 4 The reaction was terminated. The absorbance at 450nm was read using an microplate reader. Binding curves were generated by GraphPad Prism and EC of each anti-FasL antibody was calculated 50 Values.
As a result, as shown in Table 5, the selected anti-FasL chimeric antibodies FL-M04, FL-M06, FL-M07, FL-M09, FL-M13, FL-M27, FL-M37, FL-M39 to FL-M46, FL-M51, FL-M52, FL-M55, FL-M58, FL-M60 to FL-M62, FL-M65, FL-M68, FL-M69, FL-M71, FL-M76, FL-M77 all have good binding ability to human FasL antigen. The binding capacity of the anti-FasL antibody to human FasL is obviously better than that of the FasL antagonist APG101 (Fas fusion protein, apogenix); is also superior to or comparable to the control antibody MAB126-100 (commercial anti-FasL antibody, RD).
Table 5: binding ability of anti-FasL chimeric antibody to human FasL
Binding of neutralizing ligand to receptor of anti-FasL antibody:
this experiment was used to identify the ability of anti-FasL chimeric antibodies (reconstituted into human IgG4 form) to neutralize ligand FasL binding to its receptor Fas. Briefly, his-hFas prepared in example 1 was coated in 96-well plates at 0.1. Mu.g/well overnight at 4 ℃. After washing with PBST solution, 100 μl of 2% milk was added to each well. Blocking was performed for 1 hour at 37℃followed by washing with PBST solution. Each anti-FasL antibody sample was diluted to 12.0 μg/ml, followed by 1:4, and carrying out gradient dilution according to the proportion. The hFc-hFasL antigen (1.25 ug/mL) prepared in example 1 was mixed with each anti-FasL antibody diluted in a gradient, and then premixed at 37℃for 30min. The antigen-antibody premix described above was added to a 96-well plate at 100. Mu.L/well and incubated at 37℃for 1h. mu.L of anti-human IgG1Fc-AP antibody (southern Biotech,9054-04, 1:3000) was added to each well and incubated at 37℃for 1 hour. After 6 washes with PBST solution, 100. Mu.L of pNPP solution was added to each well and incubated at 37℃for 10-20 minutes. Absorbance values at 405nm were read and neutralization curves were generated by GraphPad Prism software.
As a result, it was revealed that, taking FL-M04, FL-M06, FL-M07, FL-M09, FL-M13, FL-M27 as examples, the ability of the anti-FasL chimeric antibody to neutralize FasL binding to Fas was comparable to that of the control antibody MAB126-100 (results not shown).
3.3 Activity assay of anti-FasL antibodies
anti-FasL antibodies inhibit FasL antigen-induced Jurkat apoptosis:
in the case of the addition of actinomycin D to inhibit cell division, exogenous FasL can activate the signal transduction pathway of apoptosis and mediate apoptosis, while the amount of ATP in the cells is directly proportional to the number of cells in culture. Based on the above principle, the amount of ATP in the cells can be used to reflect the level of apoptosis and thus determine the activity of anti-FasL chimeric antibodies (reconstituted into human IgG4 form) to inhibit FasL antigen-induced Jurkat apoptosis.
Jurkat cells in logarithmic growth phase (purchased from Beijing institute of both medicine cell Bank, 1101HUM-PUMC 000075) were seeded in 96-well plates, 5X 10 4 Individual cells/wells. Each antibody sample was diluted to 6.667nM, followed by 1:3, and carrying out gradient dilution according to the proportion. 50. Mu.L of actinomycin D (Hanhui pharmaceutical Co., ltd., national drug standard H20023504), 25. Mu.L of hFc-FasL recombinant fusion protein and 25. Mu.L of gradient diluted anti-FasL antibody were added to a 96-well plate containing Jurkat cells so that the final concentrations of actinomycin D, hFc-FasL recombinant fusion protein were 32ng/mL and 5ng/mL, respectively. At 37 ℃,5% CO 2 Culturing for 24 hours under the condition. By means ofLuminescence cell viability assay kit (Promega, G7572) detects the amount of ATP present, which is proportional to the luminescence signal generated, i.e., adding to 96 well cell culture platesReagents, 50. Mu.L per well, mixThen incubated at room temperature for 10min. The fluorescence value was read with a microplate reader. Curves were generated by GraphPad Prism software and the IC of each anti-FasL antibody was calculated 50 Values.
As shown in Table 6, the anti-FasL chimeric antibodies FL-M04, FL-M06, FL-M07, FL-M09, FL-M13, FL-M27, FL-M37, FL-M39 to FL-M46, FL-M51, FL-M52, FL-M55, FL-M58, FL-M60 to FL-M62, FL-M65, FL-M68, FL-M69, FL-M71, FL-M76, FL-M77 all have a significant inhibitory effect on FasL antigen-induced Jurkat apoptosis. The ability of the anti-FasL antibody to inhibit FasL antigen-induced Jurkat apoptosis was significantly better than that of control APG101 and comparable to control antibody 119-4A (anti-FasL antibody, apogenix).
Table 6: ability of anti-FasL chimeric antibodies to inhibit FasL antigen-induced apoptosis in Jurkat cells
anti-FasL antibodies inhibit FasL antigen-induced apoptosis of HepG2 cells:
the experimental principle is the same as above, and the level of apoptosis is reflected by the amount of ATP in the cells, so that the activity of the anti-FasL chimeric antibody (reconstructed into human IgG4 form) for inhibiting FasL antigen-induced HepG2 cell apoptosis is determined.
HepG2 cells in logarithmic growth phase (from the cell bank of the Beijing institute of synergetic medicine, 1101HUM-PUMC 000035) were seeded in 96-well plates, 2X 10 4 Individual cells/wells. Each antibody sample was diluted to 6.667nM, followed by 1:3, and carrying out gradient dilution according to the proportion. 50. Mu.L of actinomycin D, 25. Mu.L of hFc-FasL recombinant fusion protein and 25. Mu.L of gradient diluted anti-FasL antibody were added to a 96-well plate containing HepG2 cells so that the final concentration of actinomycin D, hFc-FasL recombinant fusion protein was 1. Mu.g/mL and 5ng/mL, respectively. At 37 ℃,5% CO 2 Culturing for 48 hours under the condition. By means ofCells by luminescenceThe activity detection kit (Promega, G7572) detects the amount of ATP present, which is proportional to the luminescent signal generated. Namely, adding to 96-well cell culture platesReagents, 50 μl per well, were mixed and incubated at room temperature for 10min. The fluorescence value was read with a microplate reader. Curves were generated by GraphPad Prism software and the IC of each anti-FasL antibody was calculated 50 Values.
As shown in Table 7, the anti-FasL chimeric antibodies FL-M04, FL-M06, FL-M07, FL-M09, FL-M13, FL-M27, FL-M37, FL-M39 to FL-M46, FL-M51, FL-M52, FL-M55, FL-M58, FL-M60 to FL-M62, FL-M65, FL-M68, FL-M69, FL-M71, FL-M76, FL-M77 all have a significant inhibitory effect on FasL antigen-induced apoptosis of HepG2 cells. The capacity of the anti-FasL antibody for inhibiting FasL antigen induced HepG2 cell apoptosis is obviously better than that of control APG101; in addition, the anti-FasL antibodies are obviously superior to the control antibody MAB126-100 except that FL-M27, FL-M46, FL-M52 and FL-M65 are basically equivalent to the control antibody MAB126-100.
Table 7: ability of anti-FasL chimeric antibodies to inhibit FasL antigen-induced apoptosis of HepG2 cells
anti-FasL antibodies inhibit FasL antigen-induced NF- κB signaling pathway activation:
in the case of inhibiting cell division by the addition of actinomycin D, exogenous FasL can activate NF- κB signaling in addition to the signaling pathway that activates apoptosis. After blocking the apoptotic pathway with Caspase inhibitors, exogenous FasL can only induce NF- κB signaling pathway activation. HepG2-Dual (InvivoGen, hepG2 d-nfis) is a NF-. Kappa.B-SEAP and IRF-Lucia Dual reporter cell line in which expression of Secreted Embryonic Alkaline Phosphatase (SEAP) is initiated upon activation of the exogenous FasL-induced NF-. Kappa.B pathway, which is expressed by QUANTI-Blue TM Substrate conversion was determined. Based on the above experimental principles, the activity of an anti-FasL chimeric antibody (reconstituted into human IgG4 form) to inhibit activation of the NF- κB signaling pathway induced by FasL antigen was determined by SEAP activity in HepG 2-Dual.
HepG2-Dual cells in logarithmic growth phase were seeded in 96-well plates, 1X 10 5 Individual cells/wells. Each antibody sample was diluted to 625nM followed by gradient dilution. hFc-FasL (final concentration of 700 ng/ml), actinomycin D, caspase inhibitor Z-VAD-FMK (Biyun, C1202-5 mg) and gradient diluted anti-FasL antibody were added to 96-well plates containing HepG2-Dual cells at 37deg.C, 5% CO 2 Culturing for 24 hours. 40. Mu.L of cell culture supernatant was taken with 160. Mu.L of preheated QUANTI-Blue TM (Invivogen) solution was mixed, incubated for 90 minutes, and absorbance at 650nm was read. Curve was generated by GraphPad Prism software and EC were calculated for each anti-FasL antibody 50 Values.
As shown in Table 8, the anti-FasL chimeric antibodies FL-M06, FL-M39 to FL-M46, FL-M51, FL-M52, FL-M55, FL-M58, FL-M60 to FL-M62, FL-M65, FL-M68 and FL-M69 all have a remarkable inhibitory effect on activation of NF- κB signaling pathway induced by FasL antigen. Among the above anti-FasL antibodies, the other antibodies were significantly better than control APG101 except that FL-M55 was substantially equivalent to control APG101.
Table 8: anti-FasL chimeric antibodies inhibiting FasL antigen-induced NF- κB signaling pathway activation

Claims (22)

  1. An isolated antibody that specifically recognizes FasL, wherein the anti-FasL antibody comprises:
    (i)V H the V is H Comprising V as shown in the amino acid sequence SEQ ID NO 99 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L The V is L Comprising V as shown in amino acid sequence SEQ ID NO:127 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (ii)V H comprising V as shown in amino acid sequence SEQ ID NO:100 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 128 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (iii)V H comprising V as shown in amino acid sequence SEQ ID NO:101 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:129 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (iv)V H comprising V as shown in amino acid sequence SEQ ID NO:102 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:130 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (v)V H comprising V as shown in amino acid sequence SEQ ID NO:103 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO. 131 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (vi)V H comprising V as shown in amino acid sequence SEQ ID NO 104 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO. 132 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (vii)V H comprising V as shown in amino acid sequence SEQ ID NO 105 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:133 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (viii)V H comprising V as shown in amino acid sequence SEQ ID NO:106 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising, for example, ammoniaV shown in the base acid sequence SEQ ID NO 134 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (ix)V H comprising V as shown in amino acid sequence SEQ ID NO:107 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:135 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (x)V H comprising V as shown in amino acid sequence SEQ ID NO. 108 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:136 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xi)V H comprising V as shown in amino acid sequence SEQ ID NO. 109 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 137 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xii)V H comprising V as shown in amino acid sequence SEQ ID NO. 110 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:138 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xiii)V H comprising V as shown in amino acid sequence SEQ ID NO:111 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 139 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xiv)V H comprising V as shown in amino acid sequence SEQ ID NO 112 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:140 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xv)V H comprising as amino acid sequence SEQ IDV shown by NO:113 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 as set forth in amino acid sequence SEQ ID NO 141;
    (xvi)V H comprising V as shown in amino acid sequence SEQ ID NO:114 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:142 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xvii)V H comprising V as shown in amino acid sequence SEQ ID NO 115 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:143 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xviii)V H comprising V as shown in amino acid sequence SEQ ID NO:116 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO. 144 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xix)V H comprising V as shown in amino acid sequence SEQ ID NO. 117 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in the amino acid sequence SEQ ID NO:145 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xx)V H comprising V as shown in amino acid sequence SEQ ID NO:118 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 146 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xxi)V H comprising V as shown in amino acid sequence SEQ ID NO:119 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:147 L IncludedLC-CDR1, LC-CDR2 and LC-CDR3 of (a);
    (xxii)V H comprising V as shown in amino acid sequence SEQ ID NO:120 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:148 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xxiii)V H comprising V as shown in amino acid sequence SEQ ID NO:121 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:149 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xxiv)V H comprising V as shown in amino acid sequence SEQ ID NO. 122 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:150 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xxv)V H comprising V as shown in amino acid sequence SEQ ID NO. 123 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO:151 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xxvi)V H comprising V as shown in amino acid sequence SEQ ID NO 124 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 152 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3;
    (xxvii)V H comprising V as shown in amino acid sequence SEQ ID NO. 125 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 153 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; or (b)
    (xxviii)V H Comprising V as shown in amino acid sequence SEQ ID NO:126 H ComprisingHC-CDR1, HC-CDR2 and HC-CDR3;
    v (V) L Comprising V as shown in amino acid sequence SEQ ID NO 154 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
  2. An isolated antibody that specifically recognizes FasL, wherein the antibody comprises:
    (i)V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:67, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:77;
    (ii)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:78;
    (iii)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:51, LC-CDR2 comprising amino acid sequence SEQ ID NO:67, and LC-CDR3 comprising amino acid sequence SEQ ID NO:79;
    (iv)V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:33; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence80 of sequence SEQ ID NO;
    (v)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:34; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:81;
    (vi)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO 53, LC-CDR2 comprising amino acid sequence SEQ ID NO 69, and LC-CDR3 comprising amino acid sequence SEQ ID NO 82;
    (vii)V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 21, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 36; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO. 54, LC-CDR2 comprising amino acid sequence SEQ ID NO. 70, and LC-CDR3 comprising amino acid sequence SEQ ID NO. 83;
    (viii)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:84;
    (ix)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising ammoniaThe amino acid sequence SEQ ID NO:55, LC-CDR2 comprising the amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:85;
    (x)V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:85;
    (xi)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:85;
    (xii)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:72, and LC-CDR3 comprising amino acid sequence SEQ ID NO:85;
    (xiii)V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:85;
    (xiv)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 3Comprises an amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:56, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:85;
    (xv)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 38; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:86;
    (xvi)V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 9, HC-CDR2 comprising the amino acid sequence SEQ ID NO 26, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO 57, LC-CDR2 comprising amino acid sequence SEQ ID NO 73, and LC-CDR3 comprising amino acid sequence SEQ ID NO 87;
    (xvii)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 27, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 40; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO 58, LC-CDR2 comprising amino acid sequence SEQ ID NO 73, and LC-CDR3 comprising amino acid sequence SEQ ID NO 88;
    (xviii)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 10, HC-CDR2 comprising the amino acid sequence SEQ ID NO 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 41; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO 59, LC-CDR2 comprising amino acid sequence SEQ ID NO 68, and LC-CDR3 comprising amino acid sequence SEQ ID NO 89;
    (xix)V H The V is H Comprising:HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 37; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:55, LC-CDR2 comprising amino acid sequence SEQ ID NO:71, and LC-CDR3 comprising amino acid sequence SEQ ID NO:90;
    (xx)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 42; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 60, LC-CDR2 comprising the amino acid sequence SEQ ID NO 74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 91;
    (xxi)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 29, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 43; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:61, LC-CDR2 comprising amino acid sequence SEQ ID NO:75, and LC-CDR3 comprising amino acid sequence SEQ ID NO:92;
    (xxii)V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 29, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 44; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO. 62, LC-CDR2 comprising the amino acid sequence SEQ ID NO. 75, and LC-CDR3 comprising the amino acid sequence SEQ ID NO. 93;
    (xxiii)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 13, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 30, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 45; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:63, LC-CDR2 comprising the amino acid sequence SEQ ID NO:73, and LC-CDR3, comprisingContains an amino acid sequence SEQ ID NO. 94;
    (xxiv)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 14, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 46; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:51, LC-CDR2 comprising the amino acid sequence SEQ ID NO:68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:95;
    (xxv)V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 15, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 47; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO. 64, LC-CDR2 comprising the amino acid sequence SEQ ID NO. 68, and LC-CDR3 comprising the amino acid sequence SEQ ID NO. 96;
    (xxvi)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 16, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 31, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 48; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:65, LC-CDR2 comprising amino acid sequence SEQ ID NO:76, and LC-CDR3 comprising amino acid sequence SEQ ID NO:97;
    (xxvii)V H the V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 17, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 49; v (V) L The V is L Comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO 66, LC-CDR2 comprising amino acid sequence SEQ ID NO 74, and LC-CDR3 comprising amino acid sequence SEQ ID NO 98; or (b)
    (xxviii)V H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 17, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 50; v (V) L The V is L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO:60, LC-CDR2 comprising the amino acid sequence SEQ ID NO:74, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:91.
  3. An isolated antibody specifically recognizing FasL according to claim 1 or 2, comprising:
    (i)V H comprising the amino acid sequence set forth in SEQ ID NO. 99 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 99; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 127 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 127;
    (ii)V H comprising the amino acid sequence set forth in SEQ ID NO. 100 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 100; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 128 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 128;
    (iii)V H Comprising the amino acid sequence set forth in SEQ ID NO. 101 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 101; v (V) L Comprising the amino acid sequence shown in SEQ ID NO. 129 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 129;
    (iv)V H comprising the amino acid sequence set forth in SEQ ID NO. 102 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 102; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 130 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 130;
    (v)V H comprising the amino acid sequence shown in SEQ ID NO. 103 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 103; to be used forV (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 131 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 131;
    (vi)V H comprising the amino acid sequence set forth in SEQ ID NO. 104 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 104; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 132 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 132;
    (vii)V H comprising the amino acid sequence shown in SEQ ID NO. 105 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 105; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 133 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 133;
    (viii)V H comprising the amino acid sequence set forth in SEQ ID NO. 106 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 106; v (V) L Comprising the amino acid sequence shown in SEQ ID NO. 134 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 134;
    (ix)V H comprising the amino acid sequence shown in SEQ ID NO. 107 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 107; v (V) L Comprising the amino acid sequence shown in SEQ ID NO. 135 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 135;
    (x)V H Comprising the amino acid sequence set forth in SEQ ID NO. 108 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 108; v (V) L Comprising the amino acid sequence shown in SEQ ID NO. 136 or a variant thereof having at least about 80% sequence with the amino acid sequence shown in SEQ ID NO. 136Identity;
    (xi)V H comprising the amino acid sequence shown in SEQ ID NO. 109 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 109; v (V) L Comprising the amino acid sequence shown in SEQ ID NO. 137 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 137;
    (xii)V H comprising the amino acid sequence set forth in SEQ ID NO. 110 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 110; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 138 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 138;
    (xiii)V H comprising the amino acid sequence set forth in SEQ ID NO. 111 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 111; v (V) L Comprising the amino acid sequence shown as SEQ ID NO. 139 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 139;
    (xiv)V H comprising the amino acid sequence set forth in SEQ ID NO. 112 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 112; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 140 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 140;
    (xv)V H comprising the amino acid sequence shown in SEQ ID NO. 113 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 113; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 141 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 141;
    (xvi)V H comprising the amino acid sequence shown as SEQ ID NO. 114 or a variant thereof, said variant being identical to SEQ ID NO. 114 has at least about 80% sequence identity to the amino acid sequence set forth in seq id no; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 142 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 142;
    (xvii)V H Comprising the amino acid sequence set forth in SEQ ID NO. 115 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 115; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 143 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 143;
    (xviii)V H comprising the amino acid sequence set forth in SEQ ID NO. 116 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 116; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 144 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 144;
    (xix)V H comprising the amino acid sequence shown as SEQ ID NO. 117 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 117; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 145 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 145;
    (xx)V H comprising the amino acid sequence set forth in SEQ ID NO. 118 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 118; v (V) L Comprising the amino acid sequence shown as SEQ ID NO. 146 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 146;
    (xxi)V H comprising the amino acid sequence set forth in SEQ ID NO. 119 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 119; v (V) L Comprising the amino acid sequence shown as SEQ ID NO. 147 or a variant thereofThe variant has at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO 147;
    (xxii)V H comprising the amino acid sequence set forth in SEQ ID NO. 120 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 120; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 148 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 148;
    (xxiii)V H comprising the amino acid sequence set forth in SEQ ID NO. 121 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 121; v (V) L Comprising the amino acid sequence shown as SEQ ID NO. 149 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 149;
    (xxiv)V H Comprising the amino acid sequence set forth in SEQ ID NO. 122 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 122; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 150 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 150;
    (xxv)V H comprising the amino acid sequence shown in SEQ ID NO. 123 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 123; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 151 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 151;
    (xxvi)V H comprising the amino acid sequence set forth in SEQ ID NO. 124 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 124; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 152 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 152;
    (xxvii)V H which comprisesAn amino acid sequence shown as SEQ ID NO. 125 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 125; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 153 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 153; or (b)
    (xxviii)V H Comprising the amino acid sequence set forth in SEQ ID NO. 126 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 126; v (V) L Comprising the amino acid sequence set forth in SEQ ID NO. 154 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 154.
  4. An isolated antibody specifically recognizing FasL according to any one of claims 1-3, wherein the antibody comprises an Fc fragment.
  5. The isolated antibody specifically recognizing FasL according to claim 4, wherein the antibody is a full-length IgG antibody.
  6. The isolated antibody specifically recognizing FasL according to claim 5, wherein the antibody is a full length IgG1, igG2, igG3 or IgG4 antibody.
  7. The isolated antibody specifically recognizing FasL according to any one of claims 1-6, wherein the antibody is a chimeric, humanized or fully human antibody.
  8. An isolated antibody specifically recognizing FasL according to any of claims 1-3 is an antigen binding fragment, wherein said antigen binding fragment is selected from the group consisting of Fab, fab ', F (ab)' 2 Fab' -SH, single chain antibodies (scFv), fv fragments, dabs, fd, nanobodies (nanobodies), diabodies (diabodies), and linear antibodies.
  9. A nucleic acid molecule encoding the antibody of any one of claims 1-8 that specifically recognizes FasL.
  10. A vector comprising the nucleic acid molecule of claim 9.
  11. An isolated host cell comprising the antibody of any one of claims 1-8 that specifically recognizes FasL, the nucleic acid molecule of claim 9, or the vector of claim 10.
  12. A method of making an antibody that specifically recognizes FasL, comprising:
    a) Culturing the host cell of claim 11 under conditions effective to express an antibody that specifically recognizes FasL; and
    b) The expressed antibodies that specifically recognize FasL are obtained from the host cell.
  13. A pharmaceutical composition comprising an antibody that specifically recognizes FasL according to any one of claims 1-8, a nucleic acid molecule according to claim 9, a vector according to claim 10, an isolated host cell according to claim 11 or an antibody produced by the method according to claim 12, and a pharmaceutically acceptable carrier.
  14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition further comprises an additional agent selected from the group consisting of an immunosuppressant, an anti-inflammatory agent, an anti-tumor agent, a growth inhibitor, a cytotoxic agent, a chemotherapeutic agent, or a vascular inhibitor.
  15. Use of an antibody according to any one of claims 1-8, a nucleic acid molecule according to claim 9, a vector according to claim 10, an isolated host cell according to claim 11, an antibody produced by a method according to claim 12, or a pharmaceutical composition according to any one of claims 13-14 for the preparation of a medicament for the treatment, prevention and/or amelioration of a disease or disorder.
  16. A method of treating a disease or disorder, the method comprising administering to an individual in need thereof an effective dose of the antibody of any one of claims 1-8, the nucleic acid molecule of claim 9, the vector of claim 10, the isolated host cell of claim 11, the antibody produced by the method of claim 12, or the pharmaceutical composition of any one of claims 13-14.
  17. The use according to claim 15 or the method of treatment according to claim 16, wherein the disease or condition is an inflammatory disease, cancer or autoimmune disease associated with the FasL-Fas signaling pathway.
  18. The use or method of treatment according to claim 17 wherein the disease or condition is selected from pemphigus, transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, acute lung injury, acute respiratory distress syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, myocardial infarction, cardiomyopathy, ischemic reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis b, acute viral hepatitis c, chronic hepatitis b, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury/failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, cancer.
  19. The use or method of treatment according to claim 18, wherein the cancer is FasL positive cancer.
  20. The use according to any one of claims 15, 17-19, wherein the medicament is administered in combination with another agent.
  21. The method of treatment according to any one of claims 16-19, further comprising administering to the individual in need thereof another agent.
  22. The use according to claim 20 or the method of treatment according to claim 21, wherein the further agent is selected from the group consisting of immunosuppressants, anti-inflammatory agents, anti-tumour agents, growth inhibitors, cytotoxic agents, chemotherapeutic agents or vascular inhibitors.
CN202380009454.2A 2022-01-21 2023-01-16 Antibody specifically recognizing FasL and application thereof Pending CN116829594A (en)

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WO2024083021A1 (en) * 2022-10-20 2024-04-25 北京三诺佳邑生物技术有限责任公司 Antibody combination specifically binding to trail or fasl, and bispecific antibody

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EP1490405B1 (en) * 2002-03-21 2007-08-22 Eli Lilly And Company ANTAGONISTIC ANTI-hFAS LIGAND HUMAN ANTIBODIES AND FRAGMENTS THEREOF
EP3353208A1 (en) * 2015-09-23 2018-08-01 Apogenix AG Anti-cd95l antibody

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