TW202241942A - Sars-cov-2 binding molecules and uses thereof - Google Patents

Abstract

The present disclosure relates to SARS-CoV-2-binding molecules and methods of using them. The present disclosure provides affinity matured SARS-CoV-2-binding molecules with improved physicochemical property. Further, the disclosure provides methods for producing the molecules, pharmaceutical compositions comprising such a molecule as an active ingredient, and therapeutic methods using the molecules or pharmaceutical compositions. Furthermore, the inventors assessed the SARS-CoV-2-binding molecules for binding to and neutralization of SARS-CoV-2 proteins and treatment of SARS-CoV-2 infection.

Description

SARS-COV-2 binding molecules and uses thereof

The present invention relates to SARS-CoV-2 binding molecules and methods of use thereof.

Antibodies are powerful therapeutic agents because both the Fab and Fc portions of antibodies can be used to neutralize the target. After an antibody binds to its target via the Fab region, the Fc region can recruit molecules, such as complement molecules or Fc receptors, to further activate the immune system. Then, the target will be activated by such methods as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). ) mechanism is eliminated.

Complement-dependent cytotoxicity (CDC) is mediated by the "classical" complement pathway, a cascade of enzymatic reactions involving complement proteins C1 to C9. Activation of the classical pathway is first triggered upon binding of complement CIq to antibody Fc. Complement protein C1q is a larger protein complex consisting of six globular heads and a collagen-like tail, and each globular head is capable of interacting with antibody Fc. Because the individual globular heads in C1q have a weak affinity for antibody Fc, C1q binds only weakly to monomeric IgG and does not activate the classical pathway. This weak affinity is necessary for homeostasis because of the higher concentrations of C1q and antibodies in the blood. However, when the target is densely coated with antibodies, CIq is able to engage multiple Fcs and bind with high affinity, and thus activate the complement pathway. Activation of the classical pathway cascade results in the deposition of proteins such as complement C4b and C3b onto target surfaces. C4b and C3b mark targets for phagocytosis by cells expressing complement receptors such as CR1 to CR4 and CRIg. From C3b, the classical pathway cascade also proceeds further and leads to the deposition of C5b, C6, C7, C8 and C9 proteins, which assemble into the pore-forming C5b-9 membrane-attack complex (MAC). Formation of MAC on the target surface disrupts membrane integrity and eventually causes target dissolution. Antibody-mediated CDC activity has long been known for its ability to mediate bacterial killing and was discovered in 1895 by Jules Bordet. More recently, antibody-mediated CDC activity has also been described to mediate the clearance of several different types of viruses (Front Microbiol. 2017; 8: 1117).

Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are mediated by the interaction between antibody Fc and cells expressing Fcγ receptors. In ADCC, effector cytotoxic cells, such as natural killer cells, recognize antibody-bound targets and release lytic enzymes to destroy the targets. In ADCP, phagocytes, such as macrophages, monocytes, and neutrophils, take up antibody-opsonized targets and clear them from circulation. Although ADCP is an important process of protective immunity, some pathogens exploit the ability of ADCP to enhance their infectivity in a process called antibody-dependent enhancement (ADE). ADE occurs when antibodies enhance pathogen entry into host cells via Fcγ receptors. This occurs when the antibody titer is insufficient to neutralize the pathogen, or when the antibodies against the pathogen are non-neutralizing in nature. To avoid therapeutically administered antibodies with ADE function, mutations are introduced into the Fc region to reduce or silence Fcγ receptor binding function. Alternatively, Fc subclasses with native weak Fc gamma receptor binding function, such as IgG2 and IgG4, are used.

The ability of sub-neutralizing antibodies to promote disease in humans via ADE has been well documented in Dengue virus. Although there is currently no definitive evidence of ADE in human coronavirus disease in vivo, there is in vitro evidence that ADE can occur. Yip et al. (Yip et al. Virol. J. 11, 82 (2014)) showed that human macrophages can be infected by SARS-CoV due to IgG-mediated ADE, and this infection route requires the binding of FcγRII receptors and arraignment. Similarly, Wan et al. (Wan et al. J. Virol. 94, e02015-19 (2020)) showed that targeting the receptor binding domain of the Middle East respiratory syndrome (Middle East respiratory syndrome; MERS) coronavirus spike protein domain; RBD) can enhance virus entry.

Some antibodies binding to SARS-CoV-2 have been reported (Hansen et al. Science. Vol. 369, Issue 6506, pp. 1010-1014).

[preface] However, designing SARS-CoV-2 binding molecules with sufficient binding affinity for viral infections (such as coronavirus infections) and/or physicochemical properties suitable for treating or preventing viral infections or reducing the incidence of viral infections, and in addition designing has substantial SARS-CoV-2 binding molecules with reduced Fcγ receptor binding and maintained or increased complement C1q binding activity remain a challenge. Production of such molecules is one of the potential strategies to reduce the risk of antibody-dependent enhancement (ADE) in coronavirus infection caused by virus entry into host cells via Fcγ receptors while having sufficient clearance of the virus of interest. The risk of ADE may arise from antibodies against coronavirus strains that are endemic in the human population, such as HKU1, OC43, NL63, and 229E. Cross-reactive antibodies that bind weakly to SARS-CoV-2 may have the potential to mediate ADE.

Accordingly, there is a need to provide alternative SARS-CoV-2 binding molecules, such as SARS-CoV-2 binding molecules with favorable properties; and related methods.

The present invention provides the following:

[1] An isolated antibody that binds to SARS-CoV-2, wherein the antibody comprises: (i) HVR-H1 comprising the amino acid sequence X _YEMN , wherein X is L, _I or S (SEQ ID NO: 109), (ii) HVR-H2 comprising the amino acid sequence VISYX ₁ GSNKYYADSVKG, wherein X ₁ is E or D (SEQ ID NO: 110), (iii) comprising the amino acid sequence LITMX ₁ RGX ₂ X ₃ HVR _- H3 of _X4 , wherein X1 is T or V, X2 is P or _A , _X3 is D or Q, _X4 is Y or G (SEQ ID NO: 111), (iv) comprising amino acid HVR-L1 of the sequence RASQX ₁ IX ₂ X ₃ YLN, wherein X ₁ is S or E, X ₂ is S or E, X ₃ is S or D (SEQ ID NO: 112), (v) comprises an amino acid sequence HVR-L2 of AAX ₁ X ₂ LQX ₃ , wherein X ₁ is S or E, X ₂ is S or E, X ₃ is I or G (SEQ ID NO: 113), and (vi) comprises the amino acid sequence QX ₁ HVR-L3 of SYNLPRT, wherein X ₁ is E or Q (SEQ ID NO: 114).

[2] The antibody according to [1], wherein the antibody comprises: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61, 64, 67, 70, 73 or 76, (ii) comprising the amine of SEQ ID NO: 62, 65, 68, 71, 74 or 77 HVR-H2 of amino acid sequence, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63, 66, 69, 72, 75 or 78, (iv) comprising SEQ ID NO: 79, 82, 85 , 88, 91, 94, 97, 100, 103 or 106 of the amino acid sequence of HVR-L1, (v) comprising SEQ ID NO: 80, 83, 86, 89, 92, 95, 98, 101, 104 or HVR-L2 having an amino acid sequence of 107, and (vi) HVR-L3 comprising an amino acid sequence of SEQ ID NO: 81, 84, 87, 90, 93, 96, 99, 102, 105 or 108.

[3] An isolated antibody that binds to SARS-CoV-2, wherein the antibody comprises: (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90; (b) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 91, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 92, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 93; (c) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:86, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 87; (d) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:95, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (e) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74, (iii) comprising SEQ ID NO: 75 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:89, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90; (f) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74, (iii) comprising SEQ ID NO: 75 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 91, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 92, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 93; (g) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74, (iii) comprising SEQ ID NO: 75 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:86, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 87; (h) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74, (iii) comprising SEQ ID NO: 75 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:95, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (i) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 77, (iii) comprising SEQ ID NO: 78 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:89, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90; (j) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 77, (iii) comprising SEQ ID NO: 78 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 91, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 92, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 93; (k) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 77, (iii) comprising SEQ ID NO: 78 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:86, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 87; (l) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 77, (iii) comprising SEQ ID NO: 78 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:95, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (m) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62, (iii) comprising SEQ ID NO: 63 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 97, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 98, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 99; (n) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 64, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 65, (iii) comprising SEQ ID NO: 66 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:83, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84; (o) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 77, (iii) comprising SEQ ID NO: 78 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:83, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84; (p) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74, (iii) comprising SEQ ID NO: 75 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:83, (vi ) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84; (q) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68, (iii) comprising SEQ ID NO: 69 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:83, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84; (r) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68, (iii) comprising SEQ ID NO: 69 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102; (s) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 97, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 98, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 99; (t) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 103, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 104, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 105; (u) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108; (v) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 80, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 81; (w) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62, (iii) comprising SEQ ID NO: 63 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 80, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 81; or (x) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 64, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 65, (iii) comprising SEQ ID NO: 66 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102.

[4] The antibody according to any one of [1] to [3], which is a monoclonal antibody.

[5] The antibody according to any one of [1] to [4], which is a human antibody, a humanized antibody or a chimeric antibody.

[6] The antibody according to any one of [1] to [5], which comprises (a) a VH having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NO: 2 to 7 sequence; (b) a VL sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NO: 42 and 44 to 52; or (c) a VH sequence such as (a) and a sequence such as The VL sequence in (b).

[7] The antibody according to [6], which comprises the VH sequence of any one of SEQ ID NO: 2 to 7.

[8] The antibody according to [6] or [7], which comprises the VL sequence of any one of SEQ ID NO: 42 and 44 to 52.

[9] An isolated antibody that binds to SARS-CoV-2, wherein the antibody comprises: (a) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 46, (b) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 47, (c) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 45, (d) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 48, (e) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 46, (f) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 47, (g) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 45, (h) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 48, (i) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 46, (j) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 47, (k) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 45, (l) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 48, (m) the VH sequence of SEQ ID NO: 2 and the VL sequence of SEQ ID NO: 49, (n) the VH sequence of SEQ ID NO: 3 and the VL sequence of SEQ ID NO: 44, (o) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 44, (p) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 44, (q) the VH sequence of SEQ ID NO: 4 and the VL sequence of SEQ ID NO: 44, (r) the VH sequence of SEQ ID NO: 4 and the VL sequence of SEQ ID NO: 50, (s) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 49, (t) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 51, (u) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 52, (v) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 42, (w) the VH sequence of SEQ ID NO: 2 and the VL sequence of SEQ ID NO: 42, or (x) VH sequence of SEQ ID NO: 3 and VL sequence of SEQ ID NO: 50.

[10] The antibody according to any one of [1] to [9], wherein the antibody further comprises a variant Fc region comprising at least one amino acid change relative to the parent Fc region, wherein when compared to the parent Fc region, In the present Fc region, the variant Fc region has substantially reduced FcγR-binding activity and maintained or increased C1q-binding activity.

[11] The antibody according to [10], wherein the variant Fc region comprises Ala at position 234 according to EU numbering and Ala at position 235 according to EU numbering.

[12] The antibody according to [10] or [11], wherein the variant Fc region comprises an amino acid change at any one of the following (a) to (c): (a) positions 267, 268 and 324; (b) positions 236, 267, 268, 324 and 332; and (c) positions 326 and 333, Wherein these positions are according to the EU number.

[13] The antibody according to [12], wherein the variant Fc region comprises amino acids selected from the group consisting of the following (a) to (g): (a) Glu at position 267; (b) Phe at position 268; (c) Thr at position 324; (d) Ala at position 236; (e) Glu at position 332; (f) Ala, Asp, Glu, Met or Trp at position 326; and (g) Ser at position 333, Wherein these positions are according to the EU number.

[14] The antibody according to any one of [10] to [13], wherein the variant Fc region comprises amino acids selected from the group consisting of the following (a) to (f): (a) Ala at position 434; (b) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; (c) Leu at position 428, Ala at position 434 and Thr at position 436 (d) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; (e) Leu at position 428 and Ala at position 434; and (f) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440; Wherein these positions are according to the EU number.

[15] A pharmaceutical composition comprising the antibody according to any one of [1] to [14] and a pharmaceutically acceptable carrier.

[16] The antibody according to any one of [1] to [14] or the pharmaceutical composition according to [15], which is used for treating and/or preventing SARS-CoV-2 infection.

[17] A method for treating SARS-CoV-2 infection, comprising administering to an individual suffering from SARS-CoV-2 infection an effective amount of the antibody according to any one of [1] to [14] or such The pharmaceutical composition of [15].

[18] Use of the antibody according to any one of [1] to [14] or the pharmaceutical composition according to [15] for the manufacture of a medicament for treating and/or preventing SARS-CoV-2 infection.

[19] Use of the antibody according to any one of [1] to [14] or the pharmaceutical composition according to [15] for treating and/or preventing SARS-CoV-2 infection.

[20] An isolated nucleic acid encoding the antibody according to any one of [1] to [14].

[21] A host cell or vector comprising the nucleic acid according to [20].

[22] A method for producing the antibody according to any one of [1] to [14], which comprises culturing the host cell according to [21].

[23] An isolated antibody produced by the method of [22].

[24] A set comprising the composition according to [15] and a package insert including instructions for administering to an individual for treating or preventing SARS-CoV-2 infection.

[25] A method for detecting the presence of SARS-CoV-2 in a sample, the method comprising: making the sample and the antibody according to any one of [1] to [14] allow the antibody to interact with SARS-CoV-2 contacting under binding conditions; detecting whether a complex is formed between the antibody and SARS-CoV-2; wherein the complex formation indicates the presence of SARS-CoV-2 in the sample.

The techniques and procedures described or referenced herein are generally well understood by those skilled in the art and are generally employed using well-known methods, such as the widely used methods described in: Sambrook et al., Molecular Cloning: A Laboratory Manual , p. 3rd Edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (FM Ausubel et al., eds., (2003)); Methods in Enzymology Series (Academic Press, Inc.): PCR 2: A Practical Approach (MJ MacPherson, BD Hames and GR Taylor (1995)), Harlow and Lane (1988) Antibodies , A Laboratory Manual and Animal Cell Culture (RI Freshney (1987)); Oligonucleotide Synthesis (MJ Gait, 1984) ); Methods in Molecular Biology , Humana Press; Cell Biology: A Laboratory Notebook (JE Cellis, 1998) Academic Press; Animal Cell Culture (RI Freshney, 1987); Introduction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (eds. A. Doyle, JB Griffiths and DG Newell, 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (eds. DM Weir and CC Blackwell); Gene Transfer Vectors for Mammalian Cells (JM Miller and MP Calos eds., 1987); PCR: The Polymeras e Chain Reaction , (Mullis et al., 1994); Current Protocols in Immunology (JE Coligan et al., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997 ); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (ed. D. Catty., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (edited by P. Shepherd and C. Dean, Oxford University Press , 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (eds. M. Zanetti and JD Capra, Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (eds. VT DeVita et al., JB Lippincott Company, 1993).

The following definitions and detailed description are provided to facilitate understanding of the invention illustrated herein.

I. Definition

Amino acid modification Amino acid modification means any one of substitution, deletion, addition and insertion, or a combination thereof. In the present invention, amino acid changes can be reformulated as amino acid mutations or amino acid modifications. For amino acid changes in the amino acid sequence of the antigen-binding molecule, known methods such as the site-directed mutagenesis method (Kunkel et al. (Proc. Natl. Acad. Sci. USA (1985) 82, 488-492)) and overlap extension PCR. In addition, several known methods can also be used as amino acid alteration methods for substitution with unnatural amino acids (Annu Rev. Biophys. Biomol. Struct. (2006) 35, 225-249; and Proc. Natl. Acad. Sci . USA (2003) 100 (11), 6353-6357). For example, it is suitable to use a cell-free translation system (Clover Direct (Protein Express)) containing a tRNA with a complementary amber suppressor tRNA binding to one of the stop codons (UAG codon (amber codon)) unnatural amino acids.

In the present specification, when describing a site where an amino acid is changed, the meaning of the term "and/or" includes every combination in which "and" and "or" are appropriately combined. Specifically, for example, "the amino acid at position 33, 55 and/or 96 is substituted" includes the following amino acid changes: (a) position 33, (b) position 55, (c) position 96 , (d) amino acids at positions 33 and 55, (e) positions 33 and 96, (f) positions 55 and 96, and (g) positions 33, 55 and 96.

Also, herein, as an expression indicating a change in amino acid, an expression showing a one-letter or three-letter code of the amino acid before and after the change, respectively, on the left and right of the number indicating a specific position can be used appropriately. For example, the alteration N100bL or Asn100bLeu used when substituting an amino acid contained in an antibody variable region indicates that the Asn at position 100b (according to Kabat numbering) is substituted with Leu. That is, the number shows the amino acid position according to the Kabat numbering, the one-letter or three-letter amino acid code written before the number (to the left of the number) shows the amino acid before the substitution, and is written after the number (to the right of the number) )'s one-letter or three-letter amino acid code indicates the substituted amino acid. Similarly, the alteration P238D or Pro238Asp used when substituting amino acids of the Fc region contained in the constant region of an antibody indicates that the Pro at position 238 (according to EU numbering) is substituted with Asp. That is, the number shows the amino acid position according to the EU numbering, the one-letter or three-letter amino acid code written before the number (to the left of the number) shows the amino acid before the substitution, and is written after the number (to the right of the number) )'s one-letter or three-letter amino acid code indicates the substituted amino acid.

For the purposes herein, an "acceptor human framework" is one comprising a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or human consensus framework as defined below The structure of the amino acid sequence. An acceptor human framework "derived from" a human immunoglobulin framework or human consensus framework may comprise the same amino acid sequence of a human immunoglobulin framework or human consensus framework, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 1 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to a VL human immunoglobulin framework sequence or a human consensus framework sequence.

"Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (eg, an antigen-binding molecule or antibody) and its binding partner (eg, an antigen). As used herein, unless otherwise indicated, "binding affinity" refers to an intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (eg, an antigen binding molecule and antigen, or an antibody and antigen). The affinity of a molecule X for its partner Y can generally be expressed by the dissociation constant (Kd (KD)). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary examples for measuring binding affinity are described below.

The structure of the antigen-binding domain of an antigen-binding molecule/antibody that binds to an epitope is called a paratope. The paratope is stably bound to the epitope via hydrogen bonds, electrostatic forces, van der Waals' forces, hydrophobic bonds, or the like acting between the epitope and the paratope. This binding force between an epitope and a paratope is called "affinity" (see also above). When multiple antigen-binding domains bind to multiple antigens, the total binding force is called "avidity". For example, when an antibody comprising multiple antigen-binding domains (ie, a polyvalent/multivalent antibody) binds to multiple epitopes, affinity acts synergistically, and avidity may be higher than avidity.

An "affinity matured" antigen binding molecule/antibody refers to an antigen that possesses one or more alterations in one or more hypervariable regions (HVRs) compared to a parent antigen binding molecule/parent antibody that does not possess such alterations Binding molecules/antibodies, such alterations result in increased affinity of the antigen-binding molecule/antibody for the antigen.

The terms "anti-SARS-CoV-2 antigen-binding molecule", "anti-SARS-CoV-2 antibody", "antigen-binding molecule that binds to SARS-CoV-2" and "antibody that binds to SARS-CoV-2" refer to An antigen-binding molecule/antibody capable of binding to SARS-CoV-2 with an affinity sufficient to render the antigen-binding molecule/antibody useful as a diagnostic and/or therapeutic and/or prophylactic agent in targeting SARS-CoV-2. In one embodiment, the anti-SARS-CoV-2 antigen-binding molecule or anti-SARS-CoV-2 antibody binds to an irrelevant non-SARS-CoV-2 protein to an extent that is less than about the antigen-binding molecule/antibody binds to SARS-CoV-2 10% of binding as measured eg by radioimmunoassay (RIA). In certain embodiments, the antigen binding molecule/antibody that binds to SARS-CoV-2 has a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less , 0.1 nM or less, 0.01 nM or less or 0.001 nM or less (eg 10 ^-8 M or less, 10 ^-8 M to 10 ^-13 M, eg 10 ^-9 M to 10 ^-13 M). In certain embodiments, the anti-SARS-CoV-2 antigen binding molecule or anti-SARS-CoV-2 antibody binds to an epitope of SARS-CoV-2 that is present in a different species of SARS-CoV-2 for conservative.

Antigen-binding molecules that bind to SARS-CoV-2 As used herein, the term "antigen-binding molecule" refers to any molecule comprising an antigen-binding site, an antigen-binding portion, or any molecule that has binding activity for an antigen, and may further be Refers to molecules, such as peptides or proteins, that are about five amino acids or longer in length. Peptides and proteins are not limited to those derived from living organisms, and for example, they may be polypeptides produced from artificially designed sequences. It can also be any naturally occurring polypeptide, synthetic polypeptide, recombinant polypeptide, and the like. A scaffold molecule comprising a known stable conformational structure (such as an α/β barrel) as a backbone and a portion of the molecule making up the antigen binding site is also an example of an antigen binding molecule described herein.

In one aspect, the antigen-binding molecules described herein can be antigen-binding molecules that bind to SARS-CoV-2 (also referred to herein as "SARS-CoV-2-binding molecules"). molecule/SARS-CoV-2 binding molecule)").

In certain embodiments, the SARS-CoV2 binding molecules of the invention are generally antibodies. In certain embodiments, the SARS-CoV-2 binding molecules of the present invention are "single-chain Fv (scFv)", "single-chain antibody", "Fv", "single-chain Fv 2 (scFv2)", "Fab" , "F(ab')2", VHH, VL, VH, single domain antibody or any antibody fragment.

In certain embodiments, the SARS-CoV2 binding molecules of the invention bind to the SARS-CoV-2 Spike (S) protein. In some embodiments, the SARS-CoV2 binding molecules of the present invention bind to the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) protein.

The term "antibody" is used herein in the broadest sense and encompasses various antibody structures including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (such as bispecific antibodies), and antibody fragments or antigen-binding fragments, provided that It is sufficient that it exhibits the desired antigen-binding activity.

"Antibody fragment" and "antigen-binding fragment" refer to a molecule that is different from an intact antibody, including the portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments and antigen-binding fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single chain antibody molecules (e.g. scFv); VHH; VL ; VH; single-domain antibodies; multispecific antibodies formed from antibody fragments/antigen-binding fragments and minimal recognition units composed of amino acid residues mimicking the hypervariable regions (HVR) of antibodies (e.g., isolated Complementarity Determining Regions (CDRs)). In some embodiments, the antibody fragment or antigen-binding fragment may retain at least about one, at least about two, at least about three, at least about four, at least about five, or at least about six HVR/CDR regions/sequences of the antibody .

An "antibody that binds to the same epitope" as a reference antibody is an antibody that, in a competition assay, blocks the binding of the reference antibody to its antigen by 50% or more, and conversely, in a competition assay, the reference antibody blocks The antibody binds 50% or more to its antigen. An exemplary competitive analysis is provided herein.

The term "chimeric" antibody refers to an antibody in which a portion of the heavy chain and/or light chain is derived from a particular source or species, and the remainder of the heavy chain and/or light chain is derived from a different source or species.

The "class" of an antibody refers to the type of constant domain or region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these antibodies can be further divided into subclasses (isotypes), such as IgG ₁ , IgG ₂ , IgG ₃ , IgG ₄ , IgA ₁ and _IgA2 . The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively.

As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cell function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (such as radioisotopes of ²¹¹ At, ¹³¹ I, ¹²⁵ I, ⁹⁰ Y, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁵³ Sm, ²¹² Bi, ³² P, ²¹² Pb, and Lu); chemotherapeutic agents or medications (such as methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), cranberry (doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, or other intercalating agents); growth inhibitors; enzymes and their Fragments, such as nucleolytic enzymes; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof; and various antitumor or anticancer agent.

"Effector functions" refer to those biological activities attributable to the Fc region of an antibody, which vary with antibody isotype. Examples of antibody effector functions include: Clq binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; ) downregulation; and B cell activation.

An "effective amount" of a pharmaceutical agent (eg, a pharmaceutical formulation) refers to an amount effective at dosages and for periods of time necessary to achieve the desired therapeutic or prophylactic result. Dosage and administration of agents (eg, pharmaceutical formulations) of the invention can be determined by one of ordinary skill in clinical pharmacology or pharmacokinetics. See, eg, Mordenti and Rescigno, (1992) Pharmaceutical Research. 9:17-25; Morenti et al., (1991) Pharmaceutical Research. 8:1351-1359; and Mordenti and Chappell, "The use of interspecies scaling in toxicokinetics", Toxicokinetics and New Drug Development; Yacobi et al. (eds.) (Pergamon Press: NY, 1989), pp. 42-96. The effective amount of an active agent of the invention to be employed will depend, for example, on the goal of treatment, the route of administration and the condition of the individual. Accordingly, a therapist may be required to titrate the dosage and adjust the route of administration as necessary to obtain the optimum therapeutic effect.

"Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3 and FR4. Thus, in VH (or VL), the HVR and FR sequences generally appear in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

The terms "full-length antibody", "intact antibody" and "whole antibody" are used interchangeably herein to refer to an antibody having a structure substantially similar to that of a native antibody or having a heavy chain comprising an Fc region as defined herein .

The terms "host cell", "host cell strain" and "host cell culture" are used interchangeably and refer to a cell into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived therefrom (regardless of the number of passages). The nucleic acid content of the progeny may not be exactly the same as that of the parental cells, but may contain mutations. Included herein is the screening or selection of mutant progeny having the same function or biological activity against the original transformed cell.

A "human antibody" is an antibody whose amino acid sequence corresponds to that of an antibody produced by a human being or a human cell, or derived from a non-human source utilizing the human antibody repertoire or other human antibody coding sequences. This definition of a human antibody specifically excludes humanized antibodies comprising non-human antigen-binding residues.

A "human consensus framework" is a framework representing the most frequently occurring amino acid residues in a series of human immunoglobulin VL or VH framework sequences. Generally, human immunoglobulin VL or VH sequences are selected from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest , Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), Vols. 1-3. In one embodiment, for VL, the subgroup is subgroup Kappa I as in Kabat et al., supra. In one embodiment, for VH, the subgroup is subgroup III as in Kabat et al., supra.

A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one, and usually two variable domains, wherein all or substantially all of the variable domains (e.g., CDRs) of the HVRs correspond to non- Those of a human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally can comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody (eg, a non-human antibody) refers to an antibody that has been humanized.

As used herein, the term "hypervariable region" or "HVR" refers to regions within an antibody variable domain that are hypervariable in sequence ("complementarity determining regions" or "CDRs") and/or form structurally defined loops ( "hypervariable loop") and/or contain antigen contact residues ("antigen contacts"). In general, antibodies comprise six HVRs: three in the VH (H1, H2, H3), and three in the VL (L1, L2, L3). Herein, exemplary HVRs include: (a) occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2) and hypervariable loops at 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) occurs at amino acid residues 24-34 ( CDRs at L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2) and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest , 5th edition. Public Health Service, National Institutes of Health (Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) occurs at amino acid residues 27c-36 (L1) Antigenic contacts at , 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2) and 93-101 (H3) (MacCallum et al . J. Mol. Biol. 262: 732-745 (1996)); and (d) a combination of (a), (b) and/or (c), including HVR amino acid residues 46-56 (L2), 47-56 (L2) , 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3) and 94-102 (H3).

Unless otherwise indicated, HVR residues and other residues (eg, FR residues) in variable domains are numbered herein according to Kabat et al ., supra.

An "immunoconjugate" is an antibody that binds to one or more heterologous molecules, including but not limited to cytotoxic agents.

An "individual/subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rodents) mouse). In certain embodiments, the individual/subject is a human. The term "subject" includes patients and non-patients. The term "patient" refers to an individual who suffers or may not suffer from a medical condition, such as a SARS-CoV-2 infection, while "non-patient" refers to an individual who does not and may not suffer from the medical condition. "Non-patient" includes healthy individuals, non-diseased individuals, and/or individuals without such medical condition.

An "isolated" antibody is one that has been separated from a component of its natural environment. The term "isolated" does not necessarily mean excluding artificial or synthetic mixtures with other components or the presence of impurities (eg, due to incomplete purification). In particular, isolated antibodies are also intended to include those antibodies which have been chemically synthesized or engineered. In various embodiments, an isolated antibody is obtained by removing or purifying it from its natural environment, by selecting from an antibody source (such as a phage display library or a B cell antibody library), by chemical synthesis, and/or by Obtained using antibody engineering techniques (such as modifying the sequence and/or structure of the parental antibody). In some embodiments, antibodies are purified to greater than 95% or 99% purity, such as by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or determined by reverse phase HPLC). For a review of methods for assessing antibody purity see, eg, Flatman et al., J. Chromatogr. B 848:79-87 (2007).

An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from components of its natural environment. Isolated nucleic acid includes a nucleic acid molecule contained in cells that normally contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location other than its natural chromosomal location.

"Isolated nucleic acid encoding an anti-SARS-CoV-2 antibody" refers to nucleic acid molecules encoding one or more of the antibody's heavy and light chains (or fragments thereof), including such nucleic acid molecules and the presence of such nucleic acid molecules in a single vector or in separate vectors. Such nucleic acid molecules at one or more locations in the host cell.

As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind to the same epitope, although variant antibodies may exist, e.g. Mutations exist or arise during the production of monoclonal antibody preparations, and such variants generally exist in small amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is directed against a single determinant on the antigen. Thus, the modifier "monoclonal" indicates that the antibody is characterized as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring that the antibody be produced by any particular method. For example, monoclonal antibodies for use in accordance with the present invention can be produced by a variety of techniques including, but not limited to, the fusionoma method, recombinant DNA methods, phage display methods, and the use of genetically modified genes containing all or part of the human immunoglobulin loci. Methods of breeding animals, such methods of making monoclonal antibodies described herein, and other exemplary methods.

"Naked antibody" refers to an antibody that is not conjugated with a heterologous moiety (eg, a cytotoxic moiety) or a radioactive label. Naked antibodies can be present in pharmaceutical formulations.

"Native antibody" refers to a naturally occurring immunoglobulin molecule of varying structure. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons that are composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N-terminus to C-terminus, each heavy chain has a variable region (VH), also called variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2 and CH3). Similarly, from N-terminus to C-terminus, each light chain has a variable region (VL), also known as a variable light domain or light chain variable domain, followed by a constant light (CL) domain. The light chains of antibodies can be assigned to one of two types, called kappa (kappa) and lambda (lambda), based on the amino acid sequence of their constant domains.

The term "package insert" is used to refer to instructions normally included in commercial packages of therapeutic products that contain information on the indications, usage, dosage, administration, combination therapy, contraindications, and/or WARNING INFORMATION.

The "percent amino acid sequence identity (%)" relative to the reference polypeptide sequence is defined after aligning the reference polypeptide sequence with the candidate sequence and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and without replacing any conservative substitutions To be considered part of the sequence identity, the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a reference polypeptide sequence. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR) software or GENETYX (registered trademark) (Genetyx Co., Ltd.). Those skilled in the art can determine parameters suitable for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

The ALIGN-2 sequence comparison computer program is designed by Genentech, Inc., and the original code has been applied for user documentation at the U.S. Copyright Office, Washington D.C., 20559, where it is registered in the U.S. Copyright Registration (U.S. Copyright Registration ) under No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California or can be compiled from source. ALIGN-2 programs are compiled for UNIX operating systems, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. In the case of amino acid sequence comparison using ALIGN-2, a given amino acid sequence A and a given amino acid sequence B (or, it can be expressed as having or comprising a certain amino acid sequence with a given amino acid sequence B % Identity The % amino acid sequence identity of a given amino acid sequence A) is calculated as follows: 100 times fraction X/Y where X is the number of amino acid residues in the alignment programs of A and B that are scored as consistent matches by the sequence alignment program ALIGN-2, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of the amino acid sequence A is not equal to the length of the amino acid sequence B, the % amino acid sequence identity of A with respect to B is the same as the % amino acid sequence identity of B with respect to A not equal. Unless specifically stated otherwise, all amino acid sequence identity % values used herein were obtained using the ALIGN-2 computer program as described in the immediately preceding paragraph.

The term "pharmaceutical formulation" (also referred to herein as "pharmaceutical composition") refers to a preparation that is in a form that permits the biological activity of the active ingredients contained therein to be effective, and which does not contain ingredients necessary for the formulation to be administered. Additional components that are unacceptably toxic to the individual product.

"Pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation other than the active ingredient that is non-toxic to the individual. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers or preservatives.

Unless otherwise indicated, as used herein, the term "SARS-CoV-2" refers to SARS-CoV-2 from any vertebrate source, including mammals, such as primates (e.g., humans) and rodents (e.g., mice and rats). Any native SARS-CoV-2. The term encompasses "full-length" unprocessed SARS-CoV-2 as well as any form of SARS-CoV-2 that results from processing in cells. The term also encompasses naturally occurring variants of SARS-CoV-2, such as splice variants or allelic variants. The antigen binding molecules of the invention can bind to any variant of a SARS-CoV-2 protein. The amino acid sequence of an exemplary SARS-CoV-2 is shown in NCBI Reference Sequence: NC_045512.2 (Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1, complete genome). The amino acid sequence of an exemplary spike protein (surface glycoprotein) of SARS-CoV-2 is shown in NCBI Reference Sequence: YP_009724390.1. Examples of naturally occurring variants of SARS-CoV-2 include, but are not limited to, alpha (e.g. B.1.1.7), beta (e.g. B.1.351, B.1.351.2, B.1.351.3), delta (e.g. B.1.617.2, AY.1, AY.2, AY.3), ε (such as B.1.427 and B.1.429), γ (such as P.1, P.1.1, P.1.2), κ (such as B.1.617.1) and lambda (eg C.37) variants. A variant of SARS-CoV-2 may share at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94% of its entire length with the sequence shown in NCBI Reference Sequence: NC_045512.2 %, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5 %, at least about 99.6%, at least about 99.7%, at least about 99.8%, at least about 99.9%, at least about 99.91%, at least about 99.92%, at least about 99.93%, at least about 99.94%, at least about 99.95%, at least about 99.96 %, at least about 99.97%, at least about 99.98%, or at least about 99.99% sequence identity. The disease caused by the coronavirus first reported in 2019 is called coronavirus disease 2019 (COVID-19).

As used herein, "treatment" (and its grammatical variants, such as "treat/treating") refers to clinical intervention in an attempt to alter the natural course of the disease in the individual being treated, and may be performed for prophylaxis or in clinical during the course of pathology. Desired therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of the disease, reducing the incidence of the disease, alleviating symptoms, alleviating any direct or indirect pathological consequences of the disease, slowing the rate of disease progression, ameliorating or palliation of the disease state, and remission or improvement of prognosis. In some embodiments, antibodies of the invention are used to delay disease onset or slow disease progression.

The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to its antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of primary antibodies generally have a similar structure, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See eg Kindt et al. Kuby Immunology , 6th Ed., WH Freeman and Co., p. 91 (2007)). A single VH or VL domain may be sufficient to confer antigen binding specificity. In addition, the VH or VL domains from antibodies that bind the antigen can be used to isolate antibodies that bind a particular antigen to screen libraries of complementary VL or VH domains, respectively. See, eg, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

As used herein, the term "vector" refers to a nucleic acid molecule capable of transmitting another nucleic acid to which it has been linked. The term includes vectors that are self-replicating nucleic acid structures as well as vectors that are incorporated into the genome of a host cell into which they have been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vehicles are referred to herein as "expression vehicles." An expression vector can be introduced into a host cell by a method using a virus, an electroporation method, or the like, but introduction of an expression vector is not limited to in vitro introduction, and the vector can also be directly introduced into the body.

Unless otherwise stated, the terms "coupled" or "connected" as used in this specification are intended to cover both direct connection or connection via one or more intermediate members.

The term "and/or" (eg "X and/or Y") should be understood to mean "X and Y" or "X or Y" and should be taken to provide explicit support for either or both meanings.

In addition, in the description herein, whenever the word "substantially" is used, it should be understood to include but not limited to "full" or "completely" and the like. In addition, terms such as "comprising/comprise" and the like are intended to be non-limiting descriptive language whenever they are used, since they are broadly included in this category, in addition to other components not expressly recited. The element/component described after the term. For example, when "comprising" is used, reference to "a" feature also means reference to "at least one" of that feature. Terms such as "consisting/consist" and the like may be considered a subset of terms such as "comprising/comprise" and the like in the appropriate context. Thus, in embodiments disclosed herein that use terms such as "comprising/comprise" and the like, it should be understood that such embodiments provide The teachings of the corresponding embodiments of the terms. Additionally, terms such as "about," "approximately," and the like, whenever used, generally mean reasonable variations, such as +/- 5% variation from the disclosed value, or a 4% deviation from the disclosed value, or A deviation of 3% of the disclosed value, a deviation of 2% of the disclosed value or a deviation of 1% of the disclosed value.

Furthermore, in the description herein, certain values may be disclosed in a range. Values showing endpoints of a range are intended to illustrate preferred ranges. Whenever a range is described, it is intended that that range encompasses and teaches all possible subranges as well as individual values within that range. That is, the endpoints of the ranges should not be construed as inflexible limitations. For example, a description of a range of 1% to 5% is intended to have specifically disclosed the subranges 1% to 2%, 1% to 3%, 1% to 4%, 2% to 3%, etc. Individual values such as 1%, 2%, 3%, 4% and 5%. It should be understood that individual values within the range also include whole numbers, fractions, and decimals. In addition, whenever a range is described, it is also intended that the range encompasses and teaches values from the endpoints of the indicated numerical values to up to 2 additional decimal places or significant figures, as appropriate. For example, a description of a range of 1% to 5% is intended to specifically disclose the ranges 1.00% to 5.00% and 1.0% to 5.0%, and all intermediate values therebetween (such as 1.01%, 1.02%...4.98%, 4.99%, 5.00%, and 1.1%, 1.2%…4.8%, 4.9%, 5.0%, etc.). The purpose of the specific disclosure above applies to any depth/breadth of range.

Additionally, when describing some embodiments, the present invention may have disclosed methods and/or procedures as a specific sequence of steps. However, unless otherwise required, it should be understood that the methods or processes should not be limited to the specific order of steps disclosed. Other sequences of steps may be possible. The specific order of steps disclosed herein should not be considered unduly limiting. Unless otherwise required, the methods and/or procedures disclosed herein should not be limited to the steps performed in the order written. The order of steps may be changed and still remain within the scope of the invention.

Furthermore, it should be understood that while the present invention provides embodiments having one or more of the features/characteristics discussed herein, other alternative embodiments may deny one or more of these features, and the present invention The invention provides support for such disclaimers and such related alternative embodiments.

II. Compositions and Methods In one aspect, the invention is based in part on SARS-CoV-2 binding molecules and uses thereof. In one aspect, the invention is based in part on anti-SARS-CoV-2 antibodies and uses thereof. The antibodies of the invention are suitable for example in the diagnosis or treatment of coronavirus infections, especially coronavirus disease 2019 (COVID-19). Illustrative, non-limiting examples of SARS-CoV-2 binding molecules, SARS-CoV-2 antibodies and uses are disclosed below.

A. Exemplary Anti-SARS-CoV-2 Antibody An isolated antibody bound by a receptor binding domain (RBD).

In certain embodiments, the anti-SARS-CoV-2 antibodies of the invention block the binding of SARS-CoV-2 to host cell receptors. In certain embodiments, the anti-SARS-CoV-2 antibodies of the invention inhibit entry of SARS-CoV-2 into host cells. In other embodiments, the anti-SARS-CoV-2 antibodies of the present invention inhibit the interaction between the receptor binding domain (RBD) of the spike protein of SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2).

In certain embodiments, the anti-SARS-CoV-2 antibodies of the invention bind to the spike protein of SARS-CoV-2. In other embodiments, the anti-SARS-CoV-2 antibody of the present invention binds to the S1 domain of the spike protein of SARS-CoV-2. In other embodiments, the anti-SARS-CoV-2 antibodies of the present invention bind to the receptor binding domain (RBD) of the spike protein of SARS-CoV-2.

In certain embodiments, the anti-SARS-CoV-2 antibodies of the invention exert complement-dependent cytotoxicity (CDC) against a target virus (eg, SARS-CoV-2). In certain embodiments, the anti-SARS-CoV-2 antibody of the present invention can dissolve (virolysis) the target virus (such as SARS-CoV2) or reduce the ability of the virus to infect cells by complement.

In certain embodiments, the anti-SARS-CoV-2 antibodies of the invention inhibit antibody-dependent enhancement (ADE) observed with conventional anti-SARS-CoV-2 antibodies.

In certain embodiments, the anti-SARS-CoV-2 antibodies of the present invention bind to and/or neutralize the receptor binding domain (RBD) of the Spike protein of SARS-CoV-2. In some embodiments, the anti-SARS-CoV-2 antibodies of the invention bind to and/or neutralize one or more variants that have mutations in the RBD of the Spike protein of SARS-CoV-2. For example, spike protein variants have been mentioned in a preliminary report (preprint) by Nelson-Sathi et al. (“Mutational landscape and in silico structure models of SARS-CoV-2 Spike Receptor Binding Domain reveal key molecular determinants for virus-host interaction”; Cold Spring Harbor Laboratory, bioRxiv (biology preprint server); https://doi.org/10.1101/2020.05.02.071811). RBD variants (mutants) of the SARS-CoV-2 spike protein may include, but are not limited to, mutations at the following amino acid positions relative to the SARS-CoV-2 S protein of the Wuhan strain (reference sequence: YP_009724390.1) : P322, T323, P330, F338, V341, A344, R346, A348, N354, S359, V367, N370, P384, A411, Q414, K417, A435, N439, K444, G446, L452, Y453, L455, I468, E471 . Such mutants may include, but are not limited to: P322A, T323I, P330S, F338L, V341I, A344S, R346K, A348S, N354D, N354S, S359N, V367F, N370S, P384L, P384S, A411S, Q414K, Q414R, K457S, A43 N439K、K444R、G446V、L452R、Y453F、L455F、I468T、I468V、E471Q、A475V、G476S、S477G、S477I、S477N、T478I、P479S、N481D、G482S、V483A、V483F、V483I、E484D、E484K、E484Q、G485S、 F486S, N487R, F490L, F490S, Q493L, S494P, N501Y, Y508H, E516Q, H519Q, A520S, A520V, P521R, P521S, A522S and A522V. The above mutants and mutations can be used alone or in combination. Mutants and mutations can be combined with any amino acid modification within or outside the RBD, such as additions, insertions, deletions and substitutions. Examples of such combinations include, but are not limited to, K417N/E484K/D614G (referred to herein as the South Africa triple mutation) and del69-70/del144-145/N501Y/A570D/D614G/P681H/T716I/S982A/ D1118H (referred to herein as the UK variant).

The anti-SARS-CoV-2 antibody of the present invention can bind to and/or neutralize any spike protein mutants (including the above mutants) with any amino acid mutations (such as substitutions). In some embodiments, the anti-SARS-CoV-2 antibodies of the invention bind to and/or neutralize SARS-CoV-2 S protein RBD mutants, such as V483A and F490S. In some embodiments, anti-SARS-CoV-2 antibodies of the invention bind to and/or neutralize SARS-CoV-2 spike protein mutants with non-RBD mutations, such as D614G.

The anti-SARS-CoV-2 antibodies of the invention may have favorable physicochemical properties. In some embodiments, the anti-SARS-CoV-2 antibodies of the invention exhibit high solubility. In some embodiments, the anti-SARS-CoV-2 antibodies of the invention are substantially soluble when concentrated to about 5 mg/mL, eg, few or no visible particles are observed by visual inspection at this concentration.

The anti-SARS-CoV-2 antibodies of the present invention may have favorable pharmacokinetic properties. In some embodiments, the anti-SARS-CoV-2 antibodies of the invention exhibit favorable exposure, clearance and/or half-life properties. In some embodiments, 28 days after administration, the exposure is about 100 to about 800 μg/mL or about 200 to 600 μg/mL. In some embodiments, clearance is about 0.5 to about 15 mL/day/kg or about 2 to about 10 mL/day/kg. In some embodiments, the half-life is about 1 to about 30 days, about 5 to about 20 days, or about 8 to about 18 days.

In one aspect, the invention provides an anti-SARS-CoV-2 antibody comprising at least one, two, three, four, five or six HVRs selected from: (a) HVR-H1, It comprises the amino acid sequence of SEQ ID NO: 61, 64, 67, 70, 73 or 76; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO: 62, 65, 68, 71, 74 or 77 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 63, 66, 69, 72, 75 or 78; (d) HVR-L1, which comprises SEQ ID NO: 79, 82, 85, 88, 91, 94, 97, 100, 103 or 106 amino acid sequence; (e) HVR-L2, which comprises SEQ ID NO: 80, 83, 86, 89, 92, 95, 98, 101, the amino acid sequence of 104 or 107; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO: 81, 84, 87, 90, 93, 96, 99, 102, 105 or 108.

In one aspect, the invention provides an antibody comprising at least one, at least two or all three VH HVR sequences selected from: (a) HVR-H1 comprising SEQ ID NO: 61, 64, 67 , the amino acid sequence of 70, 73 or 76; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO: 62, 65, 68, 71, 74 or 77; and (c) HVR-H3, It comprises the amino acid sequence of SEQ ID NO: 63, 66, 69, 72, 75 or 78. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63, 66, 69, 72, 75 or 78. In another embodiment, the antibody comprises: HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63, 66, 69, 72, 75 or 78; and HVR-L3 comprising SEQ ID NO: 81, The amino acid sequence of 84, 87, 90, 93, 96, 99, 102, 105 or 108. In another embodiment, the antibody comprises: HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63, 66, 69, 72, 75 or 78; HVR-L3 comprising SEQ ID NO: 81, 84 , the amino acid sequence of 87, 90, 93, 96, 99, 102, 105 or 108; and HVR-H2, which comprises the amino acid sequence of SEQ ID NO: 62, 65, 68, 71, 74 or 77. In another embodiment, the antibody comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61, 64, 67, 70, 73 or 76; (b) HVR-H2 comprising SEQ ID NO: The amino acid sequence of ID NO: 62, 65, 68, 71, 74 or 77; and (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 63, 66, 69, 72, 75 or 78 .

In another aspect, the invention provides an antibody comprising at least one, at least two or all three VL HVR sequences selected from: (a) HVR-L1 comprising SEQ ID NO: 79, 82, 85, 88, 91, 94, 97, 100, 103 or 106 amino acid sequence; (b) HVR-L2, which comprises SEQ ID NO: 80, 83, 86, 89, 92, 95, 98, 101, the amino acid sequence of 104 or 107; and (c) HVR-L3, which comprises the amino acid sequence of SEQ ID NO: 81, 84, 87, 90, 93, 96, 99, 102, 105 or 108. In one embodiment, the antibody comprises: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 79, 82, 85, 88, 91, 94, 97, 100, 103 or 106; (b) HVR-L2, which comprises the amino acid sequence of SEQ ID NO: 80, 83, 86, 89, 92, 95, 98, 101, 104 or 107; and (c) HVR-L3, which comprises SEQ ID NO: 81 , 84, 87, 90, 93, 96, 99, 102, 105 or 108 amino acid sequence.

In another aspect, an antibody of the invention comprises: (a) a VH domain comprising at least one, at least two or all three VH HVR sequences selected from: (i) HVR-H1 comprising SEQ ID NO: the amino acid sequence of 61, 64, 67, 70, 73 or 76; (ii) HVR-H2, which comprises the amino acid sequence of SEQ ID NO: 62, 65, 68, 71, 74 or 77; and (iii) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 63, 66, 69, 72, 75 or 78; and (b) a VL domain, which comprises at least one, at least two or All three VL HVR sequences: (i) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 79, 82, 85, 88, 91, 94, 97, 100, 103 or 106; (ii) HVR- L2, which comprises the amino acid sequence of SEQ ID NO: 80, 83, 86, 89, 92, 95, 98, 101, 104 or 107; and (c) HVR-L3, which comprises SEQ ID NO: 81, 84 , 87, 90, 93, 96, 99, 102, 105 or 108 amino acid sequence.

In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70; (b) HVR-H2 comprising SEQ ID NO: 71 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 72; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 88; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 90. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70; (b) HVR-H2 comprising SEQ ID NO: 71 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 72; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 91; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 92; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 93. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70; (b) HVR-H2 comprising SEQ ID NO: 71 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 72; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 85; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 86; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 87. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70; (b) HVR-H2 comprising SEQ ID NO: 71 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 72; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 94; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 96. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising SEQ ID NO: 74 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 88; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 90. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising SEQ ID NO: 74 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 91; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 92; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 93. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising SEQ ID NO: 74 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 85; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 86; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 87. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising SEQ ID NO: 74 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 94; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 96. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76; (b) HVR-H2 comprising SEQ ID NO: 77 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 78; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 88; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 90. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76; (b) HVR-H2 comprising SEQ ID NO: 77 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 78; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 91; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 92; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 93. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76; (b) HVR-H2 comprising SEQ ID NO: 77 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 78; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 85; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 86; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 87. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76; (b) HVR-H2 comprising SEQ ID NO: 77 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 78; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 94; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 96. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising SEQ ID NO: 62 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 97; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 98; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 99. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 64; (b) HVR-H2 comprising SEQ ID NO: 65 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 66; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 82; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 84. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76; (b) HVR-H2 comprising SEQ ID NO: 77 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 78; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 82; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 84. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising SEQ ID NO: 74 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 82; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 84. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising SEQ ID NO: 68 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 82; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 84. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising SEQ ID NO: 68 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 100; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 102. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70; (b) HVR-H2 comprising SEQ ID NO: 71 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 72; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 97; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 98; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 99. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70; (b) HVR-H2 comprising SEQ ID NO: 71 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 72; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 103; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 104; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 105. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70; (b) HVR-H2 comprising SEQ ID NO: 71 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 72; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 106; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 108. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70; (b) HVR-H2 comprising SEQ ID NO: 71 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 72; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 79; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 80; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 81. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising SEQ ID NO: 62 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 79; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 80; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 81. In another aspect, the present invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 64; (b) HVR-H2 comprising SEQ ID NO: 65 (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 66; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 100; (e) HVR -L2, which comprises the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3, which comprises the amino acid sequence selected from SEQ ID NO: 102.

In another aspect, the invention provides an antibody that binds to SARS-CoV-2, wherein the antibody comprises at least one, two, three, four, five or six HVRs selected from: (i ) HVR-H1 comprising amino acid sequence X ₁ YEMN, wherein X ₁ is L, I or S (SEQ ID NO: 109), (ii) HVR-H2 comprising amino acid sequence VISYX ₁ GSNKYYADSVKG, wherein X ₁ is E or D (SEQ ID NO: 110), (iii) HVR-H3 comprising the amino acid sequence LITMX ₁ RGX ₂ X ₃ X ₄ , wherein X ₁ is T or V, X ₂ is P or A, X ₃ is D or Q, X ₄ is Y or G (SEQ ID NO: 111), (iv) HVR-L1 comprising the amino acid sequence RASQX ₁ IX ₂ X ₃ YLN, wherein X ₁ is S or E, and X ₂ is S or E, X ₃ is S or D (SEQ ID NO: 112), (v) HVR-L2 comprising the amino acid sequence AAX ₁ X ₂ LQX ₃ , wherein X ₁ is S or E, X ₂ is S or E, X ₃ is I or G (SEQ ID NO: 113), and (vi) HVR-L3 comprising the amino acid sequence QX ₁ SYNLPRT, wherein X ₁ is E or Q (SEQ ID NO: 114).

In another aspect, the present invention provides an antibody binding to SARS-CoV-2, wherein the antibody comprises: (i) HVR-H1 comprising the amino acid sequence X ₁ YEMN, wherein X ₁ is L, I or S (SEQ ID NO: 109), (ii) HVR-H2 comprising the amino acid sequence VISYX ₁ GSNKYYADSVKG, wherein X ₁ is E or D (SEQ ID NO: 110), (iii) comprising the amino acid sequence LITMX ₁ HVR-H3 of RGX ₂ X ₃ X ₄ , wherein X ₁ is T or V, X ₂ is P or A, X ₃ is D or Q, X ₄ is Y or G (SEQ ID NO: 111), (iv) HVR-L1 comprising the amino acid sequence RASQX ₁ IX ₂ X ₃ YLN, wherein X ₁ is S or E, X ₂ is S or E, X ₃ is S or D (SEQ ID NO: 112), (v) comprises HVR-L2 of amino acid sequence AAX ₁ X ₂ LQX ₃ , wherein X ₁ is S or E, X ₂ is S or E, X ₃ is I or G (SEQ ID NO: 113), and (vi) comprises amine HVR-L3 of amino acid sequence QX ₁ SYNLPRT, wherein X ₁ is E or Q (SEQ ID NO: 114).

In another aspect, the invention provides an antibody that binds to SARS-CoV-2, wherein the antibody comprises at least one, two, three, four, five or six HVRs selected from: (i ) HVR-H1 comprising amino acid sequence X _YEMN , wherein X is S, _A , I, L, M, P, V, H, F, W or Y (SEQ ID NO: 115), (ii) HVR-H2 comprising the amino acid sequence VISYX ₁ X ₂ SNKX ₃ YADSVKG, wherein X1 is D, S, T or E, X2 is G or _A , _X3 is Y or F (SEQ ID NO: 116), ( iii) HVR-H3 comprising the amino acid sequence LITMX ₁ RGX ₂ X ₃ X ₄ , wherein X ₁ is V or T, X ₂ is E, A, P, V, G, H, K or R, and X ₃ is D or Q, _X4 is Y, P, G or R (SEQ ID NO: 117), (i) HVR-L1 (SEQ ID NO: 118) comprising the amino acid sequence RASQSISSYLN, (ii) comprising the amino acid HVR-L2 of the sequence AASSLQX ₁ , wherein X ₁ is S, I, L, M, G, or F (SEQ ID NO: 119), and (iii) HVR-L3 comprising the amino acid sequence QX ₁ SYNLPRT, wherein X1 is Q, N or E (SEQ ID NO: 120); the proviso is that the antibody is not _an antibody comprising: HVR-H1, HVR-H1 contained in the H chain variable region of SEQ ID NO: 1 H2 and HVR-H3; and HVR-L1, HVR-L2 and HVR-L3 contained in the L chain variable region of SEQ ID NO: 43.

In any of the above embodiments, the anti-SARS-CoV-2 antibody can be a humanized antibody or a human antibody. In one embodiment, an anti-SARS-CoV-2 antibody comprises a HVR as in any one of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework. In some embodiments, the isolated anti-SARS-CoV-2 antibody of the present invention further comprises: heavy chain variable domain framework FR1 comprising the amino acid sequence of SEQ ID NO: 121, 122, 123 or 124; FR2 , which comprises the amino acid sequence of SEQ ID NO: 125; FR3, which comprises the amino acid sequence of SEQ ID NO: 126; FR4, which comprises the amino acid sequence of SEQ ID NO: 127. In some embodiments, the isolated anti-SARS-CoV-2 antibody of the present invention further comprises: light chain variable domain framework FR1 comprising the amino acid sequence of SEQ ID NO: 128; FR2 comprising SEQ ID NO : the amino acid sequence of 129; FR3, which comprises the amino acid sequence of SEQ ID NO: 130; FR4, which comprises the amino acid sequence of SEQ ID NO: 131.

In another aspect, the anti-SARS-CoV-2 antibody comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96% of the amino acid sequence of SEQ ID NO: 2 to 7 , 97%, 98%, 99% or 100% sequence identity of heavy chain variable domain (VH) sequences. In certain embodiments, VH sequences having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contain substitutions relative to the reference sequence ( Such as conservative substitution), insertion or deletion, but the anti-SARS-CoV-2 antibody comprising that sequence can still bind to SARS-CoV-2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NOs: 2 to 7. In certain embodiments, substitutions, insertions or deletions occur in regions outside the HVR (ie, in the FRs). Optionally, the anti-SARS-CoV-2 antibody comprises the VH sequence in SEQ ID NO: 2 to 7, including post-translational modifications of the sequence. In certain embodiments, the above-mentioned antibodies are not antibodies comprising HVR-H1, HVR-H2, and HVR-H3 contained in the H chain variable region of SEQ ID NO: 1. In a specific embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid of SEQ ID NO: 61, 64, 67, 70, 73 or 76 (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO: 62, 65, 68, 71, 74 or 77; and (c) HVR-H3, which comprises SEQ ID NO: 63, 66, The amino acid sequence of 69, 72, 75 or 78. Post-translational modifications include, but are not limited to, glutamic acid in the N-terminus of the heavy or light chain or modification of glutamic acid to pyroglutamic acid by pyroglutamination.

In another aspect, an anti-SARS-CoV-2 antibody is provided, wherein the antibody comprises at least 90%, 91%, 92%, 93%, A light chain variable domain (VL) with 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains a substitution relative to the reference sequence ( Such as conservative substitutions), insertions or deletions, but anti-PRO antibodies comprising that sequence can still bind to SARS-CoV-2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 42, 44, 52. In certain embodiments, substitutions, insertions or deletions occur in regions outside the HVR (ie, in the FRs). Optionally, the anti-SARS-CoV-2 antibody comprises the VL sequence in SEQ ID NO: 42, 44 to 52, including post-translational modifications of the sequence. In certain embodiments, the above-mentioned antibody is not an antibody comprising HVR-L1, HVR-L2, and HVR-L3 contained in the L chain variable region of SEQ ID NO: 43. In a specific embodiment, the VL comprises one, two or three HVRs selected from: (a) HVR-L1 comprising SEQ ID NO: 79, 82, 85, 88, 91, 94, 97, 100 , the amino acid sequence of 103 or 106; (b) HVR-L2, which comprises the amino acid sequence of SEQ ID NO: 80, 83, 86, 89, 92, 95, 98, 101, 104 or 107; and ( c) HVR-L3, which comprises the amino acid sequence of SEQ ID NO: 81, 84, 87, 90, 93, 96, 99, 102, 105 or 108. Post-translational modifications include, but are not limited to, glutamic acid in the N-terminus of the heavy or light chain or modification of glutamic acid to pyroglutamic acid by pyroglutamination.

In another aspect, an anti-SARS-CoV-2 antibody is provided, wherein the antibody comprises the VH in any of the embodiments provided above and the VH in any of the embodiments provided above The VL. In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NOs: 2-7 and SEQ ID NOs: 42, 44-52, respectively, including post-translational modifications of those sequences. Post-translational modifications include, but are not limited to, glutamic acid in the N-terminus of the heavy or light chain or modification of glutamic acid to pyroglutamic acid by pyroglutamination.

In another aspect, an anti-SARS-CoV-2 antibody is provided, wherein the antibody binds to SARS-CoV-2, wherein the antibody comprises: (a) the VH sequence of SEQ ID NO: 5 and SEQ ID NO: 46 The VL sequence of (b) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 47, (c) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 45, (d) SEQ ID NO: ID NO: the VH sequence of 5 and the VL sequence of SEQ ID NO: 48, (e) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 46, (f) the VH sequence of SEQ ID NO: 6 and The VL sequence of SEQ ID NO: 47, (g) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 45, (h) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 48 , (i) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 46, (j) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 47, (k) SEQ ID NO: The VH sequence of 7 and the VL sequence of SEQ ID NO: 45, (l) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 48, (m) the VH sequence of SEQ ID NO: 2 and SEQ ID NO : the VL sequence of 49, (n) the VH sequence of SEQ ID NO: 3 and the VL sequence of SEQ ID NO: 44, (o) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 44, (p ) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 44, (q) the VH sequence of SEQ ID NO: 4 and the VL sequence of SEQ ID NO: 44, (r) the VH of SEQ ID NO: 4 sequence and the VL sequence of SEQ ID NO: 50, (s) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 49, (t) the VH sequence of SEQ ID NO: 5 and the VH sequence of SEQ ID NO: 51 VL sequence, (u) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 52, (v) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 42, (w) SEQ ID The VH sequence of NO: 2 and the VL sequence of SEQ ID NO: 42, or (x) The VH sequence of SEQ ID NO: 3 and the VL sequence of SEQ ID NO: 50, including post-translational modifications of these sequences. Post-translational modifications include, but are not limited to, glutamic acid in the N-terminus of the heavy or light chain or modification of glutamic acid to pyroglutamic acid by pyroglutamination.

In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 4; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 44; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 5; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 45; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60.

In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 5; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 46; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 5; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 47; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 5; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 48; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 6; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 46; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 6; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 47; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 6; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 45; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 6; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 48; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 7; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 46; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 7; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 47; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 7; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 45; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 7; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 48; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 2; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 49; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 3; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 44; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 7; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 44; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 6; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 44; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 4; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 50; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 5; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 49; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 5; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 51; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 5; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 52; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 5; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 42; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 2; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 42; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60. In another aspect, the present invention provides an antibody comprising: (a) a VH sequence comprising the amino acid sequence of SEQ ID NO: 3; (b) a CH sequence comprising SEQ ID NO: 40 or 41 c) VL sequence, which comprises the amino acid sequence of SEQ ID NO: 50; and d) CL sequence, which comprises the amino acid sequence of SEQ ID NO: 60.

In another aspect, the invention provides an antibody that binds to the same epitope as an anti-SARS-CoV-2 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as any of the antibodies described above. In certain embodiments, an antibody is provided that binds to an epitope within a fragment of SARS-CoV-2, particularly the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein. In certain embodiments, there is provided an antibody that binds to the same epitope as any of the antibodies described above, wherein the antibody comprises a variant Fc region comprising at least one amine group in the parental Fc region An acid alteration, wherein the variant Fc region has substantially reduced FcγR binding activity and has maintained or increased C1q binding activity when compared to the parental Fc region.

In one aspect, the invention provides a SARS-CoV-2 binding molecule comprising: (i) an antigen-binding portion that specifically binds to SARS-CoV-2; and (ii) a variant Fc region comprising at least one amino acid change relative to the parental Fc region, wherein when compared to the parental Fc region When, the variant Fc region has substantially reduced FcγR binding activity and has maintained or increased C1q binding activity, and wherein the antigen-binding molecule specifically binds to the same epitope as any one of the antibodies described above.

In another aspect of the present invention, the anti-SARS-CoV-2 antibody according to any one of the above embodiments is a monoclonal antibody, including chimeric antibody, humanized antibody or human antibody. In one embodiment, the anti-SARS-CoV-2 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody or F(ab') ₂ fragment. In another embodiment, the antibody may be a full length antibody, such as a whole antibody (eg human IgGl, IgG2, IgG3 or IgG4) or other antibody class or isotype as defined herein.

In another aspect, the anti-SARS-CoV-2 antibody according to any of the above embodiments may incorporate any of the features as described in sections 1 to 7 below, singly or in combination.

1. Antibody Affinity In certain embodiments, the antibodies provided herein have a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less Small, 0.01 nM or less or 0.001 nM or less (eg 10 ^-8 M or less, 10 ^-8 M to 10 ^-13 M, eg 10 ^-9 M to 10 ^-13 M).

In certain embodiments, the affinity matured antibodies provided herein can be compared to their parental antibodies (e.g., having the H chain variable region set forth in SEQ ID NO: 1 and the L chain set forth in SEQ ID NO: 43). Antibodies in variable regions) have improved affinity (or lower Kd) and/or neutralizing capacity/efficacy for SARS-CoV-2. In certain embodiments, the affinity matured antibodies provided herein have an affinity for SARS-CoV-2 that is at least about 2 times, about 5 times, about 10 times, about 50 times higher than the affinity of their parental antibody for SARS-CoV-2 times, about 100 times, about 500 times or about 1000 times.

In certain embodiments, the antibodies provided herein exhibit similar binding/binding affinities against different variants of SARS-CoV-2. In certain embodiments, the antibodies provided herein are directed against at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, At least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, or at least about 17 variants exhibit similar binding/binding affinities. In certain embodiments, the antibodies provided herein exhibit similar binding to RBD wild-type and RBD mutants. For example, the antibodies provided herein can exhibit a relative binding of greater than 0.5 relative to RBD wild-type against RBD mutants. In certain embodiments, the antibodies provided herein are directed against at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10. At least about 11, at least about 12, at least about 13, at least about 14, at least about 15, or at least about 16 RBD mutants exhibit binding similar to RBD wild type. In certain embodiments, the antibodies provided herein are capable of neutralizing Variant of Concern (VOC) and/or Variant of Interest (VOI). In certain embodiments, the antibodies provided herein are capable of neutralizing beta, gamma, kappa, delta, and/or epsilon variants of SARS-CoV-2.

In one embodiment, Kd is measured by radiolabeled antigen binding assay ( RIA ). In one embodiment, RIA is performed with the Fab form of the antibody of interest and its antigen. For example, the solution binding affinity of a Fab for antigen is measured by equilibrating the Fab with a minimal concentration of ( ¹²⁵ I) labeled antigen in the presence of a titration series of unlabeled antigen, followed by coating with anti-Fab antibody The plate captures bound antigen (see, eg, Chen et al., J. Mol. Biol. 293:865-881 (1999)). To establish conditions for analysis, MICROTITER (registered trademark) multiwell plates (Thermo Scientific) were coated overnight with 50 mM sodium carbonate (pH 9.6) containing 5 micrograms (μg)/ml of capture anti-Fab antibody (Cappel Labs), and then blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23°C). In adsorbent-free plates (Nunc #269620), 100 pM or 26 pM [ ¹²⁵ I] antigen was mixed with serial dilutions of the Fab of interest (eg with Presta et al., Cancer Res. 57:4593-4599 (1997 ) in the same evaluation as the anti-VEGF antibody Fab-12). The Fab of interest is then incubated overnight; however, incubation can be continued for a longer period of time (eg, about 65 hours) to ensure equilibrium is reached. Thereafter, the mixture is transferred to capture culture plates for incubation at room temperature (eg, for one hour). The solution was then removed, and the plates were washed eight times with PBS containing 0.1% polysorbate 20 (TWEEN-20 (registered trademark)). When the plates had dried, 150 microliters/well of scintillant (MICROSCINT-20 ^™ ; Packard) was added and the plates were counted for tens of minutes on a TOPCOUNT ^™ gamma counter (Packard). Concentrations of each Fab that provided less than or equal to 20% of maximal binding were chosen for competitive binding assays.

According to another embodiment, Kd is measured using BIACORE (registered trademark) surface plasmon resonance analysis. For example, with immobilized antigen CM5 chips at ~10 response units (RU) at 25°C using BIACORE(R)-2000 or BIACORE(R)-3000 (BIAcore, Inc., Piscataway, NJ) analysis. In one example, N -ethyl- N' -(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N -hydroxysuccinimide were used according to the supplier's instructions. amine (NHS) to activate carboxymethylated polydextrose biosensor chips (CM5, BIACORE, Inc.). Antigen was diluted to 5 μg/ml (~0.2 μM) with 10 mM sodium acetate (pH 4.8) and then injected at a flow rate of 5 μl/min to achieve approximately 10 response units (RU) of coupled protein. After antigen injection, 1 M ethanolamine was injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of Fab in PBS (PBST) with 0.05% polysorbate 20 (TWEEN-20 ^™ ) surfactant were injected at 25°C at a flow rate of approximately 25 μl/min ( 0.78 nM to 500 nM). Binding rates (k _on ) and dissociation rate (k _off ). The equilibrium dissociation constant (Kd) was calculated as the ratio k _off /k _on . See, eg, Chen et al., J. Mol. Biol. 293:865-881 (1999). If the on-rate as determined by surface plasmon resonance analysis above exceeds 10 ⁶ M ⁻¹ s ⁻¹ , the on-rate can be determined by using fluorescence quenching techniques, such as in a spectrometer (such as with Measured in the stop-flow equipped spectrophotometer (Aviv Instruments) or 8000-series SLM-AMINCO ^TM spectrophotometer (ThermoSpectronic) of the stirred optical analysis cell, in the presence of increasing concentrations of antigens, at 25 ° C The increase or decrease in fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm bandpass) of 20 nM anti-antigen antibody (Fab format) in PBS (pH 7.2) was measured.

2. Antibody Fragments In certain embodiments, the antibodies provided herein are antibody fragments. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab') ₂ , Fv, and scFv fragments, VHH, VL, VH, single domain antibodies, and other fragments described below. For a review of certain antibody fragments, see Hudson et al., Nat. Med. 9:129-134 (2003). For a review of scFv fragments see e.g. Pluckthün, The Pharmacology of Monoclonal Antibodies , vol. 113, Rosenburg and Moore eds. (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93/16185; and US Patent Nos. 5,571,894 and 5,587,458. For a discussion of Fab and F(ab') ₂ fragments comprising salvage receptor binding epitope residues with extended in vivo half-lives, see US Patent No. 5,869,046.

Bifunctional antibodies are antibody fragments that can be bivalent or bispecific with two antigen combining sites. See eg EP 404,097; WO 1993/01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Trifunctional and tetrafunctional antibodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

A single domain antibody is an antibody fragment comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, the single domain antibody is a human single domain antibody (Domantis, Inc., Waltham, MA; see, eg, US Patent No. 6,248,516 Bl ).

Antibody fragments can be prepared by various techniques including, but not limited to, proteolytic digestion of intact antibodies as described herein and production by recombinant host cells such as E. coli or phage.

3. Chimeric and Humanized Antibodies In certain embodiments, the antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, eg, in US Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA , 81:6851-6855 (1984)). In one example, a chimeric antibody comprises non-human variable regions (eg, variable regions derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and human constant regions. In another embodiment, a chimeric antibody is a "class-switched" antibody, wherein the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

In certain embodiments, chimeric antibodies are humanized antibodies. Typically, non-human antibodies are humanized to reduce immunogenicity to humans while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs (eg, CDRs (or portions thereof)) are derived from non-human antibodies and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (eg, the antibody from which the HVR residues are derived), eg, to restore or improve antibody specificity or affinity.

Humanized antibodies and methods for their preparation are reviewed, eg, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further described, eg, in Riechmann et al., Nature 332:323-329 (1988); Queen et al. Sci. USA 86:10029-10033 (1989); US Patent Nos. 5,821,337, 7,527,791, 6,982,321 and 7,087,409; Kashmiri et al., Methods 36:25-34 ( 2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing "resurfacing");Dall'Acqua et al., Methods 36:43-60 ( 2005) (describing "FR reorganization"); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer , 83:252-260 (2000) (describing "FR reorganization" Citation Select" method).

Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using "best-fit" methods (see, e.g., Sims et al., J. Immunol. 151:2296 (1993)); Framework regions derived from the consensus sequence of human antibodies with specific subgroups of light or heavy chain variable regions (see, e.g., Carter et al., Proc. Natl. Acad. Sci. USA , 89:4285 (1992); and Presta et al., J. Immunol. , 151:2623 (1993)); human mature (somatic mutation) framework regions or human germline framework regions (see e.g. Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008) ); and framework regions derived from screening FR libraries (see, for example, Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996 )).

4. Human Antibodies In certain embodiments, the antibodies provided herein are human antibodies. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

Human antibodies can be prepared by administering the immunogen to transgenic animals that have been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, either present extrachromosomally or integrated randomly into the animal's chromosomes. In such transgenic mice, the endogenous immunoglobulin loci are generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, for example, U.S. Patent Nos. 6,075,181 and 6,150,584, which describe XENOMOUSE ^™ technology; U.S. Patent No. 5,770,429, which describes HUMAB(R) technology; U.S. Patent No. 7,041,870, which describes KM MOUSE(R) technology; and US Patent Application Publication No. US 2007/0061900, which describes VELOCIMOUSE (registered trademark) technology). The human variable regions of intact antibodies produced by such animals can be further modified, eg, by combining with different human constant regions.

Human antibodies can also be produced by fusionoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See e.g. Kozbor J. Immunol. , 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications , pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol. , 147: 86 (1991)). Human antibodies produced via human B cell fusion tumor technology are also described in Li et al., Proc. Natl. Acad. Sci. USA , 103:3557-3562 (2006). Other methods include, for example, those described in U.S. Patent No. 7,189,826 (describing the production of monoclonal human IgM antibodies from fusionoma cell lines) and Ni, Xiandai Mianyixue 26(4):265-268 (2006) (describing human-human fusionomas) their methods. Human fusion tumor technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology , 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology , 27(3):185-91 (2005).

Human antibodies can also be produced by isolating Fv clonal variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences can then be combined with the desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

5. Library-Derived Antibodies Antibodies of the invention can be isolated by screening combinatorial libraries for antibodies having one or more desired activities. For example, various methods are known in the art for generating phage display libraries and screening such libraries for antibodies with desired binding characteristics. Such methods are reviewed, e.g., in Hoogenboom et al. Methods in Molecular Biology 178:1-37 (eds. O'Brien et al., Human Press, Totowa, NJ, 2001), and further described, e.g., in 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, eds., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2): 119-132 (2004).

In certain phage display methods, repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and randomly recombined in a phage library, which can then be determined as described in Winter et al., Ann. Rev. Screening against antigen-binding phage is described in Immunol. 12:433-455 (1994). Phage typically present antibody fragments as single-chain Fv (scFv) fragments or Fab fragments. Libraries from immunized sources provide high affinity antibodies to the immunogen without the need for construction of fusionomas. Alternatively, the native lineage can be bred (e.g., from humans) to provide a single source of antibodies to a broad range of non-self as well as self-antigens without any immunization, as in EMBO J 12: 725-734 by Griffiths et al. 1993) described. Finally, primary libraries can also be prepared synthetically by cloning unrearranged V gene segments from stem cells and using PCR primers containing random sequences encoding the highly variable CDR3 region and enabling rearrangement in vitro, such as Hoogenboom and Winter, Described in J. Mol. Biol. , 227: 381-388 (1992). Patent publications describing human antibody phage libraries include, for example: U.S. Patent No. 5,750,373 and U.S. Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598 No. 2007/0237764, 2007/0292936 and 2009/0002360.

Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.

6. Multispecific Antibodies In certain embodiments, antibodies provided herein are multispecific antibodies, such as bispecific antibodies. Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites. In certain embodiments, one of the binding specificities is for SARS-CoV-2 and the other is for any other antigen. In certain embodiments, bispecific antibodies can bind to two different epitopes of SARS-CoV-2. Bispecific antibodies can also be used to localize cytotoxic agents on cells expressing SARS-CoV-2. Bispecific antibodies can be prepared as full-length antibodies or antibody fragments.

Techniques for making multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (see Milstein and Cuello, Nature 305: 537 (1983)), WO 93/08829 and Traunecker et al., EMBO J. 10: 3655 (1991)), and "pestle-and-mortar" engineering (see eg, US Patent No. 5,731,168). Multispecific antibodies can also be prepared by: engineering electrostatic targeting effects for the preparation of antibody Fc-heterodimeric molecules (WO 2009/089004A1); cross-linking two or more antibodies or fragments (see e.g. US Patent No. 4,676,980 and Brennan et al., Science , 229: 81 (1985)); generation of bispecific antibodies using leucine zippers (see e.g. Kostelny et al., J. Immunol. , 148(5):1547-1553 (1992) ); use of "bifunctional antibody" technology for the preparation of bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA , 90:6444-6448 (1993)); and use of single-chain Fv (scFv) dimers (see, e.g., Gruber et al., J. Immunol. , 152:5368 (1994)); and trispecific as described in, e.g., Tutt et al., J. Immunol. 147: 60 (1991) Antibody.

Also included herein are antibodies (including "octopus antibodies") engineered to have three or more functional antigen binding sites (see, eg, US 2006/0025576A1).

Antibodies or fragments herein also include "dual-acting Fabs" or "DAFs" that comprise an antigen-binding site that binds to SARS-CoV-2 as well as a different antigen (see eg US 2008/0069820).

7. Antibody Variants In certain embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. Amino acid sequence variants of an antibody can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues within the amino acid sequence of the antibody. Any combination of deletions, insertions and substitutions can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, such as antigen binding.

a) Substitution, insertion and deletion variants In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include HVR and FR. Conservative substitutions are shown in Table 1 under the heading "Preferred Substitutions". More substantial variations are provided in Table 1 under the heading "Exemplary Substitutions" and are further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into antibodies of interest, and the products screened for desired activities, such as retained/improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. [Table 1] initial residue Exemplary substitution better replacement Ala (A) Val; Leu; Ile Val Arg (R) Lys; Gln; Asn Lys Asn (N) Gln; His; Asp, Lys; Arg Gln Asp (D) Glu;Asn Glu Cys (C) Ser; Ala Ser Gln (Q) Asn; Glu Asn Glu (E) Asp; Gln Asp Gly (G) Ala Ala His (H) Asn; Gln; Lys; Arg Arg Ile (I) Leu; Val; Met; Ala; Phe; Norleucine Leu Leu (L) Norleucine; Ile; Val; Met; Ala; Phe Ile Lys (K) Arg; Gln; Asn Arg Met (M) Leu; Phe; Ile Leu Phe (F) Trp; Leu; Val; Ile; Ala; Tyr Tyr Pro (P) Ala Ala Ser (S) Thr Thr Thr (T) Val; Ser Trp (W) Tyr; Phe Tyr Tyr (Y) Trp; Phe; Thr; Ser Phe Val (V) Ile; Leu; Met; Phe; Ala; Norleucine Leu

Amino acids can be grouped according to common side chain properties: (1) Hydrophobicity: Norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln; (3) Acidity: Asp, Glu; (4) Alkaline: His, Lys, Arg; (5) Residues affecting chain orientation: Gly, Pro; (6) Aromaticity: Trp, Tyr, Phe.

Non-conservative substitutions will result in the exchange of a member of one of these classes for another class.

One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (eg, a humanized or human antibody). Generally, the resulting variants selected for further study will have modifications (e.g. improvements) in certain biological properties (e.g. increased affinity, reduced immunogenicity) relative to the parental antibody and/or will substantially retain the parental antibody Certain biological properties of antibodies. An exemplary substitutional variant is an affinity matured antibody, which can be conveniently generated, eg, using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated, and variant antibodies are displayed on phage and screened for specific biological activity (eg, binding affinity).

Alterations (eg, substitutions) can be made in the HVR, eg, to increase antibody affinity. May be in HVR "hotspots" (i.e. residues encoded by codons that undergo high frequency mutations during the somatic maturation process (see e.g. Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/ or antigen-contacting residues) with the resulting variant VH or VL to be tested for binding affinity for such alterations. Affinity maturation by construction of secondary libraries and reselection from secondary libraries has been described in Hoogenboom et al. Methods in Molecular Biology 178:1-37 (eds. O'Brien et al., Human Press, Totowa, NJ, (2001 )). In some embodiments of affinity maturation, diversity is introduced into variable genes selected for maturation by any of a variety of methods, such as error-prone PCR, strand shuffling, or oligonucleotide-directed mutagenesis. A secondary library is then generated. This library is then screened to identify any antibody variants with the desired affinity. Another method of introducing diversity involves the HVR-guided method of random grouping of several HVR residues (eg, 4 to 6 residues at a time). HVR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modelling. In particular, CDR-H3 and CDR-L3 are often targeted.

In certain embodiments, substitutions, insertions, or deletions may occur within one or more of the HVRs, so long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative changes that do not substantially reduce binding affinity (eg, conservative substitutions as provided herein) can be made in HVRs. Such alterations may, for example, be outside of the antigen-contacting residues in the HVR. In certain embodiments of the variant VH and VL sequences provided above, each HVR is unchanged or contains no more than one, two or three amino acid substitutions.

A suitable method for identifying residues or regions of an antibody that can be targeted for mutagenesis is called "alanine scanning mutagenesis" as described by Cunningham and Wells (1989) Science , 244:1081-1085. In this method, one or a group of residues of interest (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and identified with neutral or negatively charged amino acids (e.g., alanine or polypropylamine Acid) replacement to determine whether the interaction between antibody and antigen is affected. Additional substitutions can be introduced at amino acid positions that exhibit functional sensitivity to the initial substitution. Alternatively or additionally, the crystal structure of the antigen-antibody complex can be analyzed to identify contact points between the antibody and antigen. Such contact residues and neighboring residues can be targeted or excluded as candidates for substitution. Variants can be screened to determine whether they contain the desired property.

Amino acid sequence insertions include amino-terminal and/or carboxy-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as within sequences of single or multiple amino acid residues insert. Examples of terminal insertions include antibodies with an N-terminal methionyl residue. Other insertional variants of antibody molecules include enzymes that increase the plasma half-life of the antibody (eg, ADEPT) or fusions of polypeptides to the N- or C-terminus of the antibody.

b) Glycosylation variants In certain embodiments, the antibodies provided herein are altered to increase or decrease the degree of glycosylation of the antibody. Addition of glycosylation sites to or deletion of glycosylation sites from an antibody is conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites are created or removed.

Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise branched biantennary oligosaccharides, which are typically N-bonded to Asn297 of the CH2 domain of the Fc region. See, eg, Wright et al. TIBTECH 15:26-32 (1997). Oligosaccharides can include various carbohydrates such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose linked to GlcNAc in the "backbone" of the diantooligosaccharide structure. In some embodiments, the oligosaccharides in the antibodies of the invention may be modified in order to produce antibody variants with certain improved properties.

In one embodiment, antibody variants are provided that do not have fucose linked (directly or indirectly) to the carbohydrate structure of the Fc region. For example, the amount of fucose in such antibodies may be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose was determined by calculating the average amount of fucose at Asn297 within the sugar chain relative to all sugar structures attached to Asn 297 as measured by MALDI-TOF mass spectrometry ( For example complex, hybrid and high mannose structures) as described in eg WO 2008/077546. Asn297 refers to the asparagine residue located at about position 297 (EU numbering of Fc region residues) in the Fc region; however, due to slight sequence variations of the antibody, Asn297 can also be located about + /- 3 amino acids, ie between positions 294 and 300. Such fucosylation variants may have improved ADCC function. See, eg, US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications on "afucosylated" or "fucose-deficient" antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328 ; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; WO2002/031140; Okazaki et al . J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al . Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing afucosylated antibodies include Lec13 CHO cells lacking protein fucosylation (Ripka et al., Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Patent Application US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., especially Example 11), and knockout cell lines, such as the α-1,6-fucosyltransferase gene FUT8 gene Deletion of CHO cells (see for example Yamane-Ohnuki et al., Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng. , 94(4): 680-688 (2006); and WO2003/ 085107).

Antibody variants further possess bisecting oligosaccharides, eg, wherein the biantennary oligosaccharides linked to the Fc region of the antibody are bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, eg, in WO 2003/011878 (Jean-Mairet et al); US Patent No. 6,602,684 (Umana et al); and US 2005/0123546 (Umana et al). Also provided are antibody variants in which at least one galactose residue in the oligosaccharide is linked to the Fc region. Such antibody variants may have improved CDC function. Such antibody variants are described, eg, in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).

c) Fc region variants In certain embodiments, one or more amino acid modifications can be introduced into the Fc region of the antibodies provided herein, resulting in Fc region variants (also referred to herein as "variant Fc region variants"). Area"). Fc region variants may comprise human Fc region sequences (eg, human IgGl, IgG2, IgG3 or IgG4 Fc regions) containing amino acid modifications (eg, substitutions) at one or more amino acid positions.

C1q "C1q" is a polypeptide that includes a binding site for the Fc region of an immunoglobulin. C1q forms complex C1 together with the two serine proteases C1r and C1s: the first component of the complement-dependent cytotoxicity (CDC) pathway. Human C1q is commercially available from, eg, Quidel, San Diego, CA.

"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 the binding of the first component of the complement system (Clq) to antibodies (of the appropriate subclass) that bind to their cognate antigens. To assess complement activation, CDC assays can be performed, eg, as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996). Polypeptide variants with altered amino acid sequence of Fc region (polypeptide with Fc region variant) and increased or decreased C1q binding ability are described, for example, in US Pat. No. 6,194,551 B1 and WO 1999/51642. See also Idusogie et al. J. Immunol. 164: 4178-4184 (2000). "Complement-dependent cytotoxicity" or "CDC" herein may further refer to the reduction in the ability of a target virus (lysis of a target virus/virolysis) or virus to infect a cell by complement. Methods for assessing complement-dependent lysis or complement-dependent reduction of viral infectivity are widely known in the art, such as the use of heat-inactivated serum or serum-depleted complement components. Examples of complement-dependent viral lysis or inactivation are described in detail in Springer Semin Immunopathol. 1983; 6(4): 327-347.

"Effector functions" refer to those biological activities attributable to the Fc region of an antibody, which vary with antibody isotype. Examples of antibody effector functions include: Clq binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; ) downregulation; and B cell activation.

As used herein, the phrases "substantially lower", "substantially increase" or "substantially different" refer to the difference between two values (typically, one relative to one molecule and the other relative to a reference/comparator molecule). The degree of difference is large enough that a person skilled in the art would consider the difference between the two values to be statistically significant in the context of the biological characteristic measured in terms of the equivalent value (eg, Kd value).

The terms "Fc region" or "Fc domain" are used herein to define the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions as well as variant Fc regions. In one embodiment, the term "Fc region" or "Fc domain" includes a fragment consisting of the hinge or part thereof and CH2 and CH3 domains in an antibody molecule. The Fc region of the IgG class means, but is not limited to, the region from eg cysteine 226 (EU numbering (herein also referred to as EU index)) to the C-terminus or proline 230 (EU numbering) to the C-terminus. However, the C-terminal lysine (Lys447) or glycine-lysine (residues 446-447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also known as the EU index, as in Kabat et al., Sequences of Proteins of Immunological Interest , 5th edition. Public Health Service , as described in National Institutes of Health, Bethesda, MD, 1991.

The Fc region can be preferably obtained by partially digesting, for example, IgG1, IgG2, IgG3 or IgG4 monoclonal antibody with a proteolytic enzyme such as pepsin, and then absorbing the protein A column or protein G column. Fractions were re-eluted. Such proteolytic enzymes are not particularly limited as long as the enzyme is capable of digesting whole antibodies to constrainedly form Fab or F(ab')2 under appropriately set reaction conditions (eg, pH) of the enzyme. Examples thereof may include pepsin and papain.

An Fc region derived, for example, from naturally occurring (wild-type) IgG can be used as the "Fc region" of an antigen binding molecule. In this context, naturally occurring IgG means a polypeptide that contains the same amino acid sequence as that of IgG found in nature and belongs to the class of antibodies substantially encoded by immunoglobulin gamma genes. Naturally occurring human IgG means, for example, naturally occurring human IgGl, naturally occurring human IgG2, naturally occurring human IgG3, or naturally occurring human IgG4. Naturally occurring IgG also includes variants or analogs thereof derived spontaneously therefrom. Plural allotype sequences based on genetic polymorphism are described in Sequences of proteins of immunological interest, NIH Publication No. 91-3242 as constant regions of human IgG1, human IgG2, human IgG3 and human IgG4 antibodies, any of which or can be used in the present invention. Specifically, the sequence of human IgG1 may have DEL or EEM as the amino acid sequence at positions 356 to 358 of the EU numbering.

Fc Receptor The term "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR is a native human FcR. In some embodiments, the FcR is a receptor that binds an IgG antibody (gamma receptor) and includes the FcyRI, FcyRII, and FcyRIII subclasses, including one of 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 that differ primarily in their cytoplasmic domains. Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. The inhibitory receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain. (See eg Daëron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed, for example, in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including FcRs identified in the future, are encompassed by the term "FcR" herein.

The term "Fc receptor" or "FcR" also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)) and regulates immunoglobulin homeostasis. Methods for measuring binding to FcRn are known (see e.g. Ghetie and Ward., Immunol. Today 18(12):592-598 (1997); Ghetie et al., Nature Biotechnology, 15(7):637-640 ( 1997); Hinton et al., J. Biol. Chem. 279(8):6213-6216 (2004); WO 2004/92219 (Hinton et al.)).

Human FcRn high affinity binding polypeptides can be analyzed in vivo for human FcRn, for example, in transgenic mice or transfected human cell lines expressing human FcRn, or in primates administered a polypeptide having an Fc region variant. Binding and serum half-life. WO 2000/42072 (Presta) describes antibody variants with increased or decreased binding to FcRs. See also eg Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).

Fcγ receptor Fcγ receptor refers to a receptor capable of binding to the Fc domain of a monoclonal IgG1, IgG2, IgG3 or IgG4 antibody, and includes all members belonging to the protein family substantially encoded by the Fcγ receptor gene. In humans, this family includes: FcγRI (CD64), which includes the isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), which includes the isoform FcγRIIa (including allotypes H131 and R131), FcγRIIb (including FcγRIIb-1 and FcγRIIb-2) and FcγRIIc; and FcγRIII (CD16), which includes the isoforms FcγRIIIA (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIIb-NA1 and FcγRIIIb-NA2); and all unidentified human Fcγ receptors, Fcγ receptor isoforms and allotypes thereof. However, Fcγ receptors are not limited to these examples. Fc gamma receptors include, but are not limited to, those derived from humans, mice, rats, rabbits, and monkeys. Fc gamma receptors can be derived from any organism. Mouse Fcγ receptors include, but are not limited to, FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16), and FcγRIII-2 (CD16-2), as well as all unidentified mouse Fcγ receptors, Fcγ receptor isoforms and its allotypes. Such preferred Fcy receptors include, for example, human FcyRI (CD64), FcyRIIA (CD32), FcyRIIB (CD32), FcyRIIIA (CD16) and/or FcyRIIIB (CD16). The polynucleotide sequence and amino acid sequence of FcγRI are shown in RefSeq accession number NM_000566.3 and RefSeq accession number NP_000557.1, respectively; the polynucleotide sequence and amino acid sequence of FcγRIIA are shown in RefSeq accession number BC020823.1 and In RefSeq Accession No. AAH20823.1; the polynucleotide sequence and amino acid sequence of FcγRIIB are shown in RefSeq Accession No. BC146678.1 and RefSeq Accession No. AAI46679.1; the polynucleotide sequence and amino acid sequence of FcγRIIIA are shown respectively In RefSeq Accession No. BC033678.1 and RefSeq Accession No. AAH33678.1; and the polynucleotide sequence and amino acid sequence of FcyRIIIB are shown in RefSeq Accession No. BC128562.1 and RefSeq Accession No. AAI28563.1, respectively. In addition to the above FACS and ELISA formats, whether the Fcγ receptor has binding activity to the Fc domain of a monoclonal IgG1, IgG2, IgG3 or IgG4 antibody can be assessed by the following: ALPHA screening (Amplified Luminescent Proximity Homogeneous Assay; Amplified Luminescent Proximity Homogeneous Assay; phase analysis), BIACORE method based on surface plasmon resonance (SPR), and other methods (Proc. Natl. Acad. Sci. USA (2006) 103(11), 4005-4010).

Meanwhile, "Fc ligand" or "effector ligand" refers to a molecule, preferably a polypeptide, that binds to the Fc domain of an antibody to form an Fc/Fc ligand complex. Molecules can be derived from any organism. Binding of an Fc ligand to an Fc preferably induces one or more effector functions. Such Fc ligands include, but are not limited to, Fc receptors, Fcγ receptors, Fcα receptors, Fcβ receptors, FcRn, C1q and C3, mannan-binding lectin, mannose receptors, staphylococcal protein A, staphylococcal Protein G and viral Fcγ receptors. Fc ligands also include Fc receptor homologs (FcRH) (Davis et al., (2002) Immunological Reviews 190, 123-136), a family of Fc receptors homologous to Fcγ receptors. Fc ligands also include unidentified molecules that bind to Fc.

Fcγ Receptor Binding Activity Reduced binding activity of an Fc domain for any of the Fcγ receptors FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA and/or FcγRIIIB can be assessed by using the FACS and ELISA formats described above, And ALPHA screening (amplified luminescence proximity homogeneous analysis) and surface plasmon resonance (SPR)-based BIACORE method (Proc. Natl. Acad. Sci. USA (2006) 103(11), 4005-4010).

The ALPHA screen was performed by the ALPHA technology, based on the principles described below, using two types of beads: donor and acceptor beads. A luminescent signal is detected only when the molecule attached to the donor bead interacts biologically with the molecule attached to the acceptor bead and when the two beads are in close proximity. Upon excitation by the laser beam, the photosensitizer in the donor bead converts the oxygen surrounding the bead into excited singlet oxygen. When singlet oxygen diffuses around the donor bead and reaches the acceptor bead positioned in close proximity, a chemiluminescence reaction within the acceptor bead is induced. This reaction eventually causes light emission. If the molecule attached to the donor bead does not interact with the molecule attached to the acceptor bead, the singlet oxygen generated by the donor bead does not reach the acceptor bead and the chemiluminescent reaction does not occur.

For example, biotin-labeled antigen binding molecules or antibodies are immobilized to donor beads, and glutathione S-transferase (GST)-labeled Fcγ receptors are immobilized to acceptor beads. In the absence of an antigen binding molecule or antibody comprising a competing mutant Fc domain, Fcγ receptors interact with an antigen binding molecule or antibody comprising a wild-type Fc domain, thereby inducing a signal at 520 to 620 nm. Antigen binding molecules or antibodies with unlabeled mutant Fc domains compete with antigen binding molecules or antibodies comprising wild-type Fc domains for interaction with Fcγ receptors. Relative binding affinities can be determined by quantifying the decrease in fluorescence as a result of competition. Methods for biotinylation of antigen-binding molecules or antibodies (antibodies) using sulfo-NHS-biotin or the like are known. Suitable methods for adding a GST tag to an Fcγ receptor include methods involving in-frame fusion of a polypeptide encoding an Fcγ receptor and GST, expressing the fused gene using a cell into which a vector carrying the gene has been introduced, and then using gluten. Stathione column purification. Induced signals may preferably be analyzed based on nonlinear regression analysis, eg by fitting to a one-site competition model, using software such as GRAPHPAD PRISM (GraphPad; San Diego).

One of the substances used to observe their interaction was immobilized as a ligand on the thin gold layer of the sensor wafer. When light is shone on the backside of the sensor wafer such that total reflection occurs at the interface between the gold thin layer and the glass, the intensity of the reflected light is partially reduced at a certain point (SPR signal). Other substances whose interactions are observed are injected as analytes onto the surface of the sensor wafer. When the analyte binds to the ligand, the mass of the immobilized ligand molecule increases. This changes the index of refraction of the solvent on the sensor wafer surface. Changes in the refractive index cause a shift in the position of the SPR signal (conversely, dissociation moves the signal back to its original position). In the Biacore system, the amount of offset described above (i.e., the change in mass on the surface of the sensor wafer) is plotted on the vertical axis, and thus the change in mass over time is shown as a measurement (sense detector map). Kinetic parameters (association rate constant (ka) and dissociation rate constant (kd)) were determined from the sensorgram curves, and affinity (KD) was determined from the ratio between these two constants. Inhibition analysis is preferably used in the BIACORE method. Examples of such inhibition assays are described in Proc. Natl. Acad. Sci. USA (2006) 103(11), 4005-4010.

Fc region variants ( or variant Fc regions /Fc domain variants / variant Fc domains ) In one aspect, the Fc region of the invention comprises a variant Fc region that comprises at least one amine relative to the parent Fc region Amino acid changes (or mutations or modifications, including substitutions). Such Fc region variants may also be referred to as "variant Fc region", "Fc domain variant" or "variant Fc domain" in the present invention.

In certain embodiments, one or more amino acid changes (mutations or modifications, including amino acid substitutions, deletions, and insertions) can be introduced into the Fc region (parental Fc region) of an antibody, thereby generating Fc region variants. body. Fc region variants may comprise human Fc region sequences (eg, human IgGl, IgG2, IgG3 or IgG4 Fc regions) containing amino acid modifications (eg, substitutions) at one or more amino acid positions. For example, the heavy chain constant regions of human IgGl, human IgG2, human IgG3, and human IgG4 are shown in SEQ ID NOs: 132-135, respectively. For example, the Fc regions of human IgG1, human IgG2, human IgG3 and human IgG4 are shown as partial sequences of SEQ ID NO: 132-135.

In certain embodiments, the present invention contemplates antigen-binding molecules with some but not all effector functions, making them desirable candidates for applications where in vivo antibody half-life is critical and certain effector functions, such as ADCC ) is unnecessary or disadvantageous. In vitro and/or in vivo cytotoxicity assays can be performed to measure CDC and/or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to determine whether an antibody has FcγR binding (and thus likely ADCC activity) and/or FcRn binding ability. Primary NK cells used to mediate ADCC express FcγRIII only, whereas monocytes express FcγRI, FcγRII and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). A non-limiting example of an in vitro assay to assess ADCC activity of a molecule of interest is described in U.S. Patent 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); No. 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351 -1361 (1987)). Alternatively, non-radioactive assays can be used (see, e.g., the ACT1™ Non-radioactive Cytotoxicity Assay for Flow Cytometry (Cell Technology, Inc. Mountain View, CA); and the CytoTox 96 (registered trademark) Non-radioactive Cytotoxicity Assay (Promega , Madison, WI)). Suitable effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively or additionally, the in vivo assessment of the molecule of interest can be performed, for example, in an animal model such as that disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95: 652-656 (1998). ADCC activity. C1q binding assays can also be performed to confirm whether the antibody is capable of binding C1q and thus has CDC activity. See eg C1q and C3c binding ELISAs 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)). Known methods for assessing complement-dependent lysis or complement-dependent reduction of viral infectivity, such as the use of heat-inactivated serum or serum-depleted complement components, can also be used to assess C1q binding/complement activation. FcRn binding and in vivo clearance/half-life can also be determined using methods known in the art (see eg Petkova, S.B. et al., Int. Immunol. 18(12):1759-1769 (2006)).

In certain embodiments, compared to the corresponding sequence in the Fc region of a native or reference variant sequence (sometimes collectively referred to herein as a "parental" Fc region), the Fc region variant (or variant Fc region) comprises At least one amino acid residue is changed (eg, substituted). A variant Fc region herein will preferably have at least about 80% homology, and optimally at least about 90% homology with the native sequence Fc region and/or the parental Fc region and/or the Fc region of the parent polypeptide Sex, more preferably at least about 95% homology therewith.

A "native sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgGl Fc regions (non-A and A allotypes); native sequence human IgG2 Fc regions; native sequence human IgG3 Fc regions; and native sequence human IgG4 Fc regions and naturally occurring variants thereof.

As used herein, "parental Fc region" refers to the Fc region prior to the introduction of the amino acid changes described herein. Preferred examples of parental Fc regions include Fc regions derived from primary antibodies. Antibodies include, for example, IgA (IgA1, IgA2), IgD, IgE, IgG (IgG1, IgG2, IgG3, IgG4), IgM, and the like. Antibodies may be of human or monkey origin (eg, cynomolgus monkeys, rhesus monkeys, marmosets, chimpanzees, or baboons). Primary antibodies can also include naturally occurring mutations. Multiple allotype sequences of IgG attributable to polymorphisms are described in "Sequences of proteins of immunological interest", NIH Publication No. 91-3242, and any of them may be used in the present invention. Specifically, for human IgG1, the amino acid sequence at position 356 to 358 (EU numbering) may be DEL or EEM. Preferred examples of parental Fc regions include those derived from human IgG1 (SEQ ID NO: 132), human IgG2 (SEQ ID NO: 133), human IgG3 (SEQ ID NO: 134) and human IgG4 (SEQ ID NO: 135) The Fc region of the heavy chain constant region. Another preferred example of the parental Fc region is the Fc region derived from the heavy chain constant region SG1 (SEQ ID NO: 136). Another preferred example of the parental Fc region is the Fc region derived from the heavy chain constant region SG182 (SEQ ID NO: 137). Furthermore, the parental Fc region can be an Fc region generated by adding amino acid changes other than those described herein to an Fc region derived from a native antibody.

In certain embodiments, the variant Fc region of the invention has substantially reduced Fcγ receptor binding activity compared to the parental Fc region. In certain embodiments, the variant Fc region of the invention has maintained (not substantially reduced) C1q binding activity or increased C1q binding activity compared to the parental Fc region. In certain embodiments, the Fcγ receptor is a human Fcγ receptor, a monkey Fcγ receptor (eg, a macaque, rhesus, marmoset, chimpanzee, or baboon Fcγ receptor), or a mouse Fcγ receptor.

In the variant Fc region (or antigen-binding molecule comprising the variant Fc region) of the present invention with substantially reduced binding activity to one or more human Fcγ receptors, usually one or more amino acid mutations are present in the Fc region. In certain embodiments, the variant Fc regions described herein exhibit reduced binding affinity for Fcγ receptors compared to native IgG1 Fc regions. As used herein, human Fcγ receptors (FcγRs) include, but are not limited to, FcγRIa, FcγRIIa (including allelic variants 167H and 167R), FcγRIIb, FcγRIIIA (including allelic variants 158F and 158V), and FcγRIIIb (including etc. allelic variants NA1 and NA2). In another aspect, the variant Fc region of the invention is directed against human FcγRIa, FcγRIIa (including allelic variants 167H and 167R), FcγRIIb, FcγRIIIA (including allelic variant 158F) compared to the parental Fc region. and 158V) and FcyRIIIb (including the allelic variants NA1 and NA2) have substantially reduced binding activity.

In one aspect, the variant Fc region of the invention has substantially reduced binding activity against one or more mouse FcγRs, including but not limited to FcγRI, FcγRIIb, FcγRIII, and FcγRIV, compared to the parental Fc region. In another aspect, the variant Fc region of the invention has substantially reduced binding activity for mouse FcyRI, FcyRIIb, FcyRIII, and FcyRIV compared to the parental Fc region.

"Fcγ receptor" (herein referred to as Fcγ receptor, FcγR or FcgR) refers to a receptor that binds to the Fc region of IgG1, IgG2, IgG3 and IgG4 monoclonal antibodies and is almost meant to be encoded by the Fcγ receptor gene any member of the protein family. In humans, this family includes: FcγRI (CD64), which includes the isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), which includes the isoform FcγRIIa (including the allotypes H131 (H-type) and R131 (R-type) ), FcγRIIb (including FcγRIIb-1 and FcγRIIb-2) and FcγRIIc; and FcγRIII (CD16), which includes isoforms FcγRIIIA (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIIb-NA1 and FcγRIIIb-NA2) and any yet-to-be-discovered human FcγR, FcγR isoform or allotype, but not limited thereto. FcyRIIb1 and FcyRIIb2 have been reported as splice variants of human FcyRIIb. In addition, a splice variant known as FcyRIIb3 has been reported (J Exp Med, 1989, 170: 1369-1385). In addition to these splice variants, human FcyRIIb includes all splice variants deposited in NCBI which are NP_001002273.1, NP_001002274.1, NP_001002275.1, NP_001177757.1 and NP_003992.3. In addition, human FcγRIIb includes every previously reported polymorphism as well as FcγRIIb (Arthritis Rheum. 48:3242-3252 (2003); Kono et al., Hum. Mol. Genet. 14:2881-2892 (2005); and Kyogoju et al., Arthritis Rheum. 46:1242-1254 (2002)), and each genetic polymorphism to be reported in the future.

In FcγRIIa, there are two allotypes, one in which the amino acid at position 167 of FcγRIIa is histidine (H type) and the other in which the amino acid at position 167 is substituted with arginine (R type) (Warrmerdam, J. Exp. Med. 172:19-25 (1990)).

FcγRs include, but are not limited to, those of human, mouse, rat, rabbit, and monkey origin, and may be derived from any organism. Mouse FcyRs include, but are not limited to, FcyRI (CD64), FcyRII (CD32), FcyRIII (CD16), and FcyRIV (CD16-2), and any mouse FcyR or FcyR isoform.

The amino acid sequence of human FcγRIa is set forth in SEQ ID NO: 138; the amino acid sequence of human FcγRIIa (167H) is set forth in SEQ ID NO: 139; the amino acid sequence of human FcγRIIa (167R) is set forth in SEQ ID NO : 140; the amino acid sequence of human FcγRIIb is set forth in SEQ ID NO: 141; the amino acid sequence of human FcγRIIIA (158F) is set forth in SEQ ID NO: 142; the amino acid sequence of human FcγRIIIA (158V) is set forth In SEQ ID NO: 143; the amino acid sequence of human FcγRIIIb (NA1) is set forth in SEQ ID NO: 144; and the amino acid sequence of human FcγRIIIb (NA2) is set in SEQ ID NO: 145.

The amino acid sequence of mouse FcγRI is set forth in SEQ ID NO: 146; the amino acid sequence of mouse FcγRIIb is set forth in SEQ ID NO: 147; the amino acid sequence of mouse FcγRIII is set forth in SEQ ID NO: 148 ; and the amino acid sequence of mouse FcγRIV is set forth in SEQ ID NO: 149.

In one aspect, the variant Fc region of the invention (or an antigen-binding molecule comprising the variant Fc region) has substantially reduced FcγR binding activity based on antigen binding to the parental Fc region (or comprising the parental Fc region) molecule) FcγR binding activity of less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 2 %, less than 1%, less than 0.5%, less than 0.2% or less than 0.1%. In one aspect, the variant Fc region of the present invention has substantially reduced FcγR binding activity, which means the ratio [the difference in the RU value of the sensor map before and after the interaction between the FcγR and the variant Fc region]/[the FcγR The difference in RU value of the sensor map captured to the sensor chip before and after the change] is less than 1, less than 0.8, less than 0.5, less than 0.3, less than 0.2, less than 0.1, less than 0.08, less than 0.05, less than 0.03, less than 0.02, less than 0.01, less than 0.008, less than 0.005, less than 0.003, less than 0.002 or less than 0.001. In one embodiment, the variant Fc region (or antigen binding molecule comprising the variant Fc region) does not substantially bind to Fcγ receptors.

In one aspect, the variant Fc region of the invention has maintained (not substantially reduced) C1q binding activity or increased C1q binding activity. "Maintaining" or "not substantially reducing" the C1q binding activity means that the difference in C1q binding activity between the variant Fc region of the present invention and the parental Fc region is less than 50%, based on the C1q binding activity against the parental Fc region, Less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%. Where the variant Fc region has "increased" C1q binding activity, the difference in C1q binding activity between the variant Fc region of the invention and the parental Fc region may exceed 50%, and the variant Fc region of the invention may have a basis A C1q binding activity directed at 100% or more, 150% or more, 200% or more, 400% or more, 800% or more, or 1600% or more of the C1q binding activity of the parental Fc region. The comparison can be performed at any concentration of the antigen binding molecule, but preferably, the comparison is performed in the presence of a high concentration of the antigen binding molecule, which allows antigen binding molecules comprising variant Fc regions or parental Fc regions (control) to be assembled into hexamer. The binding activity of an antigen-binding molecule for C1q can be analyzed using a conventional C1q binding assay (for example, C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402) or by using CDC analysis (see, for example, 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)). Known methods for assessing complement-dependent lysis or complement-dependent reduction of viral infectivity, such as the use of heat-inactivated serum or serum-depleted complement components, can also be used to assess Clq binding.

The binding between the hexameric antigen-binding molecule and C1q can use known methods, such as methods based on ELISA, methods based on surface plasmon resonance (SPR), and the like. (See eg Biologicals 2019 Sep;61:76-79) assessment. Such analyzes may be performed, inter alia, under conditions that allow assembly into hexamers of antigen binding molecules comprising the variant Fc region or the parental Fc region (control).

For example, to determine the binding activity of a polypeptide containing a variant Fc region to C1q, a C1q binding ELISA can be performed. Briefly, assay plates can be coated with polypeptides containing variant Fc regions or polypeptides containing parental Fc regions (control) in coating buffer overnight at 4°C. The plates can then be washed and blocked. After washing, an aliquot of human CIq can be added to each well and incubated for 2 hours at room temperature. After further washing, 100 microliters of sheep anti-complement C1q peroxidase-binding antibody can be added to each well and incubated for 1 hour at room temperature. The plates can be washed again with wash buffer and 100 microliters of substrate buffer containing o-phenylenediamine dihydrochloride (OPD (Sigma)) can be added to each well. The oxidation reaction, observed by the yellow appearance, was allowed to proceed for 30 minutes and was stopped by adding 100 microliters of _{4.5 NH2SO4} . The absorbance at (492-405) nm can then be read. The binding activity of the Fc region to C1q can be determined by the method described in WO2018/052375.

For another example, the binding activity of an antigen binding molecule for C1q can be assessed using CDC assays, since the occurrence of target lysis by CDC indicates that binding of C1q to antibody Fc occurs, which triggers the classical complement pathway. Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738 may suitably be used - CDC analysis described in 2743 (2004). For example, CIq binding can be assayed as detailed in the Examples of the present invention. Briefly, cells stably transfected to overexpress antigen are suspended at an appropriate concentration and plated onto assay plates. Appropriate concentrations of human serum were added to each well. Antibodies were diluted in the appropriate range and added to each well. After mixing the components well, the plates were placed in an incubator and incubated for about 1 hour at 37°C with 5% CO ₂ . Cells are washed with buffer and stained with a viability dye (eg, 7AAD) and analyzed by flow cytometry to determine the percentage of cells lysed by antibody-mediated CDC.

In one aspect, the invention provides an antigen binding molecule comprising a variant Fc region with substantially reduced ADCC activity. In one aspect, the invention provides an antigen binding molecule comprising a variant Fc region with maintained (not substantially reduced) or increased CDC activity. In one aspect, the present invention provides an antigen binding molecule comprising a variant Fc region with substantially reduced ADCC activity and maintained (not substantially reduced) or increased CDC activity.

In one aspect, the variant Fc region of the invention confers substantially reduced ADCC activity on the antigen binding molecule comprising the variant Fc region, less than 50%, less than 45%, based on the ADCC activity against the antigen binding molecule comprising the parental Fc region. %, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 2%, less than 1%, less than 0.5%, less than 0.2% or Less than 0.1%.

In one aspect, the variant Fc region of the invention confers maintained (ie, not substantially reduced) CDC activity or increased CDC activity to an antigen binding molecule comprising the variant Fc region. CDC activity "maintained" or "not substantially reduced" means that the difference in CDC activity between the antigen binding molecule comprising the variant Fc region and the antigen binding molecule comprising the parental Fc region is less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%. In one aspect, the variant Fc region of the invention confers an increased CDC activity to the antigen binding molecule comprising the variant Fc region, which is greater than 100%, greater than 200%, greater than 400%, greater than 800% or more than 1600%, where CDC activity is measured as the concentration of antibody required to achieve 50% of the maximum complement-dependent lysis of target cells.

In other aspects, the variant Fc region of the invention comprises at least one amino acid change at at least one position selected from the group consisting of: 234, 235, 236, 267, 268, 324, 326, 332, and 333, according to EU number (see eg WO2018/052375).

In one aspect, the variant Fc region having substantially reduced Fcγ receptor binding activity and maintained (not substantially reduced) or increased C1q binding activity comprises Ala at position 234, Ala at position 235 and selected from the group consisting of At least one amino acid change in at least one position of the group consisting of: 236, 267, 268, 324, 326, 332 and 333 according to EU numbering.

In one aspect, the variant Fc region with substantially reduced Fcγ receptor binding activity and maintained (not substantially reduced) or increased C1q binding activity comprises Ala at position 234, Ala at position 235 and below (a ) to any of (c) additional ia amino acid changes: (a) positions 267, 268 and 324; (b) positions 236, 267, 268, 324 and 332; and (c) positions 326 and 333 , according to the EU number.

In another aspect, the variant Fc region having substantially reduced Fcγ receptor binding activity and maintained (not substantially reduced) or increased C1q binding activity comprises amino acids selected from the group consisting of: (a) Glu at position 267; (b) Phe at position 268; (c) Thr at position 324; (d) Ala at position 236; (e) Glu at position 332; , Asp, Glu, Met or Trp; and (g) Ser at position 333 according to EU numbering.

In one aspect, the variant Fc region with substantially reduced Fcγ receptor binding activity and maintained (not substantially reduced) or increased C1q binding activity comprises the following amino acids: Ala at position 234, Ala at position 235 Ala at position 326 and Ser at position 333 according to EU numbering.

In one aspect, the variant Fc region with substantially reduced Fcγ receptor binding activity and maintained (not substantially reduced) or increased C1q binding activity comprises the following amino acids: Ala at position 234, Ala at position 235 Ala at position 326 and Ser at position 333 according to EU numbering.

In one aspect, the variant Fc region with substantially reduced Fcγ receptor binding activity and maintained (not substantially reduced) or increased C1q binding activity comprises the following amino acids: Ala at position 234, Ala at position 235 Ala at position 326 and Ser at position 333 according to EU numbering.

In one aspect, the variant Fc region with substantially reduced Fcγ receptor binding activity and maintained (not substantially reduced) or increased C1q binding activity comprises the following amino acids: Ala at position 234, Ala at position 235 Ala at position 326 and Ser at position 333 according to EU numbering.

In one aspect, the variant Fc region with substantially reduced Fcγ receptor binding activity and maintained (not substantially reduced) or increased C1q binding activity comprises the following amino acids: Ala at position 234, Ala at position 235 Ala at position 326 and Ser at position 333 according to EU numbering.

In one aspect, the variant Fc region of the invention has increased FcRn binding activity at acidic pH compared to the parental Fc region.

In one aspect, preferably, the variant Fc region of the invention does not have substantially increased FcRn binding activity compared to the parental Fc region, especially at pH 7.4.

"FcRn" is structurally similar to class I major histocompatibility complex (MHC) polypeptides and exhibits 22% to 29% sequence identity with class I MHC molecules. FcRn appears as a heterodimer composed of a soluble beta or light chain (beta2 microglobulin) in complex with a transmembrane alpha or heavy chain. Like MHC, the α-chain of FcRn contains three extracellular domains (α1, α2 and α3), and its short cytoplasmic domain tethers it to the cell surface. The α1 and α2 domains interact with the FcRn-binding domain of the antibody Fc region. The polynucleotide and amino acid sequences of human FcRn can eg be derived from the precursors shown in NM_004107.4 and NP_004098.1 (containing the signal sequence), respectively.

The amino acid sequence of human FcRn (alpha chain) is set forth in SEQ ID NO: 150; and the amino acid sequence of human β2 microglobulin is set forth in SEQ ID NO: 151.

In one aspect, preferably, the variant Fc region of the invention does not have substantially increased FcRn binding activity, especially at pH 7.4, which is less than 1000-fold compared to the FcRn binding activity of the parental Fc region , less than 500 times, less than 200 times, less than 100 times, less than 90 times, less than 80 times, less than 70 times, less than 60 times, less than 50 times, less than 40 times, less than 30 times, less than 20 times, less than 10 times, less than 5 times, less than 3 times or less than 2 times. In one aspect, the variant Fc region of the present invention does not have substantially increased FcRn-binding activity, especially at pH 7.4, which means that the ratio [Sensormap of the change before and after the interaction between FcRn and the variant Fc region The difference in RU value]/[the difference in RU value of the sensor map before and after capturing FcRn onto the sensor chip] is less than 0.5, less than 0.3, less than 0.2, less than 0.1, less than 0.08, less than 0.05, less than 0.03, less than 0.02, less than 0.01, less than 0.008, less than 0.005, less than 0.003, less than 0.002 or less than 0.001.

In another aspect, the variant Fc region of the present invention may further comprise at least one amino acid change at at least one position selected from the group consisting of: 428, 434, 436, 438 and 440, according to EU numbering.

In another aspect, the variant Fc region may further comprise an amino acid selected from the group consisting of: (a) Ala at position 434; (b) Ala at position 434, Thr at position 436, Thr at position 438 Arg at position 440 and Glu at position 440; (c) Leu at position 428, Ala at position 434 and Thr at position 436; (d) Leu at position 428, Ala at position 434, Thr at position 436 Thr, Arg at position 438 and Glu at position 440; (e) Leu at position 428 and Ala at position 434; and (f) Leu at position 428, Ala at position 434, Arg at position 438 and Glu at position 440 according to EU numbering (see also WO2016/125495 which describes the relationship between amino acid changes and the binding activity of variant Fc regions).

In another aspect, the variant Fc region of the present invention comprises the following amino acids: Ala at position 234, Ala at position 235, Ala at position 326, Ser at position 333, Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438 and Glu at position 440 according to EU numbering. In another aspect, the variant Fc region of the present invention comprises the following amino acids: Ala at position 234, Ala at position 235, Ala at position 326, Ser at position 333, Leu at position 428, Ala at position 434, Arg at position 438 and Glu at position 440 according to EU numbering. In another aspect, the variant Fc region of the present invention comprises the following amino acids: Ala at position 234, Ala at position 235, Ala at position 326, Ser at position 333, Leu at position 428, and Ala at position 434, according to EU numbering. In another aspect, the variant Fc region of the present invention comprises the following amino acids: Ala at position 234, Ala at position 235, Ala at position 326, Ser at position 333, Leu at position 428, Ala at position 434 and Thr at position 436 according to EU numbering.

In another aspect, the variant Fc region of the invention comprises any of the amino acid changes described in Table 2 below (alone or in combination) (see also eg WO2018/052375). In another aspect, the variant Fc region of the invention comprises at least any one of the amino acid changes described in Table 2. [Table 2] variant name ID mutation SEQ ID NO: WT SG182 - 137 LALA SG192 L234A, L235A 152 KWES SG1085 K326W, E333S 153 EFT + AE SG1086 G236A, S267E, H268F, S324T, I332E 154 EFT SG1087 S267E, H268F, S324T 155 LALA + KWES SG1088 L234A, L235A, K326W, E333S 156 LALA + EFT + AE SG1089 L234A, L235A, G236A, S267E, H268F, S324T, I332E 157 LALA +EFT SG1090 L234A, L235A, S267E, H268F, S324T 158 LALA + KAES SG1095 L234A, L235A, K326A, E333S 159 LALA +KDES SG1096 L234A, L235A, K326D, E333S 160 LALA + KEES SG1097 L234A, L235A, K326E, E333S 161 LALA + KMES SG1098 L234A, L235A, K326M, E333S 162 LALA + ACT3 + KAES SG1105 L234A, L235A, K326A, E333S, M428L, N434A, Y436T, Q438R, S440E 163 LALA + ACT5 + KAES SG1106 L234A, L235A, K326A, E333S, M428L, N434A, Q438R, S440E 164 KAES SG1109 K326A, E333S 165 LALA + ACT3 SG1044 L234A, L235A, M428L, N434A, Y436T, Q438R, S440E 166 LALA + ACT5 SG1045 L234A, L235A, M428L, N434A, Q438R, S440E 167

In one aspect, an antigen binding molecule of the invention has substantially reduced FcyR binding activity. In one aspect, the antigen binding molecules of the invention have maintained (not substantially reduced) or increased C1q binding activity.

In one aspect, an antigen binding molecule of the invention has substantially reduced FcγR binding activity and has maintained (not substantially reduced) or increased C1q binding activity.

In one aspect, the invention provides an antigen binding molecule comprising an Fc region as follows: (i) an Fc region that exhibits reduced binding affinity for the human Fcγ receptor compared to the parental Fc region (which may be the parental native human IgG1 Fc region), wherein the Fc region variant comprises the following (f1) or (f2 ): (f1) Ala at position 234 and Ala at position 235; (f2) Ala at position 234, Ala at position 235 and Ala at position 297; wherein the amino acid positions are numbered according to the EU index.

In one aspect, the invention provides an antigen binding molecule comprising an Fc region as follows: (i) an Fc region that exhibits reduced binding affinity for a human Fcγ receptor compared to a parental Fc region (which may be a parental native human IgG1 Fc region), Wherein the Fc region further exhibits maintained (not substantially reduced) or increased C1q binding activity compared to the parental Fc region (which may be a parental native human IgG1 Fc region), Wherein the Fc region variant comprises the following (f1) or (f2): (f1) Ala at position 234 and Ala at position 235; (f2) Ala at position 234, Ala at position 235 and Ala at position 297; and wherein the Fc region variant further comprises a group selected from (f3) Amino acids of the group consisting of (f9): (f3) Glu at position 267; (f4) Phe at position 268; (f5) Thr at position 324; (f6) Ala at position 236; (f7) Glu at position 332; Ala, Asp, Glu, Met or Trp; and (f9) Ser at position 333; wherein the amino acid positions are numbered according to the EU index.

In one aspect, the invention provides an antigen binding molecule comprising an Fc region as follows: (i) an Fc region that exhibits reduced binding affinity for human Fcγ receptors compared to a parental Fc region (which may be a parental native human IgG1 Fc region), wherein compared to a parental Fc region (which may be an native human IgG1 Fc region), which Fc region further exhibits maintained (not substantially reduced) or increased C1q binding activity, and wherein compared to the parental Fc region, the Fc region further exhibits a stronger response to human FcRn under acidic conditions Strong FcRn binding affinity.

In one aspect, the invention provides an antigen binding molecule comprising an Fc region as follows: (i) an Fc region that exhibits reduced binding affinity for human Fcγ receptors compared to a parental Fc region (which may be a parental native human IgG1 Fc region), wherein compared to a parental Fc region (which may be an native human IgG1 Fc region), which Fc region further exhibits maintained (not substantially reduced) or increased C1q binding activity, wherein compared to the parental Fc region, the Fc region further exhibits stronger human FcRn under acidic conditions FcRn binding affinity, wherein the Fc region variant comprises Leu at position 428, Ala at position 434, position Thr at 436, Arg at 438 and/or Glu at 440, and Wherein the amino acid positions are numbered according to the EU index.

In one aspect, the invention provides an antigen binding molecule comprising an Fc region as follows: (i) an Fc region that exhibits reduced binding affinity for human Fcγ receptors compared to a parental Fc region (which may be a parental native human IgG1 Fc region), wherein compared to a parental Fc region (which may be an native human IgG1 Fc region), which Fc region further exhibits maintained (not substantially reduced) or increased C1q binding activity, wherein compared to the parental Fc region, the Fc region further exhibits stronger human FcRn under acidic conditions FcRn binding affinity, wherein in addition to (f1) or (f2) above and the amino acid selected from the group consisting of (f3) to (f9) above, the Fc region variant comprises Leu at position 428, Ala at position 434 and/or or Thr at position 436, and Wherein the amino acid positions are numbered according to the EU index.

Additionally, amino acid changes made for other purposes were combined in the variant Fc regions described herein.

For example, in addition to amino acid changes at positions 234 and 235, amino acid substitutions at positions selected from the group of E233, N297, P331, and P329 can be introduced to reduce the binding affinity of the Fc region for Fcγ receptors. In one embodiment, the variant Fc region comprises an amino acid substitution at position P329. In a more specific embodiment, the amino acid substitution is P329A or P329G, specifically P329G. In one embodiment, the variant Fc region comprises an amino acid substitution at position P329 and another amino acid substitution at a position selected from E233, L234, L235, N297 and P331. In a more specific embodiment, the other amino acid substitution is E233P, L234A, L235A, L235E, N297A, N297D or P331S. In particular embodiments, the Fc region comprises amino acid substitutions at positions P329, L234 and L235. In more specific embodiments, the Fc region comprises amino acid mutations L234A, L235A, and P329G ("P329G LALA"). In one such embodiment, the Fc region is an IgG1 Fc region, in particular a human IgG1 Fc region. The "P329G LALA" combination of amino acid substitutions almost completely disrupted Fcγ receptor (and complement) binding of the human IgG1 Fc region, as described in PCT Publication No. WO 2012/130831. WO 2012/130831 also describes methods of making such mutant Fc regions and methods of determining their properties, such as Fc receptor binding or effector function.

In certain embodiments, N-glycosylation of the Fc region has been eliminated. In one such embodiment, the Fc region comprises an amino acid mutation at position N297, specifically an amino acid substitution of asparagine with alanine (N297A) or aspartic acid (N297D).

In a specific embodiment, the variant Fc region exhibiting reduced binding affinity for an Fc receptor compared to a native IgG1 Fc domain is a human IgG1 Fc region comprising the amino acid substitutions L234A, L235A and N297A.

For example, amino acid substitutions that improve FcRn binding activity can be added (Hinton et al., J. Immunol. 176(1):346-356 (2006); Dall'Acqua et al., J. Biol. Chem. 281( 33):23514-23524 (2006); Petkova et al., Intl. Immunol. 18(12):1759-1769 (2006); Zalevsky et al., Nat. Biotechnol. 28(2):157-159 (2010); WO 2006/019447; WO 2006/053301; and WO 2009/086320) and amino acid substitutions to improve antibody heterogeneity or stability (WO 2009/041613). Alternatively, the following may be combined with the variant Fc region described herein: a polypeptide having antigen clearance promoting properties as described in WO 2011/122011 , WO 2012/132067, WO 2013/046704 or WO 2013/180201; Polypeptides with specific binding properties to target tissues, which are described in WO 2013/180200; polypeptides with repeated binding properties to multiple antigen molecules, which are described in WO 2009/125825, WO 2012/073992 or WO 2013/047752 . Alternatively, the amino acid changes disclosed in EP1752471 and EP1772465 can be combined in CH3 of the variant Fc region described herein where the purpose is to confer binding ability to other antigens. Alternatively, where the aim is to increase plasma retention, amino acid changes (WO 2012/016227) that lower the pi of the constant region can be combined in the variant Fc region described herein. Alternatively, amino acid changes (WO 2014/145159) that increase the pi of the constant region can be combined in the variant Fc region described herein where the purpose is to facilitate uptake into cells. Alternatively, amino acid changes that increase the pi of the constant region (WO2016/125495 and WO2016/098357) can be combined in the variant Fc region described herein where the purpose is to facilitate the elimination of the target molecule from plasma.

Amino acid changes that enhance human FcRn binding activity at acidic pH can also be combined in the variant Fc regions described herein. Specifically, such alterations may include, for example: substitution of Met by Leu at position 428 and substitution of Asn by Ser at position 434 according to EU numbering (Nat Biotechnol, 2010, 28: 157-159); substitution of Asn by Ala at position 434 (Drug Metab Dispos, April 2010; 38(4): 600-605); Met was replaced by Tyr at position 252, Ser was replaced by Thr at position 254 and Thr was replaced by Glu at position 256 (J Biol Chem, 2006, 281: 23514-23524); Thr at position 250 is replaced by Gln and Met is replaced by Leu at position 428 (J Immunol, 2006, 176(1): 346-356); Asn is replaced by His at position 434 (Clin Pharmacol Ther, 2011, 89(2): 283-290), and WO2010/106180, WO2010/045193, WO2009/058492, WO2008/022152, WO2006/050166, WO2006/053301, WO2006/031370, WO2005/127005, WO2005/127005 Variations described in /037867, WO2004/035752, WO2002/060919, etc. In another embodiment, such alterations may include, for example, at least one alteration selected from the group consisting of Leu at position 428 for Met, Ala at position 434 for Asn, and Thr at position 436 for Tyr. These changes may further include Arg substitution for Gln at position 438 and/or Glu substitution for Ser at position 440 (WO2016/125495).

In one embodiment, antigen binding molecules of the invention comprising a variant Fc region with modified effector functions include antigen binding molecules having substitutions of one or more of the following Fc region residues: 238, 265, 269, 270, 297, 327, and 329 (US Patent No. 6,737,056). Such Fc mutants include Fc mutants having substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including so-called "alanines" having residues 265 and 297 substituted with alanine. DANA' Fc mutant (US Patent No. 7,332,581).

In one embodiment, the binding of an antigen binding molecule of the invention comprising a variant Fc region to an FcR can be altered (eg, increased or decreased), as described. (See eg, US Patent No. 6,737,056; WO 2004/056312 and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001 )).

In certain embodiments, an antigen binding molecule of the invention comprises an Fc region with one or more amino acid substitutions that alter ADCC, for example positions 298, 333 and/or 334 of the Fc region (EU numbering of residues) place of replacement.

In some embodiments, alterations are made in the Fc region that result in altered (ie, increased or decreased) Clq binding and/or complement-dependent cytotoxicity (CDC), e.g., as described in US Pat. No. 6,194,551, WO 99/51642, Described in WO2011/091078 and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

In one embodiment, the half-life is increased and interacts with the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgG to the fetus ((Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J . Immunol. 24:249 (1994)) Antigen binding molecules of the invention with increased binding are described in US2005/0014934A1 (Hinton et al). These antibodies comprise an Fc region with one or more substitutions therein, one or Multiple substitutions increase the binding of the Fc region to FcRn. Such Fc variants include those having substitutions at one or more of the following Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, eg, substitution of Fc region residue 434 (US Patent No. 7,371,826).

See also Duncan and Winter, Nature 322:738-40 (1988); US Patent No. 5,648,260; US Patent No. 5,624,821; and WO 94/29351 for additional examples of Fc region variants.

In another embodiment, the antigen binding molecule may comprise an Fc region variant of the invention as described in detail herein below.

In one embodiment described herein, the Fc region of the antigen binding molecule of the invention is an IgG Fc region. In a specific embodiment, the Fc region is an IgG1 Fc region. In another specific embodiment, the Fc region is a human IgG1 Fc region.

In one non-limiting example, an antigen binding molecule of the invention specifically binds to a virus that can lead to the risk of antibody-dependent enhancement (ADE) when administered.

In the present invention, an amino acid change means any one of substitution, deletion, addition, insertion, and modification, or a combination thereof. In the present invention, an amino acid change can be reformulated as an amino acid mutation.

Amino acid changes are made by various methods known to those skilled in the art. Such methods include: site-directed mutagenesis methods (Hashimoto-Gotoh et al., Gene 152:271-275 (1995); Zoller, Meth. Enzymol. 100:468-500 (1983); Kramer et al., Nucleic Acids Res. 12 : 9441-9456 (1984)); Kramer and Fritz, Methods Enzymol. 154: 350-367 (1987); and Kunkel, Proc. Natl. Acad. Sci. USA 82:488-492 (1985)), PCR mutation method and cassette mutation methods. But not limited to this.

The number of amino acid changes introduced into the Fc region is not limited. In certain embodiments, it can be 1, 2 or less, 3 or less, 4 or less, 5 or less, 6 or less, 8 or less, 10 or less, 12 or less Small, 14 or less, 16 or less, 18 or less, or 20 or less.

In addition, antigen-binding molecules comprising the variant Fc region of the present invention can be chemically modified with various molecules such as polyethylene glycol (PEG) and cytotoxic substances. Methods for such chemical modification of polypeptides are well established in the art.

An antigen binding molecule of the invention comprising an Fc region variant has substantially reduced Fcγ receptor binding activity when compared to an antigen binding molecule comprising a parental Fc region, and/or has maintained (not substantially reduced) C1q-binding activity or increased C1q-binding activity, and/or increased FcRn-binding activity at acidic pH, and/or no substantially increased FcRn-binding activity at neutral pH.

In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 (EU numbering of residues) of the Fc region .

d) Cysteine-engineered antibody variants In certain embodiments, it may be desirable to generate cysteine-engineered antibodies, such as "thioMAbs," in which one or more residues of the antibody are cysteine-engineered Amino acid residue substitution. In particular embodiments, the substituted residue occurs at an accessible site of the antibody. By substituting these residues with cysteine, reactive thiol groups are placed at accessible sites on the antibody and can be used to conjugate the antibody to other moieties such as drug moieties or linker-drug moieties to generate immunoconjugates, as further described herein. In certain embodiments, any one or more of the following residues may be substituted with cysteine: V205 of the light chain (Kabat numbering); A118 of the heavy chain (EU numbering); and of the Fc region of the heavy chain S400 (EU number). Cysteine engineered antibodies can be produced as described, eg, in US Patent No. 7,521,541.

e) Antibody Derivatives In certain embodiments, the antibodies provided herein can be further modified to contain additional non-proteinaceous moieties known in the art and readily available. Moieties suitable for derivatization of 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, carboxymethylcellulose, polydextrose, polyvinyl alcohol, polyvinylpyrrolidone, poly- 1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyamino acid (homopolymer or random copolymer) and polydextrose Or poly(n-vinylpyrrolidone) polyethylene glycol, polypropylene glycol homopolymer, polypropylene oxide/ethylene oxide copolymer, polyoxyethylated polyols (eg glycerol), polyvinyl alcohol and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing because of its stability in water. The polymers can be of any molecular weight and can be branched or unbranched. The number of polymers attached to the antibody can vary, and if more than one polymer is attached, the polymers can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the specific properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, and the like.

In another embodiment, conjugates of antibodies and non-protein moieties that can be selectively heated by exposure to radiation are provided. In one embodiment, the non-protein moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). The radiation can be of any wavelength, and includes, but is not limited to, wavelengths that do not damage normal cells but heat the non-protein moiety to a temperature that kills cells in proximity to the antibody-non-protein moiety.

Herein the antigen binding molecules of the invention can be combined with various existing techniques. As a non-limiting example of such a combination of techniques, the generation of cells expressing a chimeric antigen receptor (CAR) using the antigen binding molecules of the invention is exemplified. Cells herein include, for example, T cells, γδT cells, NK cells, NKT cells, cytokine-induced killer (CIK) cells, and macrophages (Int J Mol Sci. (2019) 20(11), 2839, Nat Rev Drug Discov. (2020) 19(5), 308). One of the non-limiting methods for generating CAR-expressing T cells (CAR-T) involves, for example, a method in which a gene comprising a gene of the present invention that specifically binds to SARS-CoV-2 is incorporated by genetic modification technology. CARs of the antigen binding molecule, the transmembrane domain of the TCR, and the intracellular signaling domain of a co-stimulatory molecule such as CD28 for enhanced T cell activation are introduced into effector cells such as T cells.

As a non-limiting example of techniques that can be combined with the antigen-binding molecules of the invention herein, the use of the antigen-binding molecules of the invention to generate T cells redirected to the antigen-binding molecules is exemplified (Nature (1985) 314 (6012), 628-31 , Int J Cancer (1988) 41 (4), 609-15, Proc Natl Acad Sci USA (1986) 83 (5), 1453-7). T cells redirected to the antigen binding molecule are bispecific antigen binding molecules comprising either of the subunits that form the binding domain of the T cell receptor (TCR) complex on the T cell, specifically CD3ε in CD3 The binding domain of the chain and the binding domain to which the target antigen is bound by the antigen-binding molecule of the present invention.

B. Recombinant Methods and Compositions Antibodies can be produced using recombinant methods and compositions, for example, as described in US Patent No. 4,816,567. In one embodiment, isolated nucleic acids encoding the anti-SARS-CoV-2 antibodies described herein are provided. Such nucleic acids may encode amino acid sequences comprising the VL and/or amino acid sequences comprising the VH of the antibody (eg, the light and/or heavy chains of the antibody). In another embodiment, one or more vectors (eg, expression vectors) comprising such nucleic acids are provided. In another embodiment, a host cell comprising such nucleic acid is provided. In one such embodiment, the host cell comprises (eg, has been transformed): (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody; or (2) A first vector and a second vector, the first vector includes a nucleic acid encoding an amino acid sequence containing an antibody-containing VL, and the second vector includes a nucleic acid encoding an amino acid sequence containing an antibody-containing VH. In one embodiment, the host cells are eukaryotic cells, such as Chinese Hamster Ovary (CHO) cells or lymphocytes (eg, YO, NSO, Sp2/0 cells). In one embodiment, a method for preparing anti-SARS-CoV-2 antibodies is provided, wherein the method comprises culturing host cells under conditions suitable for expressing antibodies and recovering antibodies from host cells (or host cell culture medium) as appropriate, the The host cell comprises nucleic acid encoding an antibody as provided above.

For recombinant production of anti-SARS-CoV-2 antibodies, antibody-encoding nucleic acids, e.g. as described above, are isolated and inserted into one or more vectors for further cloning and/or expression in host cells . Such nucleic acids can be readily isolated and sequenced using conventional procedures, eg, by using oligonucleotide probes that are capable of binding specifically to genes encoding the antibody heavy and light chains.

Suitable host cells for the selection or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies can be produced in bacteria, especially when glycosylation and Fc effector functions are not required. For expression of antibody fragments and polypeptides in bacteria, see, eg, US Patent Nos. 5,648,237, 5,789,199 and 5,840,523. (See also Charlton, Methods in Molecular Biology , Vol . 248 (BKC Lo ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in E. coli). Following expression, antibodies can be isolated from the bacterial cell paste in the soluble fraction and can be further purified.

In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeast are suitable selection or expression hosts for antibody-encoding vectors, including glycosylation pathways that have been "humanized" to produce antibodies with partially or fully human saccharides. Fungal and yeast strains of antibodies with kylation patterns. See Gerngross, Nat. Biotech. 22:1409-1414 (2004) and Li et al., Nat. Biotech. 24:210-215 (2006).

Suitable host cells for expressing glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. A number of baculovirus strains have been identified for use in conjunction with insect cells, especially for transfection of Spodoptera frugiperda cells.

Plant cell cultures can also be used as hosts. See, eg, US Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (which describe the PLANTIBODIES ^™ technology for antibody production in transgenic plants).

Vertebrate cells can also be used as hosts. For example, mammalian cell lines suitable for growth in suspension may be suitable. Other examples of suitable mammalian host cell lines are the SV40 (COS-7) transformed monkey kidney CV1 strain; 293 or 293 cells as described); baby hamster kidney cells (BHK); mouse sertoli cells (mouse sertoli cells) (as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980) TM4 cells); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical cancer cells (HELA); canine kidney cells (MDCK); buffalo rat liver cells (BRL 3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumor cells (MMT 060562); TRI cells as described, for example, in Mather et al., Annals NY Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other suitable mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR ^- CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines, such as Y0, NS0 and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (ed . BKC Lo, Humana Press, Totowa, NJ), pp. 255-268 (2003 ).

C. Assays Anti-SARS-CoV-2 antibodies provided herein can be identified, screened, or characterized for their physical/chemical properties and/or biological activity by various assays known in the art.

1. Binding assays and other assays In one aspect, the antibodies of the present invention are tested for their antigen-binding activity by known methods such as ELISA, Western blotting, and the like.

In another aspect, competition assays can be used to identify antibodies that compete with any of the anti-SARS-CoV-2 antibodies described herein for binding to SARS-CoV-2. In certain embodiments, when such a competing antibody is present in excess, it blocks (e.g., reduces) the binding of the reference antibody to SARS-CoV-2 by at least 10%, 15%, 20%, 25%, 30% , 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more. In some instances, binding is inhibited by at least 80%, 85%, 90%, 95% or more. In certain embodiments, such competing antibodies bind to an epitope (e.g., a linear or conformational epitope) that an anti-SARS-CoV-2 antibody described herein binds to (e.g., a SARS-CoV The epitope within the fragment of -2, especially for the SARS-CoV-2 Spike protein receptor binding domain (RBD)) is the same. Detailed exemplary methods for mapping epitopes bound to antibodies are provided in Morris (1996) "Epitope Mapping Protocols", Methods in Molecular Biology Vol. 66 (Humana Press, Totowa, NJ).

In an exemplary competition assay, immobilized SARS-CoV-2 is incubated in a solution comprising a first labeled antibody that binds to SARS-CoV-2 and a second unlabeled antibody, wherein the second unlabeled antibody is tested The ability to compete with the primary antibody for binding to SARS-CoV-2. Secondary antibodies may be present in the fusion tumor supernatant. As a control, immobilized SARS-CoV-2 was incubated in a solution comprising the first labeled antibody but not the second unlabeled antibody. After incubation under conditions that allow binding of the primary antibody to SARS-CoV-2, excess unbound antibody is removed, and the amount of label bound to the immobilized SARS-CoV-2 is measured. If the amount of label bound to immobilized SARS-CoV-2 is substantially reduced in the test sample relative to the control sample, it indicates that the second antibody competes with the first antibody for binding to SARS-CoV-2. See Harlow and Lane (1988) Antibodies: A Laboratory Manual , Chapter 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

2. Activity Assays In one aspect, assays for identifying biologically active anti-SARS-CoV-2 antibodies are provided. Biological activities may include, for example, blocking the binding of SARS-CoV-2 to host cell receptors, inhibiting the entry of SARS-CoV-2 into host cells, inhibiting and/or preventing and/or reducing the incidence of host cell infection with SARS-CoV-2 , Complement-mediated opsonization and/or inactivation of SARS-CoV-2 virus. Antibodies having such biological activity in vivo and/or in vitro are also provided.

In certain embodiments, the antibodies of the invention are tested for such biological activities.

Depending on the assay, cell and/or tissue culture may be required. Cells can be examined using any of a number of different physiological assays. Alternatively or in addition, molecular analysis can be performed, including but not limited to: Western blotting, to monitor expression and/or test for protein-protein interactions; mass spectrometry, to monitor other chemical modifications; etc. In some embodiments, such methods utilize animal hosts. For example, an animal host suitable for the present invention can be any mammalian host, including primates, ferrets, cats, dogs, cows, horses, and rodents such as mice, hamsters, rabbits, and rats. In some embodiments, the animal host is vaccinated, infected with, or otherwise exposed to the virus prior to or concurrently with administration of the test antibody. Untreated and/or vaccinated animals can be used in any of a variety of studies. For example, such animal models can be used in virus transmission studies as known in the art. A test antibody can be administered to a suitable animal host before, during, or after virus transmission studies in order to determine the efficacy of the test antibody in blocking viral binding and/or infectivity in the animal host.

In certain embodiments, antibodies of the invention are tested for biological activity in blocking the binding interaction between the SARS-CoV-2 Spike protein and a host cell receptor, including but not limited to ACE2. The binding interaction between the Spike protein and the host cell receptor can be performed by ELISA or BIACORE®.

In certain embodiments, antibodies of the invention are tested for biological activity in a SARS-CoV-2 Spike protein pseudotyped lentivirus neutralization assay. This method is described in detail by Crawford et al. Viruses. 2020 May;12(5). Briefly, antibodies were pre-incubated with SARS-CoV-2 Spike protein pseudotyped lentiviruses and thereafter added to target cells expressing SARS-CoV2 viral entry receptors such as ACE2. Pseudoviruses are engineered to carry reporter genes, such as luciferase or fluorescent proteins, which are expressed upon successful entry and infection of target cells. Antibody neutralizing activity is determined by its ability to inhibit pseudovirus infection of target cells.

In certain embodiments, antibodies of the invention are tested for biological activity in inhibiting killing of target cells by live SARS-CoV-2 virus. Similar to the pseudotyped lentivirus assay, antibodies were first pre-incubated with live SARS-CoV-2 virus and then added to target cells. In this assay, target cells not only express SARS-CoV2 viral entry receptors for infection, but are also susceptible to infection and killed by the virus. One such candidate target cell is Vero E6 cells. The ability of antibodies to inhibit virus infection of target cells was analyzed using a cell viability assay enumerating the percentage of viable cells remaining after exposure to virus. Alternatively, target cells can be fixed shortly after infection and stained for the presence of viral antigen to quantify the number of viral foci. This approach will allow the ability of the antibodies to be assessed to block early viral entry.

In certain embodiments, antibodies are tested for their ability to prevent or reduce infection in animals that are permissive to infection with SARS-CoV-2, such as but not limited to transgenic mice, hamsters, and non-human primates. biological activity. Because the SARS-CoV-2 spike protein does not bind mouse ACE2 well, transgenic mice that overexpress human ACE2, such as K18-hACE2 mice, can be used. Hamsters are a suitable small animal model for infection because they are susceptible to infection with the SARS-CoV-2 virus and have lung lesions similar to those observed in COVID-19 patients. The antibody can be administered to the animal either before or after infection with the SARS-CoV-2 virus. The ability of antibodies to prevent or reduce infection in animals can be determined by reduction in body weight loss, reduction in lung virus titers as measured by qPCR, reduction in cytokine production and/or lung pathology as measured by ELISA or qPCR Histological changes.

D. Immunoconjugates The invention also provides immunoconjugates comprising an anti-SARS-CoV-2 antibody herein in combination with one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents Agents, toxins (such as protein toxins, enzymatically active toxins or fragments thereof of bacterial, fungal, plant or animal origin) or radioactive isotopes.

In one embodiment, the immunoconjugate is an antibody-drug conjugate (ADC), wherein the antibody is combined with one or more drugs, including but not limited to maytansinoids (see U.S. Patent No. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1); auristatin (auristatin), such as monomethyl aristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Patent No. 5,635,483 and 5,780,588 and 7,498,298); dolastatin; calicheamicin or its derivatives (see U.S. Pat. Nos. 5,770,710, 5,773,001 and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. 58:2925-2928 (1998); Anthracyclines Anthracyclines such as daunomycin or doxorubicin (see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); U.S. Patent No. 6,630,579); methotrexate; vindesine; taxanes such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; trichothecene; and CC1065.

In another embodiment, the immunoconjugate comprises an antibody as described herein conjugated to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, diphtheria toxin ( diphtheria toxin), exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, Mo Modeccin A chain, α-sarcin, Aleurites fordii protein, carnation (dianthin) protein, Pokeweed (Phytolacca americana) protein (PAPI, PAPII and PAP -S), momordica charantia inhibitor, curcin, crotin, saponaria officinalis inhibitor, gelonin, mitogellin, limited yeast Restrictocin, phenomycin, enomycin and tricothecene.

In another embodiment, the immunoconjugate comprises an antibody as described herein conjugated to a radioactive atom to form a radioconjugate. Various radioactive isotopes can be used to make radioconjugates. Examples include radioactive isotopes of ²¹¹ At, ¹³¹ I, ¹²⁵ I, ⁹⁰ Y, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁵³ Sm, ²¹² Bi, ³² P, ²¹² Pb, and Lu. When radioconjugates are used for detection, they may contain radioactive atoms for scintigraphic studies, such as Tc-99m or ¹²³ I; or for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging). Spin labels for magnetic resonance imaging (MRI), such as iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

Conjugates of antibodies and cytotoxic agents can be prepared using a variety of bifunctional protein coupling agents such as N-butadiimino-3-(2-pyridyldithio)propane Succimidyl ester (SPDP), succimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imino esters (such as dimethyl diiminoadipate hydrochloride), active esters (such as disuccimidyl suberate), aldehydes (such as pentamethylene aldehydes), bis-azido compounds (such as bis(p-azidobenzoyl)hexamethylenediamine), bisnitrogen derivatives (such as bis-(p-diazobenzoyl)-ethylenediamine), diazide Isocyanates (such as toluene 2,6-diisocyanate) and bis-reactive fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238: 1098 (1987). Carbon-14 labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of the radionuclide to the antibody. See WO94/11026. A linker may be a "cleavable linker" that facilitates release of the cytotoxic drug in the cell. For example, acid-labile linkers, peptidase-sensitive linkers, photolabile linkers, dimethyl linkers, or linkers containing disulfide bonds can be used (Chari et al., Cancer Res. 52:127- 131 (1992); US Patent No. 5,208,020).

Immunoconjugates or ADCs herein specifically encompass, but are not limited to, such conjugates prepared with crosslinking agents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP , SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC and sulfo-SMPB and SVSB (butane imido-(4-vinylsulfone)benzoate), and such cross-linking agents are commercially available (eg, from Pierce Biotechnology, Inc., Rockford, IL., U.S.A).

E. Methods and compositions for diagnosis and detection In certain embodiments, any of the anti-SARS-CoV-2 antibodies provided herein are useful for detecting the presence of SARS-CoV-2 in a sample. Samples may be obtained from any source. For example, the samples can be biological samples, medical samples, environmental samples, food samples, etc. In some embodiments, the sample comprises a biological sample. As used herein, the term "detection" encompasses quantitative or qualitative detection. In certain embodiments, the biological sample comprises cells or tissues, such as serum, whole blood, plasma, biopsy sample, tissue sample, cell suspension, saliva, sputum, oral fluid, cerebrospinal fluid, amniotic fluid, ascitic fluid, breast milk , colostrum, mammary gland secretion, lymph, urine, sweat, tears, gastric juice, synovial fluid, peritoneal fluid, visual lens fluid, nasal fluid, anterior nostril fluid, nasal middle turbinate fluid, pharyngeal fluid, nasopharyngeal fluid, Oropharyngeal fluid, mucus, or processed parts thereof.

In one embodiment, an anti-SARS-CoV-2 antibody for use in a method of diagnosis or detection is provided. In another aspect, a method of detecting the presence of SARS-CoV-2 in a sample is provided. In certain embodiments, the methods comprise contacting a sample with an anti-SARS-CoV-2 antibody as described herein under conditions permissive for the binding of the anti-SARS-CoV-2 antibody to SARS-CoV-2, and detecting the anti-SARS-CoV-2 antibody Whether complexes are formed between CoV-2 antibodies and SARS-CoV-2. In various embodiments, complex formation is indicative of the presence of SARS-CoV-2 in the sample. In various embodiments, the absence of complex formation indicates the absence of SARS-CoV-2 in the sample. Such methods can be in vitro or in vivo methods. In one embodiment, anti-SARS-CoV-2 antibodies are used to select individuals suitable for treatment with anti-SARS-CoV-2 antibodies, for example, where SARS-CoV-2 is the biomarker used to select patients.

Exemplary conditions that can be diagnosed using the antibodies of the invention include SARS-CoV-2 infection and diseases and/or symptoms caused by or associated with SARS-CoV-2 infection.

In certain embodiments, labeled anti-SARS-CoV-2 antibodies are provided. Labels include, but are not limited to, labels or moieties for direct detection, such as fluorescent, chromogenic, electron-dense, chemiluminescent, and radioactive labels, as well as moieties for indirect detection, such as through enzymatic reactions or molecular interactions, such as enzymes or ligands. ). Exemplary labels include, but are not limited to, radioactive isotopes ^32P , ^14C , ^125I , ^3H , and ^131I ; fluorophores, such as rare earth chelates or luciferin and its derivatives; rose bengal and its derivatives; acyl; umbelliferone; luciferases, such as firefly luciferase and bacterial luciferase (US Patent No. 4,737,456); luciferin; enzyme (HRP); alkaline phosphatase; beta-galactosidase; glucoamylase; lysozyme; Oxidative enzymes, such as uricase and xanthine oxidase, coupled to enzymes that employ hydrogen peroxide to oxidize dye precursors, such as HRP, lactoperoxidase, or microperoxidase; biotin/avidin; spin tags; phage tags; stable free radicals and similar tags.

F. Pharmaceutical formulations Pharmaceutical formulations of anti-SARS-CoV-2 antibodies as described herein (also referred to herein as "pharmaceutical compositions") are prepared by combining such antibodies of the desired purity with a or a plurality of optional pharmaceutically acceptable carriers ( Remington's Pharmaceutical Sciences 16th Edition, Osol, A. Ed. (1980)), in the form of a lyophilized formulation or an aqueous solution. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers, such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and Methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexahydroxylquaternium chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol, or benzyl alcohol ; alkyl p-hydroxybenzoates, such as methyl or propyl p-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol; low molecular weight ( less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, asparagine Amides, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose or sorbitol; a salt-forming counterion, such as sodium; a metal complex (for example, a Zn-protein complex); and/or a nonionic surfactant, such as polyethylene glycol (PEG). Exemplary herein Pharmaceutically acceptable carriers further include interstitial drug dispersants, such as soluble neutral active hyaluronidase glycoprotein (sHASEGP), for example human soluble PH-20 hyaluronidase glycoprotein, such as rHuPH20 (HYLENEX (registered trademark) , Baxter International, Inc.). Certain exemplary sHASEGPs (including rHuPH20) and methods of use are described in U.S. Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, sHASEGP is combined with one or more Other glycosaminoglycanase (such as chondroitinase) combinations.

Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958. Aqueous antibody formulations include those described in US Pat. No. 6,171,586 and WO 2006/044908, where the formulations include a histidine-acetate buffer.

The active ingredient can be encapsulated in microcapsules, e.g. prepared by coacervation techniques or by interfacial polymerization, e.g. hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively ; Encapsulation in colloidal drug delivery systems (such as liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th Ed., Osol, A. Ed. (1980).

Sustained release formulations can be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the antibody in the form of shaped articles such as films or microcapsules.

Formulations to be used for in vivo administration are generally sterile. Sterility is readily achieved by, for example, filtration through sterile filtration membranes.

G. Therapeutic Methods and Compositions Any of the anti-SARS-CoV-2 antibodies provided herein can be used in therapeutic methods.

In one aspect, an anti-SARS-CoV-2 antibody is provided for use in therapy. In one aspect, an anti-SARS-CoV-2 antibody is provided for use as a medicament. In other aspects, an anti-SARS-CoV-2 antibody is provided for treating and/or preventing SARS-CoV-2 infection and/or reducing its incidence. In certain embodiments, an anti-SARS-CoV-2 antibody is provided for use in a method of treating and/or preventing SARS-CoV-2 infection and/or reducing its incidence. In certain embodiments, the present invention provides an anti-SARS-CoV-2 antibody for use in treating and/or preventing and/or reducing the incidence of SARS-CoV-2 infection in individuals suffering from SARS-CoV-2 infection A method comprising administering to the individual an effective amount of an anti-SARS-CoV-2 antibody.

In other embodiments, the present invention provides an anti-SARS-CoV-2 antibody for blocking the binding of the receptor binding domain of SARS-CoV-2 to host cells and/or blocking the entry of SARS-CoV-2 into host cells middle. In certain embodiments, the present invention provides an anti-SARS-CoV-2 antibody for use in blocking the binding of the receptor binding domain of SARS-CoV-2 to host cells of an individual and/or blocking SARS-CoV-2 In a method for entering a host cell, it comprises administering to the individual an effective anti-SARS-CoV-2 antibody to block the binding of the receptor binding domain of SARS-CoV-2 to the host cell and/or block SARS-CoV-2 into the host cell. An "individual" according to any of the above embodiments is preferably a human being.

In other embodiments, the present invention provides an anti-SARS-CoV-2 antibody for exerting complement-dependent cytotoxicity (CDC) against a target virus (eg, SARS-CoV-2). In other embodiments, the present invention provides an anti-SARS-CoV-2 antibody, which is used to lyse a target virus (such as SARS-CoV-2) (virion lysis) or reduce the ability of the virus to infect cells through complement. In other embodiments, the invention provides an anti-SARS-CoV-2 antibody for use in inhibiting antibody-dependent enhancement (ADE) observed with conventional anti-SARS-CoV-2 antibodies.

In another aspect, the present invention provides a use of an anti-SARS-CoV-2 antibody for manufacturing or preparing a medicament. In one embodiment, the medicament is used to treat and/or prevent SARS-CoV-2 infection and/or reduce its incidence. In another embodiment, the drug is used in a method for treating and/or preventing SARS-CoV-2 infection and/or reducing its incidence, which comprises administering an effective amount of drug. In another embodiment, the drug is used to block the binding of the receptor binding domain of SARS-CoV-2 to the host cell and/or block the entry of SARS-CoV-2 into the host cell. In another embodiment, the drug is used in a method of blocking the binding of the receptor binding domain of SARS-CoV-2 to the host cell of an individual and/or blocking the entry of SARS-CoV-2 into the host cell, comprising administering to the individual An effective amount of medicine is used to block the binding of SARS-CoV-2 protein to the host cell and/or block the entry of SARS-CoV-2 into the host cell. An "individual" according to any of the above embodiments may be a human being.

In another embodiment, the drug is used to exert complement-dependent cytotoxicity (CDC) against a virus of interest (eg, SARS-CoV-2). In another embodiment, the drug is used to lyse a target virus (such as SARS-CoV-2) (virolysis) or reduce the ability of the virus to infect cells via complement. In another embodiment, the drug is used to inhibit antibody-dependent enhancement (ADE) observed in the presence of known anti-SARS-CoV-2 antibodies.

In another aspect, the present invention provides a method for treating and/or preventing and/or reducing the incidence of SARS-CoV-2 infection. In one embodiment, the method comprises administering to an individual having such a SARS-CoV-2 infection an effective amount of an anti-SARS-CoV-2 antibody. An "individual" according to any of the above embodiments may be a human being. In some embodiments, the present invention provides an anti-SARS-CoV-2 antibody for treating and/or preventing SARS-CoV-2 infection and/or reducing its incidence.

In another aspect, the present invention provides a method for blocking the binding of the receptor binding domain of SARS-CoV-2 to the host cells of an individual and/or blocking the entry of SARS-CoV-2 into the host cells. In one embodiment, the method comprises administering to the individual an effective amount of an anti-SARS-CoV-2 antibody to block the binding of the receptor binding domain of SARS-CoV-2 to host cells and/or to block the binding of SARS-CoV-2 2 into the host cell. In some embodiments, the present invention provides an anti-SARS-CoV-2 antibody for blocking the binding of the receptor binding domain of SARS-CoV-2 to the host cells of an individual and/or blocking the SARS-CoV- 2 into the host cell. In one embodiment, an "individual" is a human being.

In other embodiments, the present invention provides a method for exerting complement-dependent cytotoxicity (CDC) against a virus of interest (eg, SARS-CoV-2). In one embodiment, the method comprises administering to the individual an effective amount of an anti-SARS-CoV-2 antibody to exert complement-dependent cytotoxicity (CDC) against a virus of interest (eg, SARS-CoV-2). In some embodiments, the present invention provides a use of an anti-SARS-CoV-2 antibody for exerting complement-dependent cytotoxicity (CDC) against a target virus (such as SARS-CoV-2).

In other embodiments, the present invention provides a method for effecting lysis (virolysis) of a target virus (eg, SARS-CoV-2) or reducing the ability of the virus to infect cells via complement. In one embodiment, the method comprises administering to the individual an effective amount of an anti-SARS-CoV-2 antibody to effect lysis of a target virus (e.g., SARS-CoV-2) (virolysis) or to reduce viral infection by complement cell capacity. In some embodiments, the present invention provides a use of an anti-SARS-CoV-2 antibody, which is used to dissolve the target virus (such as SARS-CoV-2) (virus lysis) or reduce the ability of the virus to infect cells by complement. ability.

In other embodiments, the present invention provides a method for inhibiting antibody-dependent enhancement (ADE) observed with conventional anti-SARS-CoV-2 antibodies. In one embodiment, the method comprises administering to the individual an effective amount of an anti-SARS-CoV-2 antibody to inhibit antibody-dependent enhancement (ADE) observed with known anti-SARS-CoV-2 antibodies. In some embodiments, the present invention provides the use of an anti-SARS-CoV-2 antibody for inhibiting antibody-dependent enhancement (ADE) observed with conventional anti-SARS-CoV-2 antibodies.

In another aspect, the invention provides a pharmaceutical formulation comprising any of the anti-SARS-CoV-2 antibodies provided herein, for example, for use in any of the aforementioned methods of treatment. In one embodiment, the pharmaceutical formulation comprises any one of the anti-SARS-CoV-2 provided herein and a pharmaceutically acceptable carrier.

In another aspect, the pharmaceutical formulation is used to treat and/or prevent and/or reduce the incidence of SARS-CoV-2 infection. In another embodiment, the pharmaceutical formulation is used to block the binding of the receptor binding domain of SARS-CoV-2 to the host cell and/or to block the entry of SARS-CoV-2 into the host cell. In one embodiment, a pharmaceutical formulation is administered to an individual with a SARS-CoV-2 infection. An "individual" according to any of the above embodiments is preferably a human being. In certain embodiments, SARS-CoV-2 infection may include diseases and/or symptoms caused by or associated with SARS-CoV-2 infection, such as acute respiratory distress, pneumonia, dyspnea, fever, rhinitis, nasal congestion, Loss of smell, fatigue, diarrhea, etc.

In one embodiment, an anti-SARS-CoV-2 antibody comprising a variant Fc region of the invention can inhibit the antibody-dependent enhancement (ADE) observed with conventional anti-SARS-CoV-2 antibodies. ADE is a phenomenon in which virus bound to an antibody is phagocytosed through activating FcγRs, so that infection of cells by the virus is enhanced. Fc modifications that reduce interaction with activating FcyRs can reduce the risk of ADE. Mutations from leucine to alanine at positions 234 and 235 to form LALA mutants have been shown to reduce the risk of ADE in dengue infection in vivo (Cell Host Microbe (2010) 8, 271-283).

However, such modifications reduce other effector immune functions mediated by antibodies, such as ADCC and CDC. In particular, CDC can be expected to play an important role in the inhibition of ADE, so for therapeutic efficacy, binding of the complement component C1q of the Fc region should not be reduced. Furthermore, antibody half-life can be extended by engineering the Fc region, altering the binding affinity for its salvage receptor FcRn, which could lead to the prophylactic use of antibodies for protection against viral infection.

Antibodies of the invention may be administered by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if necessary, intralesional administration for local treatment. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. Depending in part on the short-term or chronic nature of the administration, administration may be by any suitable route, for example by injection, such as intravenous or subcutaneous injection. Various dosing schedules are contemplated herein, including, but not limited to, a single dose or multiple doses over multiple time points, bolus administration, and pulse infusion.

Antibodies of the invention will be formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the agent, the method of administration, the schedule of administration and what is known to the medical practitioner. other factors. Antibodies need not, but are optionally formulated (eg, in the form of a pharmaceutical composition) with one or more agents currently used to prevent or treat or reduce the incidence of the disorder in question. The effective amount of such other agents depends on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. These agents are generally used in the same dosage and by the route of administration as described herein, or at about 1% to 99% of the dosage described herein, or in any dosage and as empirically/clinically judged appropriate use in any way.

In order to prevent or treat a disease or reduce its incidence, the appropriate dose of the antibody of the present invention will depend on the following: the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is used for prophylaxis or therapy Targeted administration, previous therapy, patient's clinical history and response to antibodies, and the judgment of the attending physician. The antibody is suitably administered to the patient at one time or over a series of treatments. Depending on the type and severity of the disease, about 1 µg/kg to 15 mg/kg (e.g. 0.1 mg/kg-10 mg/kg) of the antibody may be an initial candidate dose for administration to a patient, whether e.g. by By one or more separate administrations or by continuous infusion. A typical daily dosage may range from about 1 μg/kg to 100 mg/kg or higher, depending on the factors mentioned above. For repeated administrations over several days or longer, treatment will generally be continued, depending on the condition, until the desired suppression of disease symptoms occurs. An exemplary dosage of antibody will be in the range of about 0.05 mg/kg to about 10 mg/kg. Thus, one or more doses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg or 10 mg/kg (or any combination thereof) may be administered to the patient. Such doses may be administered intermittently, eg, every week or every three weeks (eg, such that the patient receives from about two to about twenty, or eg, about six doses of the antibody). An initial higher loading dose can be administered, followed by one or more lower doses. An exemplary dosing regimen comprises administering [[add an exemplary dosing regimen, if known, such as "an initial loading dose of about 4 mg/kg followed by a weekly maintenance dose of antibody of about 2 mg/kg"]]. However, other dosing regimens may be suitable. The progress of this therapy is readily monitored by known techniques and analyses.

It will be appreciated that any of the above methods of formulation or treatment may be performed using the immunoconjugates of the invention instead of or in addition to anti-SARS-CoV-2 antibodies.

Herein, the antigen-binding molecule of the present invention can be administered by a method in which a nucleic acid encoding the antigen-binding molecule of the present invention is administered or incorporated into the body using a carrier or the like, and the antigen-binding molecule is directly expressed in the body, However, it can be administered without the use of a carrier. As the vector, viral vectors, plastid vectors, and even adenoviral vectors are exemplified. The nucleic acid encoding the antigen-binding molecule of the present invention can be administered directly to the body or by electroporation. For example, the antigen-binding molecule of the present invention can be administered by a method in which the mRNA encoding the antigen-binding molecule of the present invention can be chemically modified to enhance the stability of the mRNA in vivo, and the mRNA can be directly administered to humans , and can express the antigen-binding molecule of the present invention in vivo (see EP2101823B, WO2013/120629). In addition, B cells introduced with the antigen-binding molecule of the present invention can be administered (Sci Immunol. (2019), 4(35), eaax0644). Bacteria introduced with the antigen-binding molecules of the present invention can also be administered (Nature Reviews Cancer (2018) 18, 727-743).

As a non-limiting example of techniques that can be combined with the antigen-binding molecules of the invention herein, the use of the antigen-binding molecules of the invention to generate T cell-secreting T cells redirected to the antigen-binding molecules is exemplified (Trends Immunol. (2019) 40( 3) 243-257). One of the non-limiting techniques is to introduce bispecific antigen-binding molecules into effector cells (such as T cells) by genetic engineering technology, and the bispecific antigen-binding molecules comprise T cell receptors (TCRs) formed on T cells. ) complex, in particular the binding domain of the CD3ε chain in CD3 and the binding domain of the target antigen bound by the antigen-binding molecule of the present invention.

H. Articles of Manufacture In another aspect of the present invention, an article of manufacture containing materials suitable for the treatment, prevention, reduction of the incidence and/or diagnosis of the disorders described above is provided. The article comprises a container and a label or insert sheet on or accompanying the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, and the like. The container can be formed from a variety of materials such as glass or plastic. The container contains the composition alone or in combination with another composition effective for treating, preventing, reducing the incidence of, and/or diagnosing the condition, and may have a sterile access opening (e.g., the container may have a hypodermic needle-penetrable Intravenous solution bag or vial with stopper). At least one active ingredient in the composition is an antibody of the invention. The label or package insert indicates that the composition is to be used to treat or prevent or reduce the incidence of the selected condition. The article of manufacture of this embodiment of the invention may further comprise a package insert indicating that the composition is useful for treating a particular condition. Alternatively or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and Dextrose solution. It may further include other materials desired from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.

It will be appreciated that any of the above preparations may comprise an immunoconjugate of the invention instead of or in addition to an anti-SARS-CoV-2 antibody.

III. EXAMPLES Example embodiments of the present invention will be better understood and become apparent to those of ordinary skill in the art from the following discussion, taken in conjunction with, if applicable, the drawings. The following are examples of methods and compositions of the invention. It is understood that various other embodiments may be practiced, given the general description provided above. It should also be appreciated that other modifications within the scope of those skilled in the art may be made without departing from the scope of the invention. The example embodiments are not necessarily mutually exclusive, as some can be combined with one or more embodiments to form new exemplary embodiments. The example embodiments should not be considered as limiting the scope of the invention.

Example 1.1 : Identification of amino acid residues in the mutated variable region for improved binding affinity is numbered according to Kabat (Kabat et al., Sequence of proteins of immunological interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991)). The amino acid residues in the heavy chain constant region are numbered according to the "EU numbering system". (Kabat et al., Sequence of proteins of immunological interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)).

Anti-SARS-CoV-2 Spike protein receptor binding domain (RBD) antibody, called 5A6 (H chain and L chain variable regions are set forth in SEQ ID NO: 1 and SEQ ID NO: 43, respectively) is presented using phase Technology As a lead antibody is isolated from a human Fab library. 5A6 blocks the binding of the RBD of the viral spike protein to the host receptor angiotensin-converting enzyme 2 receptor (ACE2). The variable regions of the heavy and light chains of 5A6 are referred to as 5A6H.GS and 5A6L.GS, respectively. Polynucleotides encoding the variable regions of the heavy and light chains were synthesized and cloned into expression vectors containing polynucleotides encoding the heavy chain constant region SG1 sequence or the light chain constant region SK1 sequence, respectively. Recombinant antibodies were transiently expressed using the Expi293 Expression System (Thermo Fisher) according to the manufacturer's instructions. It is called parental antibody or wild type and is called 5A6-SG1 or 5A6H.GS-SG1/5A6L.GS-SK1. Recombinant antibodies were purified from transiently expressed supernatants using protein A (GE Healthcare), and the purified antibodies were formulated in D-PBS or His buffer (20 mM histidine, 150 mM NaCl, pH 6.0). If necessary, further size exclusion chromatography was performed to remove high molecular weight and/or low molecular weight components.

To identify affinity-improving mutations, more than 1000 variants were generated from the parental antibody (5A6-SG1 or 5A6H.GS-SG1/5A6L.GS-SK1). These variants are substituted with 18 other amino acids (excluding the original amino acid and cysteine) in each position in the CDR. Some positions in the framework have also been substituted. Binding affinities of clonal 5A6 and variants were measured at 25°C or 37°C using a Biacore 8K instrument (GE Healthcare). Anti-human Fc (GE Healthcare) was immobilized to all flow cells of the CM4 sensor wafer using an amine coupling kit (GE Healthcare). Antibodies were captured onto the anti-human Fc sensor surface to a capture level of approximately 200 RU. Recombinant SARS-CoV-2 S protein RBD was injected at two concentrations of 12.5 nM and 50 nM. All antibodies and analytes were prepared in ACES pH 7.4 containing 20 mM ACES, 150 mM NaCl, 0.05% Tween 20, 0.005% NaN ₃ . The analysis temperature was set at 25°C. The sensor surface was regenerated with 3M _MgCl2 at each cycle. Binding affinity was determined by processing the data using Biacore Insight evaluation software version 3.0.12.15655 (GE Healthcare) and fitting it to a 1:1 binding model.

Affinity-improved variants were selected and the kinetics of the selected variants are listed in Table 3. [table 3]

Example 1.2 : Generation of Affinity Matured Antibody The framework of 5A6 from the human Fab library is not a human germline framework sequence. The framework of 5A6 of the heavy and light chains was replaced with human germline framework sequences. After evaluating several human germline sequences, 5A602H and 5A605L were generated as the variable regions of the heavy and light chains, respectively. Selected human germline frameworks are listed in Table 4. [Table 4] Framework 1 Framework 2 Framework 3 Framework 4 5A602H IGHV3-64*04 IGHV3-30*01 IGHV3-48*03 JH1 5A605L IGKV1D-39*01 IGKV3-20*01 IGKV1D-39*01 JK4

The mutations identified in Table 3 were combined and this combination resulted in several variants with increased affinity for the SARS-CoV-2 S protein RBD. These mutations in the CDRs and/or framework were introduced into 5A602H and 5A605L, and finally one variant was selected. The selected variant of the variable region was designated 5A6AM1 and consisted of 5A602H0835 (SEQ ID NO: 2) and 5A605L0494 (SEQ ID NO: 42) as the variable regions of the heavy and light chains, respectively.

Example 2.1 : Further Engineering to Improve Various Properties of the 5A6AM1 Antibody When a solution of 5A6AM1-SG1 was concentrated, visible/insoluble particles were observed. Visible/non-visible insoluble particles in protein formulations were considered to indicate low solubility of the protein of interest. Low solubility of therapeutic proteins can limit the concentration in the formulation and make drug development difficult, especially when the drug needs to be in high concentration in the formulation/solution.

Various assays have been reported to assess antibody characteristics such as antibody self-interactions, cross-interactions, melting temperature, hydrophobicity, aggregated species, low molecular species, monomer content, non-specific binding. (PNAS Jan. 31, 2017 114 (5) 944-949., PLoS ONE 8(2): e57479., MAbs. Jan-Dec 2020; 12(1): 1683432.). 5A6AM1-SG1 was assessed in several assays and found to have unfavorable physicochemical properties compared to the negative control antibody (Antibody A, as shown in Table 6).

To overcome these challenges, further engineering was performed by introducing mutations into 5A6AM1-SG1. After several rounds of combination, several variants with improved physicochemical properties were successfully produced, as shown in Table 6. To compare the solubility of each antibody, a visual inspection assessment was performed. All variants were concentrated to 5 mg/mL using Amicon Ultra 0.5 mL filters (Merck) and transferred to deactivated clear glass inserts (Waters). The inspector inspected the samples in the vials and scored the degree of visible particles (VP) using the scoring system shown in Table 5 below. Visual inspection scores were calculated as averages from at least three inspectors, as shown in Table 6. All variants showed fewer visible particles in solution compared to 5A6AM1-SG1. In addition to the reduction in visible particles, several variants showed improved binding affinity for the RBD domain of the SARS-CoV-2 S protein compared to 5A6AM1. [table 5] definition score A large number of VPs were observed 4 A small amount of VP was observed 3 Very few VPs observed 2 VP was barely observed 1.5 VP not observed 1 [Table 6]

Example 2.2 : Characterization of engineered antibodies Several variants were selected and generated with human heavy chain constant regions or human modified heavy chain constant regions. The names and sequences of the antibodies are shown in Table 7. [Table 7]

注意： n.d. KD歸因於微弱結合反應無法測定。 # 動力學常數kd接近可藉由儀器量測之極限 * 雙相結合，KD無法唯一判定 ^a將抗體捕獲於蛋白質AG感測器表面上，且注射不同濃度之特定抗原。 ^b將抗原捕獲於抗His標籤感測器表面上，且注射不同濃度之各抗體。 A Biacore 8K instrument (GE Healthcare) was used to measure the binding affinity of the clone 5A6 and variants against the recombinant SARS-CoV-2 S protein RBD and mutants (V483A and F490S). Protein A/G was immobilized to all flow cells of the CM4 sensor chip using an amine coupling kit (GE Healthcare). Antibodies were captured onto the protein A/G sensor surface to a capture level of approximately 200 RU. Recombinant SARS-CoV-2 S protein RBD and mutants (V483A and F490S) were injected at different concentrations (6.25 nM-100 nM, two-fold serial dilution). All antibodies and analytes were prepared in ACES pH 7.4 containing 20 mM ACES, 150 mM NaCl, 0.05% Tween 20, 0.005% NaN ₃ . The analysis temperature was set at 37°C. The sensor surface was regenerated with 10 mM glycine-HCl pH 1.5 at each cycle. Binding affinity was determined by processing the data using Biacore Insight evaluation software version 3.0.12.15655 (GE Healthcare) and fitting it to a 1:1 binding model. The binding affinities of cloned 5A6 and variants binding to the trimeric SARS-CoV-2 S protein were determined using a Biacore T200 instrument (GE Healthcare) at 37°C. Anti-histidine antibodies (GE Healthcare) were immobilized to all flow cells of the CM5 sensor wafer using an amine coupling kit (GE Healthcare). Capture of trimeric SARS-CoV-2 S protein with polyhistidine tag at C-terminus (D614G) and trimeric SARS-CoV-2 S protein with polyhistidine tag at C-terminus to antihistamine On the surface of the acid sensor, between 200-300 RU capture content. Next, clone 5A6 and variants were injected at different concentrations (6.25 nM-100 nM, two-fold serial dilution). All antibodies and analytes were prepared in ACES pH 7.4 containing 20 mM ACES, 150 mM NaCl, 0.05% Tween 20, 0.005% NaN ₃ . The sensor surface was regenerated with 10 mM Gly-HCl pH 1.5 at each cycle. Binding kinetics and affinities were determined by processing the data using Biacore T200 evaluation software version 2.0 (GE Healthcare) and fitting it to a 1:1 binding model. Binding kinetics of cloned 5A6 and affinity-improved variants binding to the SARS-CoV-2 S protein RBD and mutants (V483A and F490S), trimeric SARS-CoV-2 S protein, and trimeric SARS-CoV-2 (D614G) The chemical parameters are shown in Table 8. Affinity maturation of the clone 5A6 achieved more than 1000-fold affinity improvement for the restoration of binding to the SARS-CoV-2 S protein RBD and binding to the SARS-CoV-2 S protein RBD mutants (V483A and F490S). Clone 5A6 also showed improved binding to trimeric SARS-CoV-2 S protein and trimeric SARS-CoV-2 (D614G) after affinity maturation. [Table 8]

Note: nd KD could not be determined due to weak binding response. # The kinetic constant kd is close to the limit that can be measured by the instrument * Two-phase binding, KD cannot uniquely determine ^aThe antibody is captured on the surface of the protein AG sensor, and different concentrations of specific antigens are injected. ^b Antigens were captured on the anti-His tag sensor surface and different concentrations of each antibody were injected.

Size exclusion chromatography (SEC) analysis was performed to measure high molecular weight species (HWM) and low molecular weight species (LWM). Each of the transiently expressed selected antibodies was duplicated and purified separately, and subjected to SEC analysis. The mean values of the HWM peak, main peak and LWM peak were calculated, as shown in Table 9. The engineered antibody exhibits a lower amount of HMW compared to the parental antibody. [Table 9] Antibody name HMW(%) Main peak (%) LMW(%) CV_5A6H.GS-SG1/5A6L.GS-SK1 24.1 75.9 0.0 CV_5A602H0835-SG1/5A605L0494-SK1 1.4 97.4 1.2 CV_5A602H0874-SG1/5A605L0522-SK1 1.6 98.3 0.1 CV_5A602H0872-SG1/5A605L0535-SK1 1.6 98.4 0.0 Average value of N=2

The full-length amino acid sequences of antibody variable regions are shown in Table 10. [Table 10] Full-length amino acid sequences of antibody variable regions SEQ name SEQ ID NO: Amino acid sequence Kabat CDR is bold and underlined 5A6H.GS 1 QVQLQESGGGLVQPGGSLRLSCAASGFTFS SYEMN WVRQAPGKGLEWVA VISYDGSNKYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR LITMVRGEDY WGQGTLVTVSS 5A602H0835 2 QVQLVESGGGLVQPGGSLRLSCSASGWTFS LYEMN WVRQAPGKGLEWVA VISYEGSNKYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR LITMTRGPDY WGQGTLVTVSS 5A602H0845 3 QVQLVESGGGLVQPGGSLRLSCSASGFTFS SYEMN WVRQAPGKGLEWVA VISYEGSNKYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR LITMVRGAQG WGQGTLVTVSS 5A602H0874 4 QVQLVESGGGLVQPGGSLRLSCSASEWTFS IYEMN WVRQAPGKGLEWVA VISYDGSNKYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR LITMTRGPDY WGQGTLVTVSS 5A602H0872 5 QVQLVESGGGLVQPGGSLRLSCSASEWTFS IYEMN WVRQAPGKGLEWVA VISYEGSNKYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR LITMTRGPDY WGQGTLVTVSS 5A602H0880 6 QVQLVESGGGLVQPGGSLRLSCSASEFTFS IYEMN WVRQAPGKGLEWVA VISYDGSNKYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR LITMVRGAQG WGQGTLVTVSS 5A602H0877 7 QVQLVESGGGLVQPGGSLRLSCSASEFTFS SYEMN WVRQAPGKGLEWVA VISYDGSNKYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR LITMVRGAQG WGQGTLVTVSS 5A605L0494 42 DIQMTQSPSSLSASVGDRVTITC RASQSISSYLN WYQQKPGQAPRLLIY AASSLQI GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QESYNLPRT FGGGTKLEIK 5A6L.GS 43 DIQLTQSPSSLSASVGHRVTITC RASQSISSYLN WYQQKPGKAPKLLIY AASSLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYNLPRT FGGGTKLEVL 5A605L0522 44 DIQMTQSPSSLSASVGDRVTITC RASQEIESYLN WYQQKPGQAPRLLIY AAEELQI GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QESYNLPRT FGGGTKLEIK 5A605L0535 45 DIQMTQSPSSLSASVGDRVTITC RASQEISDYLN WYQQKPGQAPRLLIY AAEELQG GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYNLPRT FGGGTKLEIK 5A605L0531 46 DIQMTQSPSSLSASVGDRVTITC RASQEIESYLN WYQQKPGQAPRLLIY AAEELQG GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QESYNLPRT FGGGTKLEIK 5A605L0534 47 DIQMTQSPSSLSASVGDRVTITC RASQEIESYLN WYQQKPGQAPRLLIY AAEELQG GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYNLPRT FGGGTKLEIK 5A605L0536 48 DIQMTQSPSSLSASVGDRVTITC RASQSIEDYLN WYQQKPGQAPRLLIY AAEELQG GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYNLPRT FGGGTKLEIK 5A605L0315 49 DIQMTQSPSSLSASVGDRVTITC RASQSISSYLN WYQQKPGQAPRLLIY AASSLQG GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYNLPRT FGGGTKLEIK 5A605L0523 50 DIQMTQSPSSLSASVGDRVTITC RASQEISDYLN WYQQKPGQAPRLLIY AAEELQI GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QESYNLPRT FGGGTKLEIK 5A605L0505 51 DIQMTQSPSSLSASSVGDRVTITC RASQEISDYLN WYQQKPGQAPRLLIY AASSLQI GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QESYNLPRT FGGGTKLEIK 5A605L0512 52 DIQMTQSPSSLSASVGDRVTITC RASQSISSYLN WYQQKPGQAPRLLIY AAEELQI GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QESYNLPRT FGGGTKLEIK

Example 3 : Evaluation of PK Profiles in Human FcRn Gene-Transformed Mice The pharmacokinetic profile in human FcRn-transgenic mice was evaluated. The results are shown in Figure 1.

Figure 1 illustrates the plasma concentration-time profiles of 5A6CCS1-SG1095ACT3 and 5A6CCS1-SG1095 (which are listed in Table 7) in human FcRn transgenic mice administered with IVIG after intravenous administration. Quantification was performed by ECLIA using the SARS-CoV-2 S protein RBD from Acro Biosystems coated on culture plates and a sulfo-tag-labeled anti-human IgG that recognized a specific mutation of the administered antibody as a detection antibody. Antibody concentration.

After 28 days of administration, the concentration of 5A6CCS1-SG1095ACT3 was shown to be higher than that of 5A6CCS1-SG1095. As shown in Table 11, the AUC in 5A6CCS1-SG1095ACT3 was 564 days*μg/mL and the AUC in 5A6CCS1-SG1095 was 245 days*μg/mL. The half-life in 5A6CCS1-SG1095ACT3 was 16.7 days and the half-life in 5A6CCS1-SG1095 was 10.8 days. The clearance rate was 3.57 mL/day/kg in 5A6CCS1-SG1095ACT3 and 8.25 mL/day/kg in 5A6CCS1-SG1095. Compared with 5A6CCS1-SG1095, 5A6CCS1-SG1095ACT3 showed higher exposure, longer half-life and lower clearance. [Table 11] AUCINF CL T _1/2 day*μg/mL mL/day/kg sky 5A6CCS1-SG1095ACT3 564 3.57 16.7 5A6CCS1-SG1095 245 8.25 10.8

Table 11 shows the area under the curve (AUC), half-life (T _1/2 ) and total clearance of 5A6CCS1-SG1095ACT3 and 5A6CCS1-SG1095 in human FcRn transgenic mice administered IVIG after intravenous administration.

Example 4.1 : Biacore binding assay of 5A6CCS1 for RBD mutants Using a Biacore 8K instrument (GE Healthcare), a series of RBD mutants reported in the cycle were tested for binding to 5A6CCS1. 5A6 and 5A6CCS1 were captured onto the protein A/G sensor surface to a capture level of approximately 300 RU. Recombinant SARS-CoV-2 S protein RBD and mutants (K417N, N439K, K444R, G446V, Y453F, N481D, G482S, V483A, E484K, E484Q, G485S, F486S, N487R, F490S, N501Y, and triple RBD mutation K417N/E484K/N501Y). Binding responses of 5A6 and 5A6CCS1 to recombinant RBD wild-type or mutants were normalized to capture levels.

Figure 2 illustrates the relative binding of RBD mutants relative to RBD wild type for 5A6 and 5A6CCS1. 5A6 showed less than 0.5 relative binding to RBD wild type for RBD mutants V483A, E484K, F486S, F490S, and triple RBD mutation K417N/E484K/N501Y. For all mutants, 5A6CCS1 showed similar binding to RBD wild type, but slightly lower binding to E484K and the triple RBD mutation K417N/E484K/N501Y, while relative binding to RBD wild type was higher than 0.5.

example 4-2 : use SARS-CoV-2 Antibody Neutralization Analysis of Spike Glycoprotein Pseudoviruses

method

Antibody neutralization assay of SARS-CoV-2 spike glycoprotein pseudovirus was used to inoculate CHO ^- ACE2 cells at a density of 3.2 × 104 cells in a 96-well flat transparent bottom black polystyrene TC-treated microplate (Corning , #3904) in 100 µL complete medium without geneticin. Incubate serially diluted IgG with an equal volume of pseudovirus (6 ng of p24) in a 96-well flat-bottomed cell culture dish (Costar, #3596) in a final volume of 50 μL for one hour at 37 degrees Celsius (°C) , and the mixture was added to a monolayer of pre-seeded CHO ACE2 cells twice. One hour after the pseudovirus infection at 37°C, 150 µl of medium was added to each well, and the cells were further incubated for an additional 48 hours. After removal of medium, cells were washed twice with sterile PBS and then lysed in 20 µL of 1× passive lysis buffer (Promega, E1941 ) for 30 minutes at 37° C. with gentle shaking at 400 rpm. Next, luciferase activity was assessed on a Promega GloMax luminometer using the luciferase assay system (Promega, E1510). Relative luciferase units (RLU) were converted to percent neutralization and plotted using PRISM (Graphpad) with nonlinear regression curve fitting.

To assess antibody neutralizing potential, pseudoviruses expressing wild-type or mutant SARS-CoV-2 spike glycoproteins tagged with a luciferase reporter were generated. Neutralization of pseudoviruses was assessed using CHO cells stably expressing human ACE2 (CHO-ACE2) as a target. Mutant pseudoviruses with the following single mutations were generated: K417N, V483A, E484K, N501Y and D614G. In addition, pseudoviruses carrying multiple mutations were also produced: K417N/E484K/D614G (hereinafter referred to as the South African triple mutation) and del69-70/del144-145/N501Y/A570D/D614G/P681H/T716I/S982A/D1118H (hereinafter referred to as for the UK variant).

Figure 3 illustrates the neutralization of the parental 5A6 and engineered 5A6CCS1 antibodies against SARS-CoV-2 pseudoviruses.

As shown in Figure 3, the parental 5A6 antibody was unable to neutralize the V483A and E484K single mutant pseudoviruses, as well as the South African triple mutation containing the E484K mutation. In contrast, the affinity-improved 5A6CCS1 was able to neutralize the V483A, E484K and South African triple mutant viruses.

example 4-3 : Infect SARS-CoV-2 Syrian golden hamster (Golden Syrian Hamster) antibody therapy

method

Antibody Treatment of Syrian Golden Hamsters Infected with SARS-CoV-2 6-8 week old female Syrian golden hamsters (Janvier labs, France) were anesthetized and treated with 70 μL containing 1 × 10 ⁵ pfu SARS-CoV-2 (D614G) virus (Virus strain Slovakia/SK-BMC5/2020) (Global Archive of European Viruses) for intranasal infection. Six hours after infection, hamsters received an intraperitoneal injection of antibodies at the indicated doses. Left lungs were placed in RNAlater at 4°C overnight and then stored at -80°C until RNA extraction for viral load quantification by qRT-PCR. The superior, middle, posterior vena cava and right lower lobe were snap frozen in liquid nitrogen and then stored at -80°C until processed for infectious particle detection (TCID ₅₀ ).

Viral load determination in lungs by qRT -PCR Viral RNA extraction was performed using the QIAamp Viral RNA Mini Kit (Qiagen) and RT-PCR was performed using the SuperScript III One-Step qRT-PCR Kit 1 (Life Technologies, #11732) . SARS-CoV-2 RNA was quantified using the IP2 and IP4 primers that detect the RNA-dependent RNA polymerase gene (RdRp) and the ORF1ab gene detection primer. The sequences of the forward primer, reverse primer and control probe are provided in Table 12. [Table 12] Primers used to detect SARS-CoV-2 RNA RdRp gene/nCoV_IP nCoV_IP2-12669Fw ATGAGCTTAGTCCTGTTG nCoV_IP2-12759Rv CTCCCTTTGTTGTGTTGT nCoV_IP2-12696b probe (+) AGATGTCTTGTGCTGCCGGTA [5']Hex [3']BHQ-1 RdRp gene/nCoV_IP4 nCoV_IP4-14059Fw GGTAACTGGTATGATTTCG nCoV_IP4-14146Rv CTGGTCAAGGTTAATATAGG nCoV_IP4-14084 probe (+) TCATACAAACCACGCCAGG [5']Fam [3']BHQ-1 ORF1ab gene/nCoV ORF1ab_Fw CCGCAAGGTTTCTTCTTCGTAAG ORF1ab_Rv TGCTATGTTTAGTGTTCCAGTTTTC ORF1ab_probe AAGGATCAGTGCCAAGCTCGTCGCC [5']Hex [3'] BHQ-1

Figure 4 illustrates pneumovirus titers of hamsters infected with live SARS-CoV-2 virus following treatment with 5A6CCS1 antibody.

To confirm whether the engineered 5A6CCS1 antibody has neutralizing efficacy against live SARS-CoV-2 virus, the efficacy of the antibody was tested in a hamster model of SARS-CoV-2 infection. Hamsters were intranasally infected with 1×10 ⁵ pfu of SARS-CoV-2 (D614G) virus (strain Slovakia/SK-BMC5/2020), and 6 hours later, 5A6CCS1 antibody was administered intraperitoneally. For a control antibody, IC17-hIgG1 binding to an unrelated antigen (KLH) was administered. Hamsters were sacrificed after 4 days and lungs were harvested for determination of viral load. As shown in Figure 4, 5A6CCS1 significantly reduced lung viral load in a dose-dependent manner, as determined by qRT-PCR of the SARS-CoV-2 RNA-dependent RNA polymerase gene and the ORF1ab gene.

Example 5 : Parental 5A6 and engineered 5A6CCS1 antibodies neutralize SARS-CoV-2 pseudoviruses of various related variants (VOC) and variants of interest ( VOI) Figure 5 illustrates parental 5A6 and engineered The 5A6CCS1 antibody neutralizes SARS-CoV-2 pseudoviruses of various VOCs and VOIs (β, γ, κ, δ, and ε).

As shown in Figure 5, the parental 5A6 antibody was unable to neutralize the β (B.1.351) or γ (P.1) variants, both containing the E484K mutation, or the κ (B.1.617.1) variant, which contained the E484Q mutation. body. In contrast, the affinity-improved 5A6CCS1 was able to neutralize these three mutant pseudoviruses. In addition, the affinity-improved 5A6CCS1 also showed enhanced potency in neutralizing the delta (B.1.617.2) variant and the epsilon (B.1.429) variant pseudoviruses.

Although the foregoing disclosure has been described in some detail by way of illustration and examples for purposes of clarity of understanding, the descriptions and examples should not be viewed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated by reference in their entirety.

[application] The present invention provides affinity-matured SARS-CoV-2 binding molecules with improved physicochemical properties, SARS-CoV-2 binding molecules that can increase the clearance rate of concerned coronaviruses while reducing the risk of ADE, and methods for preparing the antigen-binding molecules , Pharmaceutical compositions comprising such SARS-CoV-2 binding molecules as active ingredients and methods of treatment using such pharmaceutical compositions.

As demonstrated in the Examples, in order to identify mutations that improve affinity for SARS-CoV-2, parental antibody 5A6, which is an anti-SARS-CoV-2 Spike (S) protein receptor binding domain (RBD) antibody, was generated Variants. Furthermore, to reduce the insolubility of the antibody, further engineering was performed by introducing mutations that improve the physicochemical properties. The resulting variants exhibit useful characteristics, such as enhanced affinity for the SARS-CoV-2 S protein RBD, trimeric SARS-CoV-2 S protein, and several SARS-CoV-2 S protein mutants, and increased solubility.

[ Fig. 1 ] Fig. 1 illustrates the plasma concentration-time curves of 5A6CCS1-SG1095ACT3 and 5A6CCS1-SG1095 in human FcRn transgenic mice administered with IVIG after intravenous administration. [ FIG. 2 ] FIG. 2 illustrates the relative binding of RBD mutants relative to RBD wild type against 5A6 and 5A6CCS1 . [Fig. 3-1] Fig. 3-1 illustrates the neutralization of the parental 5A6 and the engineered 5A6CCS1 antibody against the SARS-CoV-2 pseudovirus. [Fig. 3-2] Fig. 3-2 illustrates the neutralization of the parental 5A6 and the engineered 5A6CCS1 antibody against the SARS-CoV-2 pseudovirus. [ FIG. 4 ] FIG. 4 illustrates pneumovirus titers of hamsters infected with live SARS-CoV-2 virus after treatment with 5A6CCS1 antibody. [Figure 5] Figure 5 illustrates the neutralization of SARS-CoV-2 pseudoviruses of various VOCs and VOIs (β, γ, κ, δ, and ε) by parental 5A6 and engineered 5A6CCS1 antibodies.

         
           <![CDATA[ <110> Chugai Pharmaceutical Co., Ltd. (CHUGAI SEIYAKU KABUSHIKI KAISHA)]]>
                 Agency for Science, Technology and Research
           <![CDATA[ <120> SARS-COV-2 binding molecules and their uses]]>
           <![CDATA[ <130> 2101807]]>
           <![CDATA[ <160> 167 ]]>
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          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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          Ser Leu Arg Leu Ser Cys Ala Ala Ser Trp Phe Thr Phe Ser Ser Tyr
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          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 9]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 9]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Trp Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 10]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 10]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Met Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 11]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 11]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ala Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 12]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 12]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 13]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 13]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Leu Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 14]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 14]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Met Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 15]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 15]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 16]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 16]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Val Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 17]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 17]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 18]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 18]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Phe Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 19]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 19]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Trp Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 20]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 20]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 21]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 21]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Ser Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 22]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 22]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Thr Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 23]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 23]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 24]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 24]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Ala Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 25]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 25]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 26]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 26]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Thr Arg Gly Glu Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 27]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 27]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Ala Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 28]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 28]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Pro Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 29]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 29]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Val Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 30]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 30]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Gly Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 31]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 31]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly His Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 32]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 32]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Lys Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 33]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 33]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Arg Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 34]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 34]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Gln Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 35]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 35]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Pro Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 36]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 36]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Gly Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 37]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 37]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Ile Thr Met Val Arg Gly Glu Asp Arg Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 38]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 38]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 39]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 39]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Ala Ala Leu Pro Ala Pro Ile Ser Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 40]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 40]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Ala Ala Leu Pro Ala Pro Ile Ser Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 41]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 41]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Ala Ala Leu Pro Ala Pro Ile Ser Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr
          305 310 315 320
          Arg Lys Glu Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 42]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 42]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Leu Gln Ile Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Glu Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 43]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 43]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          His Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Leu
                      100 105
           <![CDATA[ <210> 44]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 44]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Glu Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Glu Glu Leu Gln Ile Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Glu Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 45]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 45]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Asp Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Glu Glu Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 46]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 46]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Glu Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Glu Glu Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Glu Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 47]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 47]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Glu Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Glu Glu Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 48]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 48]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Glu Asp Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Glu Glu Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 49]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 49]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Ser Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 50]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 50]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Asp Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Glu Glu Leu Gln Ile Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Glu Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 51]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 51]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Asp Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Leu Gln Ile Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Glu Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 52]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 52]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Glu Glu Leu Gln Ile Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Glu Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 53]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 53]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          His Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Leu Gln Ile Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Leu
                      100 105
           <![CDATA[ <210> 54]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 54]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          His Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Leu Gln Leu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Leu
                      100 105
           <![CDATA[ <210> 55]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 55]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          His Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Ser Leu Gln Met Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Leu
                      100 105
           <![CDATA[ <210> 56]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 56]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          His Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Ser Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Leu
                      100 105
           <![CDATA[ <210> 57]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 57]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          His Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Ser Leu Gln Phe Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Leu
                      100 105
           <![CDATA[ <210> 58]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 58]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          His Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Leu
                      100 105
           <![CDATA[ <210> 59]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 59]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          His Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Ser Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Glu Ser Tyr Asn Leu Pro Arg
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Leu
                      100 105
           <![CDATA[ <210> 60]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 60]]>
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
          1 5 10 15
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
                      20 25 30
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
                  35 40 45
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
              50 55 60
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
          65 70 75 80
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                          85 90 95
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
                      100 105
           <![CDATA[ <210> 61]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 61]]>
          Leu Tyr Glu Met Asn
          1 5
           <![CDATA[ <210> 62]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 62]]>
          Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 63]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 63]]>
          Leu Ile Thr Met Thr Arg Gly Pro Asp Tyr
          1 5 10
           <![CDATA[ <210> 64]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 64]]>
          Ser Tyr Glu Met Asn
          1 5
           <![CDATA[ <210> 65]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 65]]>
          Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 66]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 66]]>
          Leu Ile Thr Met Val Arg Gly Ala Gln Gly
          1 5 10
           <![CDATA[ <210> 67]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 67]]>
          Ile Tyr Glu Met Asn
          1 5
           <![CDATA[ <210> 68]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 68]]>
          Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 69]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 69]]>
          Leu Ile Thr Met Thr Arg Gly Pro Asp Tyr
          1 5 10
           <![CDATA[ <210> 70]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 70]]>
          Ile Tyr Glu Met Asn
          1 5
           <![CDATA[ <210> 71]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 71]]>
          Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 72]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 72]]>
          Leu Ile Thr Met Thr Arg Gly Pro Asp Tyr
          1 5 10
           <![CDATA[ <210> 73]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 73]]>
          Ile Tyr Glu Met Asn
          1 5
           <![CDATA[ <210> 74]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 74]]>
          Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 75]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 75]]>
          Leu Ile Thr Met Val Arg Gly Ala Gln Gly
          1 5 10
           <![CDATA[ <210> 76]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 76]]>
          Ser Tyr Glu Met Asn
          1 5
           <![CDATA[ <210> 77]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 77]]>
          Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 78]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 78]]>
          Leu Ile Thr Met Val Arg Gly Ala Gln Gly
          1 5 10
           <![CDATA[ <210> 79]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 79]]>
          Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 80]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 80]]>
          Ala Ala Ser Ser Leu Gln Ile
          1 5
           <![CDATA[ <210> 81]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 81]]>
          Gln Glu Ser Tyr Asn Leu Pro Arg Thr
          1 5
           <![CDATA[ <210> 82]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 82]]>
          Arg Ala Ser Gln Glu Ile Glu Ser Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 83]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 83]]>
          Ala Ala Glu Glu Leu Gln Ile
          1 5
           <![CDATA[ <210> 84]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 84]]>
          Gln Glu Ser Tyr Asn Leu Pro Arg Thr
          1 5
           <![CDATA[ <210> 85]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 85]]>
          Arg Ala Ser Gln Glu Ile Ser Asp Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 86]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 86]]>
          Ala Ala Glu Glu Leu Gln Gly
          1 5
           <![CDATA[ <210> 87]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 87]]>
          Gln Gln Ser Tyr Asn Leu Pro Arg Thr
          1 5
           <![CDATA[ <210> 88]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 88]]>
          Arg Ala Ser Gln Glu Ile Glu Ser Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 89]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 89]]>
          Ala Ala Glu Glu Leu Gln Gly
          1 5
           <![CDATA[ <210> 90]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 90]]>
          Gln Glu Ser Tyr Asn Leu Pro Arg Thr
          1 5
           <![CDATA[ <210> 91]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 91]]>
          Arg Ala Ser Gln Glu Ile Glu Ser Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 92]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 92]]>
          Ala Ala Glu Glu Leu Gln Gly
          1 5
           <![CDATA[ <210> 93]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 93]]>
          Gln Gln Ser Tyr Asn Leu Pro Arg Thr
          1 5
           <![CDATA[ <210> 94]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 94]]>
          Arg Ala Ser Gln Ser Ile Glu Asp Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 95]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 95]]>
          Ala Ala Glu Glu Leu Gln Gly
          1 5
           <![CDATA[ <210> 96]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 96]]>
          Gln Gln Ser Tyr Asn Leu Pro Arg Thr
          1 5
           <![CDATA[ <210> 97]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 97]]>
          Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 98]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 98]]>
          Ala Ala Ser Ser Leu Gln Gly
          1 5
           <![CDATA[ <210> 99]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 99]]>
          Gln Gln Ser Tyr Asn Leu Pro Arg Thr
          1 5
           <![CDATA[ <210> 100]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 100]]>
          Arg Ala Ser Gln Glu Ile Ser Asp Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 101]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 101]]>
          Ala Ala Glu Glu Leu Gln Ile
          1 5
           <![CDATA[ <210> 102]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 102]]>
          Gln Glu Ser Tyr Asn Leu Pro Arg Thr
          1 5
           <![CDATA[ <210> 103]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 103]]>
          Arg Ala Ser Gln Glu Ile Ser Asp Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 104]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 104]]>
          Ala Ala Ser Ser Leu Gln Ile
          1 5
           <![CDATA[ <210> 105]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 105]]>
          Gln Glu Ser Tyr Asn Leu Pro Arg Thr
          1 5
           <![CDATA[ <210> 106]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 106]]>
          Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 107]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 107]]>
          Ala Ala Glu Glu Leu Gln Ile
          1 5
           <![CDATA[ <210> 108]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 108]]>
          Gln Glu Ser Tyr Asn Leu Pro Arg Thr
          1 5
           <![CDATA[ <210> 109]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> HVR-H1]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (1)..(1)]]>
           <![CDATA[ <223> Xaa is Leu, Ile or Ser]]>
           <![CDATA[ <400> 109]]>
          Xaa Tyr Glu Met Asn
          1 5
           <![CDATA[ <210> 110]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> HVR-H2]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (5)..(5)]]>
           <![CDATA[ <223> Xaa is Glu or Asp]]>
           <![CDATA[ <400> 110]]>
          Val Ile Ser Tyr Xaa Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 111]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> HVR-H3]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (5)..(5)]]>
           <![CDATA[ <223> Xaa is Thr or Val]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (8)..(8)]]>
           <![CDATA[ <223> Xaa is Pro or Ala]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (9)..(9)]]>
           <![CDATA[ <223> Xaa is Asp or Gln]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (10)..(10)]]>
           <![CDATA[ <223> Xaa is Tyr or Gly]]>
           <![CDATA[ <400> 111]]>
          Leu Ile Thr Met Xaa Arg Gly Xaa Xaa Xaa
          1 5 10
           <![CDATA[ <210> 112]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> HVR-L1]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (5)..(5)]]>
           <![CDATA[ <223> Xaa is Ser or Glu]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (7)..(7)]]>
           <![CDATA[ <223> Xaa is Ser or Glu]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (8)..(8)]]>
           <![CDATA[ <223> Xaa is Ser or Asp]]>
           <![CDATA[ <400> 112]]>
          Arg Ala Ser Gln Xaa Ile Xaa Xaa Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 113]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> HVR-L2]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (3)..(3)]]>
           <![CDATA[ <223> Xaa is Ser or Glu]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (4)..(4)]]>
           <![CDATA[ <223> Xaa is Ser or Glu]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (7)..(7)]]>
           <![CDATA[ <223> Xaa is Ile or Gly]]>
           <![CDATA[ <400> 113]]>
          Ala Ala Xaa Xaa Leu Gln Xaa
          1 5
           <![CDATA[ <210> 114]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> HVR-L3]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (2)..(2)]]>
           <![CDATA[ <223> Xaa is Glu or Gln]]>
           <![CDATA[ <400> 114]]>
          Gln Xaa Ser Tyr Asn Leu Pro Arg Thr
          1 5
           <![CDATA[ <210> 115]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> HVR-H1]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (1)..(1)]]>
           <![CDATA[ <223> Xaa is Ser, Ala, Ile, Leu, Met, Pro, Val, His, Phe, Trp or Tyr]]>
           <![CDATA[ <400> 115]]>
          Xaa Tyr Glu Met Asn
          1 5
           <![CDATA[ <210> 116]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> HVR-H2]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (5)..(5)]]>
           <![CDATA[ <223> Xaa is Asp, Ser, Thr or Glu]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (6)..(6)]]>
           <![CDATA[ <223> Xaa is Gly or Ala]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (10)..(10)]]>
           <![CDATA[ <223> Xaa is Tyr or Phe]]>
           <![CDATA[ <400> 116]]>
          Val Ile Ser Tyr Xaa Xaa Ser Asn Lys Xaa Tyr Ala Asp Ser Val Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 117]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> HVR-H3]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (5)..(5)]]>
           <![CDATA[ <223> Xaa is Val or Thr]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (8)..(8)]]>
           <![CDATA[ <223> Xaa is Glu, Ala, Pro, Val, Gly, His, Lys or Arg]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (9)..(9)]]>
           <![CDATA[ <223> Xaa is Asp or Gln]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (10)..(10)]]>
           <![CDATA[ <223> Xaa is Tyr, Pro, Gly or Arg]]>
           <![CDATA[ <400> 117]]>
          Leu Ile Thr Met Xaa Arg Gly Xaa Xaa Xaa
          1 5 10
           <![CDATA[ <210> 118]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> HVR-L1]]>
           <![CDATA[ <400> 118]]>
          Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 119]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> HVR-L2]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (7)..(7)]]>
           <![CDATA[ <223> Xaa is Ser, Ile, Leu, Met, Gly or Phe]]>
           <![CDATA[ <400> 119]]>
          Ala Ala Ser Ser Leu Gln Xaa
          1 5
           <![CDATA[ <210> 120]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> HVR-L3]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (2)..(2)]]>
           <![CDATA[ <223> Xaa is Gln, Asn or Glu]]>
           <![CDATA[ <400> 120]]>
          Gln Xaa Ser Tyr Asn Leu Pro Arg Thr
          1 5
           <![CDATA[ <210> 121]]>
           <![CDATA[ <211> 30]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 121]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Trp Thr Phe Ser
                      20 25 30
           <![CDATA[ <210> 122]]>
           <![CDATA[ <211> 30]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 122]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser
                      20 25 30
           <![CDATA[ <210> 123]]>
           <![CDATA[ <211> 30]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 123]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ser Ala Ser Glu Trp Thr Phe Ser
                      20 25 30
           <![CDATA[ <210> 124]]>
           <![CDATA[ <211> 30]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 124]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ser Ala Ser Glu Phe Thr Phe Ser
                      20 25 30
           <![CDATA[ <210> 125]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 125]]>
          Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala
          1 5 10
           <![CDATA[ <210> 126]]>
           <![CDATA[ <211> 32]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 126]]>
          Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln
          1 5 10 15
          Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                      20 25 30
           <![CDATA[ <210> 127]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 127]]>
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
          1 5 10
           <![CDATA[ <210> 128]]>
           <![CDATA[ <211> 23]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 128]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys
                      20
           <![CDATA[ <210> 129]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 129]]>
          Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
          1 5 10 15
           <![CDATA[ <210> 130]]>
           <![CDATA[ <211> 32]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 130]]>
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
          1 5 10 15
          Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
                      20 25 30
           <![CDATA[ <210> 131]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 131]]>
          Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
          1 5 10
           <![CDATA[ <210> 132]]>
           <![CDATA[ <211> 330]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 132]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
          225 230 235 240
          Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                          325 330
           <![CDATA[ <210> 133]]>
           <![CDATA[ <211> 326]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 133]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
          1 5 10 15
          Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
          65 70 75 80
          Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
                      100 105 110
          Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
                  115 120 125
          Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
              130 135 140
          Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
          145 150 155 160
          Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
                          165 170 175
          Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
                      180 185 190
          Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
                  195 200 205
          Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
              210 215 220
          Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
          225 230 235 240
          Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
                          245 250 255
          Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
                      260 265 270
          Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
                  275 280 285
          Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
              290 295 300
          Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
          305 310 315 320
          Ser Leu Ser Pro Gly Lys
                          325
           <![CDATA[ <210> 134]]>
           <![CDATA[ <211> 377]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 134]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Thr Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro
                      100 105 110
          Arg Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg
                  115 120 125
          Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys
              130 135 140
          Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro
          145 150 155 160
          Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
                          165 170 175
          Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
                      180 185 190
          Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr
                  195 200 205
          Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
              210 215 220
          Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His
          225 230 235 240
          Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
                          245 250 255
          Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
                      260 265 270
          Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
                  275 280 285
          Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
              290 295 300
          Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Ser Gly Gln Pro Glu Asn Asn
          305 310 315 320
          Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
                          325 330 335
          Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile
                      340 345 350
          Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln
                  355 360 365
          Lys Ser Leu Ser Leu Ser Pro Gly Lys
              370 375
           <![CDATA[ <210> 135]]>
           <![CDATA[ <211> 327]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 135]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
          1 5 10 15
          Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
          65 70 75 80
          Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
                      100 105 110
          Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
                  115 120 125
          Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
              130 135 140
          Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
          145 150 155 160
          Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
                          165 170 175
          Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
                      180 185 190
          Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
                  195 200 205
          Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
              210 215 220
          Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
          225 230 235 240
          Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
                          245 250 255
          Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
                      260 265 270
          Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
                  275 280 285
          Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
              290 295 300
          Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
          305 310 315 320
          Leu Ser Leu Ser Leu Gly Lys
                          325
           <![CDATA[ <210> 136]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 136]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 137]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 137]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 138]]>
           <![CDATA[ <211> 374]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 138]]>
          Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
          1 5 10 15
          Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
                      20 25 30
          Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
                  35 40 45
          Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
              50 55 60
          Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
          65 70 75 80
          Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
                          85 90 95
          Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser Arg
                      100 105 110
          Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
                  115 120 125
          Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
              130 135 140
          Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
          145 150 155 160
          Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg Tyr
                          165 170 175
          Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu Leu Phe Pro Ala Pro
                      180 185 190
          Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu Glu Gly Asn Leu Val
                  195 200 205
          Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln Arg Pro Gly Leu Gln
              210 215 220
          Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr Leu Arg Gly Arg Asn
          225 230 235 240
          Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg Arg Glu Asp Ser Gly
                          245 250 255
          Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Gly Asn Val Leu Lys Arg
                      260 265 270
          Ser Pro Glu Leu Glu Leu Gln Val Leu Gly Leu Gln Leu Pro Thr Pro
                  275 280 285
          Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met Phe Leu
              290 295 300
          Val Asn Thr Val Leu Trp Val Thr Ile Arg Lys Glu Leu Lys Arg Lys
          305 310 315 320
          Lys Lys Trp Asp Leu Glu Ile Ser Leu Asp Ser Gly His Glu Lys Lys
                          325 330 335
          Val Ile Ser Ser Leu Gln Glu Asp Arg His Leu Glu Glu Glu Leu Lys
                      340 345 350
          Cys Gln Glu Gln Lys Glu Glu Gln Leu Gln Glu Gly Val His Arg Lys
                  355 360 365
          Glu Pro Gln Gly Ala Thr
              370
           <![CDATA[ <210> 139]]>
           <![CDATA[ <211> 316]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 139]]>
          Met Thr Met Glu Thr Gln Met Ser Gln Asn Val Cys Pro Arg Asn Leu
          1 5 10 15
          Trp Leu Leu Gln Pro Leu Thr Val Leu Leu Leu Leu Ala Ser Ala Asp
                      20 25 30
          Ser Gln Ala Ala Pro Pro Lys Ala Val Leu Lys Leu Glu Pro Pro Trp
                  35 40 45
          Ile Asn Val Leu Gln Glu Asp Ser Val Thr Leu Thr Cys Gln Gly Ala
              50 55 60
          Arg Ser Pro Glu Ser Asp Ser Ile Gln Trp Phe His Asn Gly Asn Leu
          65 70 75 80
          Ile Pro Thr His Thr Gln Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn
                          85 90 95
          Asp Ser Gly Glu Tyr Thr Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp
                      100 105 110
          Pro Val His Leu Thr Val Leu Ser Glu Trp Leu Val Leu Gln Thr Pro
                  115 120 125
          His Leu Glu Phe Gln Glu Gly Glu Thr Ile Met Leu Arg Cys His Ser
              130 135 140
          Trp Lys Asp Lys Pro Leu Val Lys Val Thr Phe Phe Gln Asn Gly Lys
          145 150 155 160
          Ser Gln Lys Phe Ser His Leu Asp Pro Thr Phe Ser Ile Pro Gln Ala
                          165 170 175
          Asn His Ser His Ser Gly Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr
                      180 185 190
          Thr Leu Phe Ser Ser Lys Pro Val Thr Ile Thr Val Gln Val Pro Ser
                  195 200 205
          Met Gly Ser Ser Ser Pro Met Gly Val Ile Val Ala Val Val Ile Ala
              210 215 220
          Thr Ala Val Ala Ala Ile Val Ala Ala Val Val Ala Leu Ile Tyr Cys
          225 230 235 240
          Arg Lys Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys Ala Ala
                          245 250 255
          Gln Phe Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys Arg Gln
                      260 265 270
          Leu Glu Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly Tyr Met
                  275 280 285
          Thr Leu Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile Tyr Leu
              290 295 300
          Thr Leu Pro Pro Asn Asp His Val Asn Ser Asn Asn
          305 310 315
           <![CDATA[ <210> 140]]>
           <![CDATA[ <211> 316]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 140]]>
          Met Thr Met Glu Thr Gln Met Ser Gln Asn Val Cys Pro Arg Asn Leu
          1 5 10 15
          Trp Leu Leu Gln Pro Leu Thr Val Leu Leu Leu Leu Ala Ser Ala Asp
                      20 25 30
          Ser Gln Ala Ala Pro Pro Lys Ala Val Leu Lys Leu Glu Pro Pro Trp
                  35 40 45
          Ile Asn Val Leu Gln Glu Asp Ser Val Thr Leu Thr Cys Gln Gly Ala
              50 55 60
          Arg Ser Pro Glu Ser Asp Ser Ile Gln Trp Phe His Asn Gly Asn Leu
          65 70 75 80
          Ile Pro Thr His Thr Gln Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn
                          85 90 95
          Asp Ser Gly Glu Tyr Thr Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp
                      100 105 110
          Pro Val His Leu Thr Val Leu Ser Glu Trp Leu Val Leu Gln Thr Pro
                  115 120 125
          His Leu Glu Phe Gln Glu Gly Glu Thr Ile Met Leu Arg Cys His Ser
              130 135 140
          Trp Lys Asp Lys Pro Leu Val Lys Val Thr Phe Phe Gln Asn Gly Lys
          145 150 155 160
          Ser Gln Lys Phe Ser Arg Leu Asp Pro Thr Phe Ser Ile Pro Gln Ala
                          165 170 175
          Asn His Ser His Ser Gly Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr
                      180 185 190
          Thr Leu Phe Ser Ser Lys Pro Val Thr Ile Thr Val Gln Val Pro Ser
                  195 200 205
          Met Gly Ser Ser Ser Pro Met Gly Val Ile Val Ala Val Val Ile Ala
              210 215 220
          Thr Ala Val Ala Ala Ile Val Ala Ala Val Val Ala Leu Ile Tyr Cys
          225 230 235 240
          Arg Lys Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys Ala Ala
                          245 250 255
          Gln Phe Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys Arg Gln
                      260 265 270
          Leu Glu Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly Tyr Met
                  275 280 285
          Thr Leu Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile Tyr Leu
              290 295 300
          Thr Leu Pro Pro Asn Asp His Val Asn Ser Asn Asn
          305 310 315
           <![CDATA[ <210> 141]]>
           <![CDATA[ <211> 291]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 141]]>
          Met Gly Ile Leu Ser Phe Leu Pro Val Leu Ala Thr Glu Ser Asp Trp
          1 5 10 15
          Ala Asp Cys Lys Ser Pro Gln Pro Trp Gly His Met Leu Leu Trp Thr
                      20 25 30
          Ala Val Leu Phe Leu Ala Pro Val Ala Gly Thr Pro Ala Ala Pro Pro
                  35 40 45
          Lys Ala Val Leu Lys Leu Glu Pro Gln Trp Ile Asn Val Leu Gln Glu
              50 55 60
          Asp Ser Val Thr Leu Thr Cys Arg Gly Thr His Ser Pro Glu Ser Asp
          65 70 75 80
          Ser Ile Gln Trp Phe His Asn Gly Asn Leu Ile Pro Thr His Thr Gln
                          85 90 95
          Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn Asp Ser Gly Glu Tyr Thr
                      100 105 110
          Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp Pro Val His Leu Thr Val
                  115 120 125
          Leu Ser Glu Trp Leu Val Leu Gln Thr Pro His Leu Glu Phe Gln Glu
              130 135 140
          Gly Glu Thr Ile Val Leu Arg Cys His Ser Trp Lys Asp Lys Pro Leu
          145 150 155 160
          Val Lys Val Thr Phe Phe Gln Asn Gly Lys Ser Lys Lys Phe Ser Arg
                          165 170 175
          Ser Asp Pro Asn Phe Ser Ile Pro Gln Ala Asn His Ser His Ser Gly
                      180 185 190
          Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr Thr Leu Tyr Ser Ser Ser Lys
                  195 200 205
          Pro Val Thr Ile Thr Val Gln Ala Pro Ser Ser Ser Pro Met Gly Ile
              210 215 220
          Ile Val Ala Val Val Thr Gly Ile Ala Val Ala Ala Ile Val Ala Ala
          225 230 235 240
          Val Val Ala Leu Ile Tyr Cys Arg Lys Lys Arg Ile Ser Ala Asn Pro
                          245 250 255
          Thr Asn Pro Asp Glu Ala Asp Lys Val Gly Ala Glu Asn Thr Ile Thr
                      260 265 270
          Tyr Ser Leu Leu Met His Pro Asp Ala Leu Glu Glu Pro Asp Asp Gln
                  275 280 285
          Asn Arg Ile
              290
           <![CDATA[ <210> 142]]>
           <![CDATA[ <211> 254]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 142]]>
          Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Leu Val Ser Ala
          1 5 10 15
          Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
                      20 25 30
          Gln Trp Tyr Arg Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
                  35 40 45
          Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
              50 55 60
          Ser Leu Ile Ser Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
          65 70 75 80
          Val Asp Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
                          85 90 95
          Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln
                      100 105 110
          Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
                  115 120 125
          His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
              130 135 140
          Gly Lys Gly Arg Lys Tyr Phe His His Asn Ser Asp Phe Tyr Ile Pro
          145 150 155 160
          Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Phe
                          165 170 175
          Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
                      180 185 190
          Gly Leu Ser Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln
                  195 200 205
          Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly
              210 215 220
          Leu Tyr Phe Ser Val Lys Thr Asn Ile Arg Ser Ser Thr Arg Asp Trp
          225 230 235 240
          Lys Asp His Lys Phe Lys Trp Arg Lys Asp Pro Gln Asp Lys
                          245 250
           <![CDATA[ <210> 143]]>
           <![CDATA[ <211> 254]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 143]]>
          Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Leu Val Ser Ala
          1 5 10 15
          Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
                      20 25 30
          Gln Trp Tyr Arg Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
                  35 40 45
          Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
              50 55 60
          Ser Leu Ile Ser Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
          65 70 75 80
          Val Asp Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
                          85 90 95
          Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln
                      100 105 110
          Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
                  115 120 125
          His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
              130 135 140
          Gly Lys Gly Arg Lys Tyr Phe His His Asn Ser Asp Phe Tyr Ile Pro
          145 150 155 160
          Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val
                          165 170 175
          Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
                      180 185 190
          Gly Leu Ser Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln
                  195 200 205
          Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly
              210 215 220
          Leu Tyr Phe Ser Val Lys Thr Asn Ile Arg Ser Ser Thr Arg Asp Trp
          225 230 235 240
          Lys Asp His Lys Phe Lys Trp Arg Lys Asp Pro Gln Asp Lys
                          245 250
           <![CDATA[ <210> 144]]>
           <![CDATA[ <211> 233]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 144]]>
          Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Leu Val Ser Ala
          1 5 10 15
          Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
                      20 25 30
          Gln Trp Tyr Arg Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
                  35 40 45
          Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
              50 55 60
          Asn Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
          65 70 75 80
          Val Asp Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
                          85 90 95
          Ser Asp Pro Val Gln Leu Glu Val His Val Gly Trp Leu Leu Leu Gln
                      100 105 110
          Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
                  115 120 125
          His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
              130 135 140
          Gly Lys Asp Arg Lys Tyr Phe His His Asn Ser Asp Phe His Ile Pro
          145 150 155 160
          Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val
                          165 170 175
          Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
                      180 185 190
          Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Ser Pro Pro Gly Tyr Gln
                  195 200 205
          Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly
              210 215 220
          Leu Tyr Phe Ser Val Lys Thr Asn Ile
          225 230
           <![CDATA[ <210> 145]]>
           <![CDATA[ <211> 233]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 145]]>
          Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Leu Val Ser Ala
          1 5 10 15
          Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
                      20 25 30
          Gln Trp Tyr Ser Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
                  35 40 45
          Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
              50 55 60
          Ser Leu Ile Ser Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
          65 70 75 80
          Val Asn Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
                          85 90 95
          Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln
                      100 105 110
          Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
                  115 120 125
          His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
              130 135 140
          Gly Lys Asp Arg Lys Tyr Phe His His Asn Ser Asp Phe His Ile Pro
          145 150 155 160
          Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val
                          165 170 175
          Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
                      180 185 190
          Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Ser Pro Pro Gly Tyr Gln
                  195 200 205
          Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly
              210 215 220
          Leu Tyr Phe Ser Val Lys Thr Asn Ile
          225 230
           <![CDATA[ <210> 146]]>
           <![CDATA[ <211> 404]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> House mouse]]>
           <![CDATA[ <400> 146]]>
          Met Ile Leu Thr Ser Phe Gly Asp Asp Met Trp Leu Leu Thr Thr Thr Leu
          1 5 10 15
          Leu Leu Trp Val Pro Val Gly Gly Glu Val Val Asn Ala Thr Lys Ala
                      20 25 30
          Val Ile Thr Leu Gln Pro Pro Trp Val Ser Ile Phe Gln Lys Glu Asn
                  35 40 45
          Val Thr Leu Trp Cys Glu Gly Pro His Leu Pro Gly Asp Ser Ser Thr
              50 55 60
          Gln Trp Phe Ile Asn Gly Thr Ala Val Gln Ile Ser Thr Pro Ser Tyr
          65 70 75 80
          Ser Ile Pro Glu Ala Ser Phe Gln Asp Ser Gly Glu Tyr Arg Cys Gln
                          85 90 95
          Ile Gly Ser Ser Met Pro Ser Asp Pro Val Gln Leu Gln Ile His Asn
                      100 105 110
          Asp Trp Leu Leu Leu Gln Ala Ser Arg Arg Val Leu Thr Glu Gly Glu
                  115 120 125
          Pro Leu Ala Leu Arg Cys His Gly Trp Lys Asn Lys Leu Val Tyr Asn
              130 135 140
          Val Val Phe Tyr Arg Asn Gly Lys Ser Phe Gln Phe Ser Ser Asp Ser
          145 150 155 160
          Glu Val Ala Ile Leu Lys Thr Asn Leu Ser His Ser Gly Ile Tyr His
                          165 170 175
          Cys Ser Gly Thr Gly Arg His Arg Tyr Thr Ser Ala Gly Val Ser Ile
                      180 185 190
          Thr Val Lys Glu Leu Phe Thr Thr Pro Val Leu Arg Ala Ser Val Ser
                  195 200 205
          Ser Pro Phe Pro Glu Gly Ser Leu Val Thr Leu Asn Cys Glu Thr Asn
              210 215 220
          Leu Leu Leu Gln Arg Pro Gly Leu Gln Leu His Phe Ser Phe Tyr Val
          225 230 235 240
          Gly Ser Lys Ile Leu Glu Tyr Arg Asn Thr Ser Ser Glu Tyr His Ile
                          245 250 255
          Ala Arg Ala Glu Arg Glu Asp Ala Gly Phe Tyr Trp Cys Glu Val Ala
                      260 265 270
          Thr Glu Asp Ser Ser Val Leu Lys Arg Ser Pro Glu Leu Glu Leu Gln
                  275 280 285
          Val Leu Gly Pro Gln Ser Ser Ala Pro Val Trp Phe His Ile Leu Phe
              290 295 300
          Tyr Leu Ser Val Gly Ile Met Phe Ser Leu Asn Thr Val Leu Tyr Val
          305 310 315 320
          Lys Ile His Arg Leu Gln Arg Glu Lys Lys Tyr Asn Leu Glu Val Pro
                          325 330 335
          Leu Val Ser Glu Gln Gly Lys Lys Ala Asn Ser Phe Gln Gln Val Arg
                      340 345 350
          Ser Asp Gly Val Tyr Glu Glu Val Thr Ala Thr Ala Ser Gln Thr Thr
                  355 360 365
          Pro Lys Glu Ala Pro Asp Gly Pro Arg Ser Ser Val Gly Asp Cys Gly
              370 375 380
          Pro Glu Gln Pro Glu Pro Leu Pro Pro Ser Asp Ser Thr Gly Ala Gln
          385 390 395 400
          Thr Ser Gln Ser
           <![CDATA[ <210> 147]]>
           <![CDATA[ <211> 293]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> House mouse]]>
           <![CDATA[ <400> 147]]>
          Met Gly Ile Leu Pro Phe Leu Leu Ile Pro Met Glu Ser Asn Trp Thr
          1 5 10 15
          Val His Val Phe Ser Arg Thr Leu Cys His Met Leu Leu Trp Thr Ala
                      20 25 30
          Val Leu Asn Leu Ala Ala Gly Thr His Asp Leu Pro Lys Ala Val Val
                  35 40 45
          Lys Leu Glu Pro Pro Trp Ile Gln Val Leu Lys Glu Asp Thr Val Thr
              50 55 60
          Leu Thr Cys Glu Gly Thr His Asn Pro Gly Asn Ser Ser Thr Gln Trp
          65 70 75 80
          Phe His Asn Gly Arg Ser Ile Arg Ser Gln Val Gln Ala Ser Tyr Thr
                          85 90 95
          Phe Lys Ala Thr Val Asn Asp Ser Gly Glu Tyr Arg Cys Gln Met Glu
                      100 105 110
          Gln Thr Arg Leu Ser Asp Pro Val Asp Leu Gly Val Ile Ser Asp Trp
                  115 120 125
          Leu Leu Leu Gln Thr Pro Gln Leu Val Phe Leu Glu Gly Glu Thr Ile
              130 135 140
          Thr Leu Arg Cys His Ser Trp Arg Asn Lys Leu Leu Asn Arg Ile Ser
          145 150 155 160
          Phe Phe His Asn Glu Lys Ser Val Arg Tyr His His Tyr Ser Ser Ser Asn
                          165 170 175
          Phe Ser Ile Pro Lys Ala Asn His Ser His Ser Gly Asp Tyr Tyr Cys
                      180 185 190
          Lys Gly Ser Leu Gly Arg Thr Leu His Gln Ser Lys Pro Val Thr Ile
                  195 200 205
          Thr Val Gln Gly Pro Lys Ser Ser Arg Ser Leu Pro Val Leu Thr Ile
              210 215 220
          Val Ala Ala Val Thr Gly Ile Ala Val Ala Ala Ile Val Ile Ile Leu
          225 230 235 240
          Val Ser Leu Val Tyr Leu Lys Lys Lys Gln Val Pro Asp Asn Pro Pro
                          245 250 255
          Asp Leu Glu Glu Ala Ala Lys Thr Glu Ala Glu Asn Thr Ile Thr Tyr
                      260 265 270
          Ser Leu Leu Lys His Pro Glu Ala Leu Asp Glu Glu Thr Glu His Asp
                  275 280 285
          Tyr Gln Asn His Ile
              290
           <![CDATA[ <210> 148]]>
           <![CDATA[ <211> 267]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> House mouse]]>
           <![CDATA[ <400> 148]]>
          Met Thr Leu Asp Thr Gln Met Phe Gln Asn Ala His Ser Gly Ser Gln
          1 5 10 15
          Trp Leu Leu Pro Pro Leu Thr Ile Leu Leu Leu Phe Ala Phe Ala Asp
                      20 25 30
          Arg Gln Ser Ala Ala Leu Pro Lys Ala Val Val Lys Leu Asp Pro Pro
                  35 40 45
          Trp Ile Gln Val Leu Lys Glu Asp Met Val Thr Leu Met Cys Glu Gly
              50 55 60
          Thr His Asn Pro Gly Asn Ser Ser Thr Gln Trp Phe His Asn Trp Ser
          65 70 75 80
          Ser Ile Arg Ser Gln Val Gln Ser Ser Tyr Thr Phe Lys Ala Thr Val
                          85 90 95
          Asn Asp Ser Gly Glu Tyr Arg Cys Gln Met Glu Gln Thr Arg Leu Ser
                      100 105 110
          Asp Pro Val Asp Leu Gly Val Ile Ser Asp Trp Leu Leu Leu Gln Thr
                  115 120 125
          Pro Gln Arg Val Phe Leu Glu Gly Glu Thr Ile Thr Leu Arg Cys His
              130 135 140
          Ser Trp Arg Asn Lys Leu Leu Asn Arg Ile Ser Phe Phe His Asn Glu
          145 150 155 160
          Lys Ser Val Arg Tyr His His Tyr Lys Ser Asn Phe Ser Ile Pro Lys
                          165 170 175
          Ala Asn His Ser His Ser Gly Asp Tyr Tyr Cys Lys Gly Ser Leu Gly
                      180 185 190
          Ser Thr Gln His Gln Ser Lys Pro Val Thr Ile Thr Val Gln Asp Pro
                  195 200 205
          Ala Thr Thr Ser Ser Ile Ser Leu Val Trp Tyr His Thr Ala Phe Ser
              210 215 220
          Leu Val Met Cys Leu Leu Phe Ala Val Asp Thr Gly Leu Tyr Phe Tyr
          225 230 235 240
          Val Arg Arg Asn Leu Gln Thr Pro Arg Asp Tyr Trp Arg Lys Ser Leu
                          245 250 255
          Ser Ile Arg Lys His Gln Ala Pro Gln Asp Lys
                      260 265
           <![CDATA[ <210> 149]]>
           <![CDATA[ <211> 249]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> House mouse]]>
           <![CDATA[ <400> 149]]>
          Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Val Leu Thr Ala Phe Ser
          1 5 10 15
          Gly Ile Gln Ala Gly Leu Gln Lys Ala Val Val Asn Leu Asp Pro Lys
                      20 25 30
          Trp Val Arg Val Leu Glu Glu Asp Ser Val Thr Leu Arg Cys Gln Gly
                  35 40 45
          Thr Phe Ser Pro Glu Asp Asn Ser Ile Lys Trp Phe His Asn Glu Ser
              50 55 60
          Leu Ile Pro His Gln Asp Ala Asn Tyr Val Ile Gln Ser Ala Arg Val
          65 70 75 80
          Lys Asp Ser Gly Met Tyr Arg Cys Gln Thr Ala Leu Ser Thr Ile Ser
                          85 90 95
          Asp Pro Val Gln Leu Glu Val His Met Gly Trp Leu Leu Leu Gln Thr
                      100 105 110
          Thr Lys Trp Leu Phe Gln Glu Gly Asp Pro Ile His Leu Arg Cys His
                  115 120 125
          Ser Trp Gln Asn Arg Pro Val Arg Lys Val Thr Tyr Leu Gln Asn Gly
              130 135 140
          Lys Gly Lys Lys Tyr Phe His Glu Asn Ser Glu Leu Leu Ile Pro Lys
          145 150 155 160
          Ala Thr His Asn Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Ile Gly
                          165 170 175
          His Asn Asn Lys Ser Ser Ala Ser Phe Arg Ile Ser Leu Gly Asp Pro
                      180 185 190
          Gly Ser Pro Ser Met Phe Pro Pro Trp His Gln Ile Thr Phe Cys Leu
                  195 200 205
          Leu Ile Gly Leu Leu Phe Ala Ile Asp Thr Val Leu Tyr Phe Ser Val
              210 215 220
          Arg Arg Gly Leu Gln Ser Pro Val Ala Asp Tyr Glu Glu Pro Lys Ile
          225 230 235 240
          Gln Trp Ser Lys Glu Pro Gln Asp Lys
                          245
           <![CDATA[ <210> 150]]>
           <![CDATA[ <211> 365]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 150]]>
          Met Gly Val Pro Arg Pro Gln Pro Trp Ala Leu Gly Leu Leu Leu Phe
          1 5 10 15
          Leu Leu Pro Gly Ser Leu Gly Ala Glu Ser His Leu Ser Leu Leu Tyr
                      20 25 30
          His Leu Thr Ala Val Ser Ser Pro Ala Pro Gly Thr Pro Ala Phe Trp
                  35 40 45
          Val Ser Gly Trp Leu Gly Pro Gln Gln Tyr Leu Ser Tyr Asn Ser Leu
              50 55 60
          Arg Gly Glu Ala Glu Pro Cys Gly Ala Trp Val Trp Glu Asn Gln Val
          65 70 75 80
          Ser Trp Tyr Trp Glu Lys Glu Thr Thr Asp Leu Arg Ile Lys Glu Lys
                          85 90 95
          Leu Phe Leu Glu Ala Phe Lys Ala Leu Gly Gly Lys Gly Pro Tyr Thr
                      100 105 110
          Leu Gln Gly Leu Leu Gly Cys Glu Leu Gly Pro Asp Asn Thr Ser Val
                  115 120 125
          Pro Thr Ala Lys Phe Ala Leu Asn Gly Glu Glu Phe Met Asn Phe Asp
              130 135 140
          Leu Lys Gln Gly Thr Trp Gly Gly Asp Trp Pro Glu Ala Leu Ala Ile
          145 150 155 160
          Ser Gln Arg Trp Gln Gln Gln Asp Lys Ala Ala Asn Lys Glu Leu Thr
                          165 170 175
          Phe Leu Leu Phe Ser Cys Pro His Arg Leu Arg Glu His Leu Glu Arg
                      180 185 190
          Gly Arg Gly Asn Leu Glu Trp Lys Glu Pro Pro Ser Met Arg Leu Lys
                  195 200 205
          Ala Arg Pro Ser Ser Pro Gly Phe Ser Val Leu Thr Cys Ser Ala Phe
              210 215 220
          Ser Phe Tyr Pro Pro Glu Leu Gln Leu Arg Phe Leu Arg Asn Gly Leu
          225 230 235 240
          Ala Ala Gly Thr Gly Gln Gly Asp Phe Gly Pro Asn Ser Asp Gly Ser
                          245 250 255
          Phe His Ala Ser Ser Ser Leu Thr Val Lys Ser Gly Asp Glu His His
                      260 265 270
          Tyr Cys Cys Ile Val Gln His Ala Gly Leu Ala Gln Pro Leu Arg Val
                  275 280 285
          Glu Leu Glu Ser Pro Ala Lys Ser Ser Val Leu Val Val Gly Ile Val
              290 295 300
          Ile Gly Val Leu Leu Leu Thr Ala Ala Ala Val Gly Gly Ala Leu Leu
          305 310 315 320
          Trp Arg Arg Met Arg Ser Gly Leu Pro Ala Pro Trp Ile Ser Leu Arg
                          325 330 335
          Gly Asp Asp Thr Gly Val Leu Leu Pro Thr Pro Gly Glu Ala Gln Asp
                      340 345 350
          Ala Asp Leu Lys Asp Val Asn Val Ile Pro Ala Thr Ala
                  355 360 365
           <![CDATA[ <210> 151]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <400> 151]]>
          Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser
          1 5 10 15
          Gly Leu Glu Ala Ile Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg
                      20 25 30
          His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser
                  35 40 45
          Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu
              50 55 60
          Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp
          65 70 75 80
          Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp
                          85 90 95
          Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu Ser Gln Pro Lys Ile
                      100 105 110
          Val Lys Trp Asp Arg Asp Met
                  115
           <![CDATA[ <210> 152]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 152]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 153]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 153]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Trp Ala Leu Pro Ala Pro Ile Ser Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 154]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 154]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Leu Leu Ala Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Glu Phe Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Thr Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Glu Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 155]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 155]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Glu Phe Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Thr Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 156]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 156]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Trp Ala Leu Pro Ala Pro Ile Ser Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 157]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 157]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Ala Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Glu Phe Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Thr Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Glu Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 158]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 158]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Glu Phe Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Thr Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 159]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 159]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Ala Ala Leu Pro Ala Pro Ile Ser Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 160]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 160]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Asp Ala Leu Pro Ala Pro Ile Ser Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 161]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 161]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Glu Ala Leu Pro Ala Pro Ile Ser Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 162]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 162]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Met Ala Leu Pro Ala Pro Ile Ser Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 163]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 163]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Ala Ala Leu Pro Ala Pro Ile Ser Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr
          305 310 315 320
          Arg Lys Glu Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 164]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 164]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Ala Ala Leu Pro Ala Pro Ile Ser Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr
          305 310 315 320
          Arg Lys Glu Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 165]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 165]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Ala Ala Leu Pro Ala Pro Ile Ser Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 166]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 166]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr
          305 310 315 320
          Arg Lys Glu Leu Ser Leu Ser Pro
                          325
           <![CDATA[ <210> 167]]>
           <![CDATA[ <211> 328]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic Sequence]]>
           <![CDATA[ <400> 167]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr
          305 310 315 320
          Arg Lys Glu Leu Ser Leu Ser Pro
                          325
          
      

Claims (20)

An isolated antibody that binds to SARS-CoV-2, wherein the antibody comprises: (i) HVR-H1 comprising the amino acid sequence X ₁ YEMN, wherein X ₁ is L, I or S (SEQ ID NO: 109 ), (ii) HVR-H2 comprising the amino acid sequence VISYX ₁ GSNKYYADSVKG, wherein X ₁ is E or D (SEQ ID NO: 110), (iii) comprising the amino acid sequence LITMX ₁ RGX ₂ X ₃ X ₄ HVR-H3, wherein X ₁ is T or V, X ₂ is P or A, X ₃ is D or Q, X ₄ is Y or G (SEQ ID NO: 111), (iv) comprising the amino acid sequence RASQX ₁ HVR-L1 of IX ₂ X ₃ YLN, wherein X ₁ is S or E, X ₂ is S or E, X ₃ is S or D (SEQ ID NO: 112), (v) comprises the amino acid sequence AAX ₁ X ₂ HVR-L2 of LQX ₃ , wherein X ₁ is S or E, X ₂ is S or E, X ₃ is I or G (SEQ ID NO: 113), and (vi) comprises the amino acid sequence QX ₁ SYNLPRT HVR-L3, wherein _Xi is E or Q (SEQ ID NO: 114). The antibody of claim 1, wherein the antibody comprises: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61, 64, 67, 70, 73 or 76, (ii) comprising the amine of SEQ ID NO: 62, 65, 68, 71, 74 or 77 HVR-H2 of amino acid sequence, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63, 66, 69, 72, 75 or 78, (iv) comprising SEQ ID NO: 79, 82, 85 , 88, 91, 94, 97, 100, 103 or 106 of the amino acid sequence of HVR-L1, (v) comprising SEQ ID NO: 80, 83, 86, 89, 92, 95, 98, 101, 104 or HVR-L2 having an amino acid sequence of 107, and (vi) HVR-L3 comprising an amino acid sequence of SEQ ID NO: 81, 84, 87, 90, 93, 96, 99, 102, 105 or 108. An isolated antibody that binds to SARS-CoV-2, wherein the antibody comprises: (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90; (b) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 91, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 92, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 93; (c) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:86, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 87; (d) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:95, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (e) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74, (iii) comprising SEQ ID NO: 75 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:89, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90; (f) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74, (iii) comprising SEQ ID NO: 75 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 91, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 92, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 93; (g) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74, (iii) comprising SEQ ID NO: 75 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:86, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 87; (h) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74, (iii) comprising SEQ ID NO: 75 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:95, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (i) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 77, (iii) comprising SEQ ID NO: 78 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:89, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90; (j) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 77, (iii) comprising SEQ ID NO: 78 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 91, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 92, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 93; (k) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 77, (iii) comprising SEQ ID NO: 78 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:86, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 87; (l) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 77, (iii) comprising SEQ ID NO: 78 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:95, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (m) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62, (iii) comprising SEQ ID NO: 63 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 97, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 98, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 99; (n) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 64, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 65, (iii) comprising SEQ ID NO: 66 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:83, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84; (o) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 76, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 77, (iii) comprising SEQ ID NO: 78 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:83, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84; (p) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74, (iii) comprising SEQ ID NO: 75 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:83, (vi ) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84; (q) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68, (iii) comprising SEQ ID NO: 69 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:83, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84; (r) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68, (iii) comprising SEQ ID NO: 69 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102; (s) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 97, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 98, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 99; (t) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 103, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 104, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 105; (u) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108; (v) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 70, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 71, (iii) comprising SEQ ID NO: 72 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 80, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 81; (w) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62, (iii) comprising SEQ ID NO: 63 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 80, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 81; or (x) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 64, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 65, (iii) comprising SEQ ID NO: 66 HVR-H3 of the amino acid sequence of (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101, and ( vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102. The antibody according to any one of claims 1 to 3, comprising (a) a VH sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NO: 2 to 7; (b) A VL sequence having at least 95% sequence identity to the amino acid sequence of any one of SEQ ID NO: 42 and 44 to 52; or (c) a VH sequence as in (a) and as in (b) VL sequence. The antibody according to claim 4, which comprises the VH sequence of any one of SEQ ID NO: 2 to 7. The antibody according to claim 4 or 5, which comprises the VL sequence of any one of SEQ ID NO: 42 and 44-52. An isolated antibody that binds to SARS-CoV-2, wherein the antibody comprises: (a) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 46, (b) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 47, (c) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 45, (d) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 48, (e) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 46, (f) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 47, (g) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 45, (h) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 48, (i) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 46, (j) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 47, (k) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 45, (l) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 48, (m) the VH sequence of SEQ ID NO: 2 and the VL sequence of SEQ ID NO: 49, (n) the VH sequence of SEQ ID NO: 3 and the VL sequence of SEQ ID NO: 44, (o) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 44, (p) the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 44, (q) the VH sequence of SEQ ID NO: 4 and the VL sequence of SEQ ID NO: 44, (r) the VH sequence of SEQ ID NO: 4 and the VL sequence of SEQ ID NO: 50, (s) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 49, (t) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 51, (u) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 52, (v) the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 42, (w) the VH sequence of SEQ ID NO: 2 and the VL sequence of SEQ ID NO: 42, or (x) VH sequence of SEQ ID NO: 3 and VL sequence of SEQ ID NO: 50. The antibody according to any one of claims 1 to 7, wherein the antibody further comprises a variant Fc region comprising at least one amino acid change relative to the parental Fc region, wherein when compared to the parental Fc region, The variant Fc region has substantially reduced FcγR binding activity and has maintained or increased C1q binding activity. The antibody according to claim 8, wherein the variant Fc region comprises Ala at position 234 according to EU numbering and Ala at position 235 according to EU numbering. The antibody of claim 8 or 9, wherein the variant Fc region comprises an amino acid change at any one of the following (a) to (c): (a) positions 267, 268 and 324; (b) locations 236, 267, 268, 324 and 332; and (c) positions 326 and 333, Wherein the positions are according to the EU number. The antibody according to claim 10, wherein the variant Fc region comprises amino acids selected from the group consisting of the following (a) to (g): (a) Glu at position 267; (b) Phe at position 268; (c) Thr at position 324; (d) Ala at position 236; (e) Glu at position 332; (f) Ala, Asp, Glu, Met or Trp at position 326; and (g) Ser at position 333, Wherein the positions are according to the EU number. The antibody according to any one of claims 8 to 11, wherein the variant Fc region comprises amino acids selected from the group consisting of the following (a) to (f): (a) Ala at position 434; (b) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; (c) Leu at position 428, Ala at position 434 and Thr at position 436 (d) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; (e) Leu at position 428 and Ala at position 434; and (f) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440; Wherein the positions are according to the EU number. A pharmaceutical composition comprising the antibody according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier. The antibody according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13, which is used for treating and/or preventing SARS-CoV-2 infection. A method for treating SARS-CoV-2 infection, comprising administering an effective amount of the antibody according to any one of claims 1 to 12 or the antibody according to claim 13 to an individual suffering from the SARS-CoV-2 infection Pharmaceutical composition. A use of the antibody according to any one of Claims 1 to 12 or the pharmaceutical composition according to Claim 13, for the manufacture of a medicament for treating and/or preventing SARS-CoV-2 infection. An isolated nucleic acid encoding the antibody according to any one of claims 1-12. A host cell or vector comprising the nucleic acid according to claim 17. A method for preparing the antibody according to any one of claims 1 to 12, comprising culturing the host cell according to claim 18. A method of detecting the presence of SARS-CoV-2 in a sample, the method comprising: contacting the sample with the antibody of any one of claims 1 to 12 under conditions that allow the antibody to bind to SARS-CoV-2; detecting whether a complex is formed between the antibody and SARS-CoV-2; wherein the complex formation indicates the presence of SARS-CoV-2 in the sample.

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