TW201215618A - Antibody compositions and methods of use - Google Patents

Abstract

The invention provides compositions comprising anti-gH antibodies and anti-Complex I antibodies as well as methods of using the same.

Description

201215618 Deduction 6. Description of the Invention: [Technical Field of the Invention] The present invention relates to an anti-complex I and an anti-gH antibody and a method of using the same. RELATED APPLICATIONS This application is filed on Sep. 29, 2010, the U.S. Provisional Application Nos. 61/387,735 and 61/387,725, and the U.S. Provisional Application No. 61/504,056 filed on July 1, 2011. These patent applications are hereby incorporated by reference in their entirety. ^ The reference sequence table of the sequence table submitted as the text file via the EFS network is submitted as an ASCII formatted text file along with the specification via the EFS network. The name of the slot file is "P4680Rl_Sequence Listing.TXT", and the creation period is September 2011. One, and the size is 39.9 kilobytes. The Sequence Listing submitted via the EFS network is part of the specification and is hereby incorporated by reference in its entirety. [Prior Art] Human cytomegalovirus (HCMV) is a herpesvirus and is also known as human hemovirus-5 (HHV-5). There are other types of cell giant viruses (CMV) that infect other mammals, such as murine CMV (MCMV), guinea pig CMV (GPCMV), 猿CMV (SCCMV), rhesus (rhesus) CMV (rhCMV) ) and chimpanzee CMV (CCMV). HCMV is a common herpesvirus that infects nearly 50% of the US population. For most human infected individuals, HCMV infection is asymptomatic. However, in the case of disease and immunosuppression (eg HIV infection, drug-induced immunity 158864.doc 201215618 inhibition), HCMV reactivation or primary infection can lead to a variety of clinical manifestations, such as mononucleosis (mononucleosis), hepatitis, retinitis, pneumonia, blindness and organ failure. In addition, in the context of pregnancy, obtaining a primary CMV infection, although having little effect on the mother, has a serious clinical impact in the development of the fetus. Congenital HCMV infection is of particular importance because many children born to mothers infected during pregnancy are infected in the womb and suffer from devastating clinical conditions. In the United States and Europe, 12,600 women have a primary HCMV infection during their surname and thus about 40,000 babies born to their mothers have congenital infections. In the United States, one of 750 children was born with or developed disability due to HCMV infection, including: mental retardation, hearing loss, vision loss, organ defects, and growth defects. Congenital HCMV infection is the most common infectious cause of fetal malformations. There are currently no approved therapies to prevent or treat fetal infections after a primary infection has occurred in a pregnant woman. Therefore, there is a great need in the art to find compositions and methods that prevent congenital HCMV infection. In 2005, Nigro and colleagues published a study on the administration of human CMV hyperimmune globulin (HIG) to pregnant women with primary HCMV infection (Nigro et al., (2005) TVew Eng/· «/· 353: 1350-1362). In one of the studies, only one of the 31 babies born to mothers infected with HCMV was born with a disease, and 7/14 (50%) of the children born to untreated women Born to have HCMV disease. Same as above. During pregnancy, HCMV spreads from the infected mother to the fetus via the placenta. The placenta that anchors the fetus to the uterus contains specialized epithelial cells, nucleus fibroblasts, endothelial cells, and specialized python cells. The HCMV virus surface contains various viral glycoprotein complexes that have been shown to be required for infection of the particular cell type seen in the placenta. The CMV glycoprotein complex (referred to herein as "complex I") containing gH/gL and UL128, UL130 and UL131 is specifically required for infection of endothelial cells, epithelial cells and macrophages. The CMV glycoprotein complex (referred to herein as "complex II") containing gH/gL and gO is specifically required for infection of fibroblasts. HIG has been shown to block the entry of viruses into all four placental cells susceptible to HCMV infection. φ Due to difficulties in the preparation and widespread distribution of HIG and the use of human blood products by pregnant physicians and medical groups specifically in pregnant women, it would be most beneficial to produce a composition comprising one or more monoclonal antibodies that protect the fetus from congenital HCMV infection. . Monoclonal antibody compositions have not been developed to date to prevent maternal-fetal transmission of CMV. Lanzavecchia and Macagno have revealed naturally occurring antibodies isolated from immortalized B cells of infected patients that bind to and neutralize conformal epitopes resulting from the combination of UL130 and UL13 1 or the combination of UL128, UL130 and UL131 CMV Communication (US Specialized Publication No. 2008/0213265 and No. 2009/0081230). Shenk and Wang have disclosed antibodies that bind to the protein of complex I (U.S. Patent No. 7,7,4,510). CMV neutralizing antibodies are also disclosed in U.S. Patent Publication No. 2010-0040602. In addition, anti-gH monoclonal antibody MSL-109 was tested in humans of two patient populations (allogeneic bone marrow transplant recipients and patients with AIDS and CMV retinitis) (Drobyski et al., 51:1 190-1 196 ( 1991); Boeckh et al., 5/ood Marrow 7>α/?5^/α«ί· 7:343-351 (2001); and Borucki et al. 158864.doc 201215618 person 64:103-111 (2004)), Unsuccessful. There is still a need in the art to develop monoclonal antibodies for the prevention of HCMV infection, including congenital HCMV infection. SUMMARY OF THE INVENTION The present invention provides isolated antibodies that specifically bind to HCMV complex I. In certain embodiments, an anti-Complex I antibody of the invention comprises 6 HVRs: (4) HVR-H1 comprising the amino acid sequence SEQ ID: 6; (b) comprising the amino acid sequence SEQ ID NO: 7. HVR-H2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 8; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9; (e) comprising a fragment selected from SEQ ID N : HVR-L2 of the amino acid sequence of 10-19; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. The antibodies may further comprise a light chain variable domain framework FR1 comprising the amino acid sequence SEQ ID NO: 43 and FR2 comprising the amino acid sequence SEQ ID NO: 44. In other embodiments, the anti-complex I of the invention The antibody comprises three heavy chain hypervariable regions (HVR-H1, HVR-H2 and HVR-H3) and three light chain hypervariable regions (HVR-L1, HVR-L2 and HVR-L3), wherein: (a) HVR -H1 comprises the amino acid sequence SEQ ID NO:6; (b) HVR-H2 comprises the amino acid sequence SEQ ID NO:7; (c) HVR-H3 comprises the amino acid sequence SEQ ID NO:8; (d) HVR-L1 comprises the amino acid sequence SEQ ID NO: 9; (f) HVR-L3 comprises the amino acid sequence SEQ ID NO: 20; and (e) the first amine of HVR-L2 and the light chain variable domain framework FR3 The base acid comprises the amino acid sequence SEQ ID NO:21.

In a particular embodiment, the anti-Complex I antibody comprises (a) VH comprising an amino acid sequence of SEQ ID NO: 45 or SEQ ID NO: 46 or SEQ ID 158864. doc -6 - 201215618 NO: 47; b) VL comprising the amino acid sequence SEQ ID NO: 48 or SEQ ID NO: 49. Such antibodies may further comprise a light chain variable domain framework FR3 comprising the amino acid sequence SEQ ID NO: 41 and FR4 comprising the amino acid sequence SEQ ID NO: 42. In some embodiments, the anti-Complex I antibody comprises a VH sequence and amino acid sequence having at least 95% sequence identity to the amino acid sequence SEQ ID NO: 45 or SEQ ID NO: 46 or SEQ ID NO: 47 SEQ ID NO: 48 or SEQ ID NO: 49 has a VL sequence with at least 95% sequence identity. In some embodiments, the antibody comprises a VH comprising the amino acid sequence SEQ ID NO: 45 or SEQ ID NO: 46 or SEQ ID NO: 47. In some embodiments, the anti-Complex I antibody comprises a VL comprising the amino acid sequence SEQ ID NO: 48 or SEQ ID NO: 49. In some embodiments, the anti-Complex I antibody comprises the VH sequence SEQ ID NO: 45 or SEQ ID > 10:46 and the VL sequence SEQ ID NO:49. The invention also provides isolated antibodies that specifically bind to HCMV gH. In some embodiments, the anti-gH antibody of the present invention comprises three heavy chain hypervariable regions (HVR-H1, HVR-H2, and HVR-H3) and three light chain hypervariable regions (HVR-L1, HVR-L2, and HVR-L3), wherein: (a) HVR-H1 comprises the amino acid sequence SEQ ID NO: 71; (b) HVR-H2 comprises a mutation selected from the group consisting of SEQ ID N: 72, SEQ ID NO: 73, 8 £ 10 ; ^0: 74 and 8 £(^10]^0:93 amino acid sequence; (c) HVR-H3 comprises the amino acid sequence SEQ ID NO: 75; (d) HVR-L1 contains an amino acid sequence SEQ ID NO: 76; (e) HVR-L2 comprises the amino acid sequence SEQ ID NO: 77; and (f) HVR-L3 comprises the amino acid sequence SEQ ID NO: 78. 158864.doc 201215618 In some embodiments The anti-gH antibody comprises HVR-H2 comprising the amino acid sequence SEQ ID NO: 93, wherein the amino acid at position 6 of SEQ ID NO: 93 is selected from the group consisting of Ser, Thr, Asn, Gin, Phe 'Met and A group consisting of Leu, and the amino acid at position 8 of SEQ ID NO: 93 is selected from the group consisting of Thr and Arg. In certain embodiments, the anti-gH antibody comprises an amino acid sequence comprising SEQ ID NO: 72. SEQ ID NO: 73 or HVR-H2 of SEQ ID NO: 74. In other embodiments, the anti-gH antibody comprises an amino acid sequence comprising SEQ I D NO: 94 HVR-H2, wherein the sequence comprises an amino acid selected from the group consisting of Ser, Thr, Asn, Gin, Phe, Met and Leu at position 54 (SEQ ID NO: 94). In an embodiment, the antibody further comprises an amino acid selected from the group consisting of Thr and Arg at position 56. The invention also provides an anti-gH having a VH sequence having an amino acid sequence at least 95% identical to SEQ ID NO: 94. An antibody, wherein the sequence comprises the amino acid Asn54, Ser54, Thr54, Gln54, Phe54, Met54 or Leu54 and/or Arg56^ In certain embodiments, the antibody comprises a molecule selected from the group consisting of SEQ ID NO: 87, SEQ ID NO: 88 And VH of the amino acid sequence of SEQ ID NO: 89. In some embodiments, VH comprises an amino acid sequence of 95% identical to SEQ ID NO: 94, wherein the sequence comprises an Asn54, at position 54 The amino acid of Ser54, Thr54, Gln54, Phe54, Met54 or Leu54 and/or contains Arg(Arg56) at position 56; and (b) the VL sequence is at least 95% identical to the amino acid sequence SEQ ID NO:90 Sex. In certain embodiments, VH comprises an amino acid sequence selected from the group consisting of SEQ ID NO:87, SEQ ID NO:88, and SEQ ID NO:89. In some embodiments, VL comprises an amino acid sequence 158864.doc 201215618 column SEQ ID NO:90. In certain embodiments, the antibody comprises the VH sequence SEQ ID NO: 89 and the VL sequence SEQ ID NO: 90.

In certain embodiments, an antibody of the invention specifically binds to HCMV complex I on the surface of HCMV and neutralizes HCMV with an EC90 of 0.1 pg/ml or less. In certain embodiments, the isolated anti-Complex I antibody of the invention specifically binds to HCMV complex I on the surface of HCMV and neutralizes 50% of HCMV at the following antibody concentrations: 0.05 pg/ml, 0·02 Pg/ml, 0.015 pg/ml, 0_014 pg/ml, 0.013 pg/ml, 0.012 pg/ml, 0.011 pg/ml, 0.010 pg/ml, 0_009 pg/ml, 0.008 pg/ml, 0.007 pg/ml, 0.006 Pg/ml, 0.005 pg/ml, 0.004 pg/ml, 0.003 pg/ml, 0.002 pg/ml, 0.001 pg/ml, 0.0009 pg/ml, 0.0008 pg/ml, 0.0007 pg/ml or 0.0007 pg/ml or less ( For example, in the antibody inferiority of 10-8M, ΙΟ·9 Μ, ΙΟ·10 Μ, ΙΟ·11 Μ, ΙΟ·12 Μ, ΙΟ.13 M or ΙΟ·13 M or less). In certain embodiments, an isolated anti-gH antibody of the invention specifically binds to HCMV gH. These antibodies bind to gH on the surface of HCMV and neutralize HCMV with an EC90 of 1 pg/ml or less. The isolated anti-gH antibody of the present invention binds to gH on the surface of HCMV and neutralizes 50% of HCMV at the following antibody concentrations: 0·1 pg/ml, 0.09 pg/ml, 0·08 pg/ml, 0.07 pg/ Ml, 0.06 pg/ml, 0.05 pg/ml, 0.04 pg/ml, 0.03 pg/ml, 0.02 pg/ml, 0.015 pg/ml, 0.014 pg/ml, 0.013 pg/ml, 0.012 pg/ml, 0.011 pg/ Ml, 0.010 pg/ml, 0.009 pg/ml, 0.008 pg/ml, 0.007 pg/ml, 0.006 pg/ml, 0.005 pg/ml, 0.004 pg/ml, 0.003 pg/ml, 0.002 pg/ml, 0.001 158864. Doc • 9- 201215618 pg/ml or less than 0.001 pg/ml (eg at 1〇_8 μ, 1 (Τ9 Μ, ΙΟ·10 Μ, 10·11 Μ, ΙΟ·12 Μ, 10.13 Μ or ΙΟ· The antibody of the present invention may be a monoclonal antibody, including, for example, a human antibody, a humanized antibody or a chimeric antibody. The present invention also provides an antibody fragment that specifically binds to HCMV gH and/or complex I. In a particular embodiment, an antibody that specifically binds to HCMV complex I and/or gH is a full-length IgG1 antibody. The invention also provides an isolated nucleic acid encoding an antibody that specifically binds to HCMV complex I and/or gH. provide A host cell comprising a nucleic acid encoding such antibodies. The invention further provides a method of producing an antibody comprising culturing a host cell comprising a nucleic acid encoding an antibody that specifically binds to the complex and/or antibody to produce the antibody. Further comprising recovering the antibody from the host cell. The invention also provides a medicament comprising an anti-complex antibody, or an anti-gH antibody, or a combination of an anti-complex I antibody and an anti-gH antibody, and a pharmaceutically acceptable carrier Formulations. Pharmaceutical formulations of each antibody may be used alone or in combination. The pharmaceutical formulation may further comprise another therapeutic agent (eg, ganciclovir, foscarnet, sensitization) Valganciclovir and cidoff〇vir. The invention also provides a combination comprising an anti-complex antibody, or an anti-gH antibody, or an anti-complex I antibody and an anti-gH antibody. The composition comprising each antibody may be used alone or in combination. The composition may further comprise another therapeutic agent (eg, ganciclovir, foscarnet, valganciclovir and Multi = 158864.doc 201215618 Wei). The present invention also provides a composition comprising an anti-Complex I antibody and/or an anti-gH antibody for use in inhibiting, treating or preventing HCMV infection. In some embodiments, it is used to inhibit, treat or prevent HCMV infection of a congenital HCMV infection or transplanted tissue, organ or donor or recipient of a tissue or organ transplant infected with HCMV. Other embodiments include transplant recipients for those who have previously been infected with HCMV and are at risk of reactivation. In certain embodiments, the tissue or organ transplant recipient is seronegative for HCMV infection. In certain embodiments, a composition comprising an antibody that binds to HCMV gH is separated from a composition comprising an antibody that binds to HCMV complex I. Compositions comprising an antibody of the invention can also be used in the manufacture of a medicament. The agent can be used to treat, inhibit or prevent HCMV infection, such as inhibiting, preventing or treating HCMV infection in a congenital HCMV infection or transplanted organ, tissue or donor, or an organ or tissue transplant recipient infected with HCMV. In other embodiments, the transplant recipient has previously been infected with HCMV and is at risk of reactivation. In certain embodiments, the agent may further comprise another therapeutic agent (e.g., ganciclovir, foscarnet, valganciclovir, and cidofovir). In certain embodiments, the organ or tissue transplant recipient is seronegative for HCMV infection. In certain embodiments, the composition comprising an antibody that binds to HCMV gH is in the form of a composition separate from the antibody that binds to HCMV complex I. The invention also provides a method of treating, inhibiting or preventing HCMV infection comprising administering to a patient an effective amount of a composition comprising an anti-gH antibody, an anti-complex I antibody, or a combination thereof. The invention also provides a method of treating, inhibiting, or preventing a congenital HCMV infection comprising administering to a pregnant woman an effective amount of a composition comprising an antibody of the invention or a combination thereof. The invention also provides a method of treating a fetus infected with HCMV comprising administering to a pregnant woman an effective amount of a composition comprising an antibody of the invention or a combination thereof. The invention also provides a method of treating an infant infected with HCMV or an infant exposed to HCMV during pregnancy comprising administering to the infant an effective amount of a composition comprising an antibody of the invention or a combination thereof. The invention also provides a method of treating, inhibiting or preventing HCMV infection in an organ or tissue transplant recipient comprising administering to the transplant organ or tissue recipient an effective amount of a composition comprising an antibody of the invention or a combination thereof for treatment, inhibition Or prevention of HCMV infection resulting from an organ or tissue obtained from an organ donor or tissue donor that has received or has been infected with HCMV. Other embodiments include methods used by transplant recipients who have previously been infected with HCMV and are at risk of reactivation. The method of treatment may further comprise administering to the patient another therapeutic agent (e.g., ganciclovir, Foscarnet, valganciclovir, and cidofovir). In certain embodiments, a composition comprising an antibody that binds to HCMV gH is in the form of a composition separate from a composition comprising an antibody that binds to HCMV complex I. In other embodiments, a composition comprising an antibody that binds to HCMV gH is administered concurrently with, prior to, or subsequent to a composition comprising an antibody that binds to HCMV complex I. The invention also provides an anti-Complex I antibody and/or an anti-gH antibody for use in inhibiting, treating or preventing HCMV infection. In some embodiments, it is used to inhibit, treat, or prevent congenital HCMV infection or transplanted tissue, or a tissue or organ transplant recipient who has or has been infected with HCMV. HCMV infection. Other embodiments include transplant recipients for those who have previously been infected with HCMV and are at risk of reactivation. In certain embodiments, the tissue or organ transplant recipient is seronegative for HCMV infection. The antibodies of the invention are useful in the manufacture of pharmaceutical agents. The agent can be used to treat, inhibit or prevent HCMV infection, such as inhibiting, preventing or treating HCMV infection in a congenital HCMV infection or transplanted organ, tissue or donor, or a transplant recipient of HCMV infection. In other embodiments, the transplant recipient has previously been infected with HCMV and is at risk of reactivation. In certain embodiments, the agent may further comprise another therapeutic agent (e.g., ganciclovir, foscarnet, valganciclovir, and cidofovir). In certain embodiments, the organ or tissue transplant recipient is seronegative for HCMV infection. The invention also provides a method of treating, inhibiting or preventing HCMV infection comprising administering to a patient an effective amount of an anti-gH antibody, an anti-Complex I antibody, or a combination thereof. The invention also provides a method of treating, inhibiting or preventing a congenital HCMV infection comprising administering to a pregnant woman an effective amount of an antibody of the invention or a combination thereof. The invention also provides a method of treating a fetus infected with HCMV comprising administering an effective amount of an antibody of the invention or a combination thereof to a pregnant woman. The invention also provides a method of treating, inhibiting or preventing HCMV infection in an organ or tissue transplant recipient comprising administering to the transplant organ or tissue recipient an effective amount of an antibody of the invention or a combination thereof for treating, inhibiting or preventing the cause HCMV infection of an organ or tissue obtained from an organ donor or tissue donor that has been or has been infected with HCMV. Other embodiments include methods used by transplant recipients who have previously been infected with HCMV and are at risk of reactivation. 158864.doc -13- 201215618 The method of treatment may further comprise administering to the patient another therapeutic agent (e.g., ganciclovir, Foscarnet, valganciclovir, and cidofovir). In certain embodiments, an antibody that binds to HCMV gH is administered separately from an antibody that binds to HCMV Complex I. In other embodiments, the antibody that binds to HCMV gH is administered concurrently with, prior to, or subsequent to the antibody that binds to HCMV complex I. In certain embodiments, the organ transplant is a heart, kidney, liver, lung, pancreas, intestine or thymus. In other embodiments, the tissue graft is a hand, a cornea, a skin, a face, islets of langerhans, bone marrow, stem cells, whole blood, platelets, serum, blood cells, blood vessels, heart valves, bones , osteoprogenitor cells, cartilage, Wei stalk, sputum, muscle lining 〇 The present invention also provides an antibody that binds to the same epitope as the anti-gH antibody and/or anti-complex I antibody of the present invention. Other embodiments include an antibody that binds to an epitope of HCMV gH, the epitope comprising an amino acid corresponding to an amino acid selected from the group consisting of: a tryptamine at position 168 of SEQ ID NO: Acid; aspartic acid at position 446 of SEQ ID NO: 1; proline at position 171 of SEQ ID NO: 1; and combinations thereof. Other embodiments include an antibody that binds to an epitope of HCMV complex I, the epitope comprising an amino acid corresponding to an amino acid selected from the group consisting of: at position 47 of SEQ ID NO:203 Branic acid; (ii) an amino acid at position 51 of SEQ ID NO: 203; (iii) aspartic acid at position 46 of SEQ ID NO: 203; and (iv) a combination thereof. Other embodiments include antibodies that bind to a polypeptide of HCMV complex I, wherein the polypeptide comprises 158864.doc -14 - 201215618 amino acid sequence sralpdqtrykyVEqLVdLT lnyhydas (SEQ ID NO: 194). [Comprehensive means] I. Definition For the purposes of this article, "acceptor human framework" is a light chain variable domain (VL) framework comprising a human immunoglobulin framework or a human common framework (as defined below). Or the framework of the amino acid sequence of the heavy chain variable domain (VH) framework. Acceptance from "human immunoglobulin frameworks or human common frameworks" The human human framework may comprise the same amino acid sequence of a human immunoglobulin framework or a human common 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 or less, 3 Or 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework sequence is identical to the VL human immunoglobulin framework sequence or the human co-framework sequence. "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and a binding partner (e.g., an antigen) of the molecule. As used herein, "binding affinity" refers to the inherent binding affinity that reflects the 丨:丨 interaction between members of a binding pair (e.g., an antibody and an antigen), unless otherwise indicated. The affinity of the molecule X for its conjugate Y is usually expressed by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including the methods described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below. An "affinity mature" anti-system refers to a parent antibody that does not have one or more changes in one or more hypervariable regions 158864.doc € 201215618 (HVR), having this in one or more hypervariable regions Such altered antibodies, such changes result in improved affinity of the antibody for the antigen. The terms "anti-complex I antibody" and "antibody I bind to complex I" refer to an antibody capable of binding complex I with sufficient affinity to render the antibody useful as a diagnostic and/or therapeutic agent for targeting complex I. . In one embodiment, the anti-Complex I antibody binds to an unrelated non-complex I protein to a lesser extent than about 10% of the binding of the antibody to Complex I, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the antibody has a dissociation constant (Kd) of $1 μΜ, $100 nM, $10 nM, $1 nM, $0.1 nM, 20.01 nM, or $0.001 nM (eg, 10·8 M or 10·). Below 8 M, for example, ΙΟ·8 Μ to ΙΟ·13 Μ, for example ΙΟ·9 Μ to 1 Ο·13 Μ). In certain embodiments, the anti-Complex I antibody binds to an epitope of the Complex I that is conserved between human CMV isolates. In certain embodiments, the anti-Complex I antibody binds to a conserved epitope of the complex I between CMV strains infected with different species. In certain embodiments, an "anti-Complex I antibody" binds to a conformational epitope of Complex I and, in certain embodiments, an anti-Complex J antibody and an individual protein member of Complex I that is not gH ( That is, the epitope binding within gL, UL128, UL130 or UL131). The terms "anti-gH antibody" and "antibody that binds to gH" refer to an antibody capable of binding gH with sufficient affinity to make the antibody suitable as a diagnostic agent and/or therapeutic agent for targeting gH. In one embodiment, the anti-gH antibody binds to an unrelated non-gH protein to a lesser extent than about 1% of the antibody binds to gH, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the dissociation constant (Kd) of an antibody that binds to 158864.doc •16-201215618 gH is $1, $100 nM, £10 nM, $1 nM, S0.1 nM, $0.01 nM, or $0.001 nM (eg, L〇·8 μ or l〇·8 M or less, for example, 10·8 μ to ι〇-13 Μ, for example, 10·9 M to l〇·13 Μ) ° In some embodiments, anti-gH antibody and imprint Conserved epitope binding between human cmv isolates. In certain embodiments, the anti-§11 antibody binds to an epitope determinant of gH that is conserved between cmv strains of different species. The term "antibody" is used herein in its broadest sense and encompasses various antibody structures including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies), and antibody fragments, as long as they exhibit The desired antigen binding activity can be. "Antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; bifunctional antibodies; line antibodies; single-chain antibody molecules (eg, scFv); A multispecific antibody is formed. An antibody that "binds to the same epitope as a reference antibody" refers to an antibody that blocks the binding of the reference antibody to its antigen by 5% or more in a competitive assay and, conversely, the 5 reference antibody is blocked in the competition assay. The antibody binds to its antigen for up to 50% or more. This document provides an exemplary competition check. The term "chimeric" anti-system refers to a portion of a heavy chain and/or a light chain that is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from antibodies from different sources or species.矣.. 158864.doc -17· 201215618 The “category” of an antibody refers to the type of constant or constant region of its heavy chain. There are five major antibody classes: IgA, IgD, IgE, IgG, and IgM, and several of these classes can be further divided into subclasses (isotypes), such as IgGi, IgG2, IgG3, IgG4, IgA!, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are referred to as α, δ, ε, γ, and μ, respectively.

The term "complex I" as used herein, unless otherwise indicated, refers to a source of macrovirus from any cell, including mammals infected with, for example, primates (eg, humans) and rodents (eg, mice and rats). Any natural complex I of CMV. The term encompasses all combinations of gH, gL, UL128, UL130 and UL131 polypeptides. The term also encompasses naturally occurring variants of the protein of Complex I, such as splice variants or dual gene variants. The amino acid sequence of an exemplary HCMV gH is shown in SEQ ID ΝΟ:1. The amino acid sequence of an exemplary HCMV gL is shown in SEQ ID NO: 2. An exemplary amino acid sequence of HCMV UL 128 is shown in SEQ ID NO:3. An exemplary amino acid sequence of HCMV UL130 is shown in SEQ ID NO:4. An exemplary amino acid sequence of HCMV UL 131 is shown in SEQ ID NO:5. Other exemplary sequences for HCMV gH, gL, UL128, UL130, and UL131 can be found in Genbank Accession No. GU179289 (Dargan et al, Gei F/ro/. 91: 1535-1546 (2010)), which is incorporated by reference in its entirety. SEQ ID NO: 206 (gH), SEQ ID NO: 208 (gL), SEQ ID NO: 205 (UL 128) ' SEQ ID NO: 204 (UL130) and SEQ ID NO: 203 (UL131) ) is included in this article. The term "complex II" as used herein, unless otherwise indicated, refers to a source of macrovirus from any cell, including infections such as primates. 18 158864.doc 201215618

Any natural complex II of CMV in mammals (e.g., humans) and rodents (e.g., mice and rats). This term covers all combinations of gH, gL and gO. The term also encompasses naturally occurring variants of the protein of Complex II, such as splice variants or dual gene variants. The amino acid sequence of an exemplary HCMV gH is shown in SEQ ID ΝΟ:1. The amino acid sequence of an exemplary HCMV gL is shown in SEQ ID NO:2. The amino acid sequence of an exemplary HCMV gO is shown in SEQ ID NO:209. Other exemplary sequences of HCMV gH, gL and gO can be found in Genbank accession number GUI79289 (〇3^&11 et al., 乂6! 烈.6>0/.91:1535-1546 (2〇1〇)) , which is incorporated herein by reference in its entirety, and is incorporated herein by reference to SEQ ID NO,.206 (gH), SEQ ID NO: 208 (gL) and SEQ ID NO: 207 (gO). The term "gH" as used herein, unless otherwise indicated, refers to any natural gH from any vertebrate source, including sprayed animals such as primates (eg, humans) and rodents (eg, mice and rats). . The term covers "full length" unprocessed gH and any form of gH produced by processing in cells. The term also encompasses naturally occurring variants of gH, such as splice variants or dual gene variants. Between the CMV isolates, the amino acid sequence of gH is about 95%. The amino acid sequence of an exemplary HCMV gH is shown in SEQ ID ΝΟ:1. Another exemplary sequence of HCMV gH can be found in Genbank Accession No. GUI 79289 (Dargan et al., /. Gen. Kz'o/. 91: 1535-1546 (2010)), which is incorporated herein by reference in its entirety. Medium, and is included herein as SEQ ID NO: 206 (gH). The term "cytotoxic agent" as used herein refers to a substance which inhibits or prevents the function of cells and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (eg, radioisotopes of At2", I131, I125, Y9〇, Re186, Re188, Sm153, Bi212, Pi pb2^Lu); chemotherapeutic agents or drugs (eg, amidoxime) Meth (methotrexate), adriamicin, vinca alkaloid (vincristine, vinblastine, etoposide), cranberry (doxorubicin), Meiphalan, mitomycin C, chl〇rambucil, daunorubicin or other intercalating agents; growth inhibitors; enzymes and fragments thereof 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 anti-tumor or anti-cancer agents disclosed below. "Effective function" refers to the biological activity attributable to the Fc region of an antibody' which varies with the antibody isotype. Examples of antibody effector functions include: C 1 q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; cell surface receptors (eg, B cells) Receptor) downregulation; and 8 cell activation. An "effective amount" of an agent (e.g., a pharmaceutical formulation) refers to an amount effective to achieve the desired therapeutic or prophylactic result at the required dosage and within the time required. The term "Fc region" is used herein to define the inclusion of an immunoglobulin heavy chain to > a portion of the constant region of the c-terminal region. The term includes native sequence Fc regions and variant Fc regions. In the examples, the human IgG heavy chain Fc region is from ο. % or extend from Pro230 to the slow base of the heavy chain. However, the c-terminus of the region may or may not be present in the amine acid (Lys447). Unless otherwise stated herein, I58864.doc 201215618

The number of amino acid residues in the Fc region or in the strange region is based on the eu numbering system, also known as the EU index 'as Kabat et al., o/Proie/w·? 〇 / / qing m «o / α α / / Price (4) ", 5th edition, pubHc Health Service,

National Institutes of Health, Bethesda, MD, 1991. "Framework" or "FR" refers to a variable domain residue other than a hypervariable region (Hvr) residue. The FR of the variable domain is usually composed of four FR domains: FR1, FR2, FR3, and FR4. Therefore, HVR and FR sequences usually appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4. The terms "full length antibody", "intact antibody" and "complete antibody" are used interchangeably herein to refer to an antibody having a structure substantially similar to a native antibody structure or having a heavy chain comprising an Fc region as defined herein. The terms "host cell," "host cell strain, and r-host cell culture" are used interchangeably and refer to cells into which an exogenous nucleic acid has been introduced, including progeny of such cells. Host cells include "transformants" and "transformed cells", which include primary transformed cells and their derived progeny regardless of the number of passages. The progeny may not be identical in nucleic acid content to the parental cell, but may contain mutations. Mutant progeny having the same function or biological activity as screened or selected in the original transformed cell are included herein. A "human antibody" is an antibody having an amino acid sequence corresponding to an amino acid sequence produced by a human or human cell or derived from an antibody of non-human origin, the non-human source utilizing a human antibody lineage or other human antibody coding sequence. This definition of human antibodies specifically excludes humanized antibodies comprising non-human antigen binding residues. The "human common framework" is the framework representing the most frequently occurring amino acid residues in the framework of human immunoglobulin VL or Vh 158864.doc -21 · 201215618. In general, the human immunoglobulin VL or VH sequence is selected from a subgroup of variable domain sequences. In general, the ’ _ sequence subgroup is as Kabat et al.

Immunological Interest, 5th edition, NIH Publication 91_3242

Bethesda MD (1991), subgroups in volumes 1-3. In one embodiment, for VL, the subgroup is a subgroup κ I as in Kabat et al. (supra). In one embodiment, the subgroup of VH' is subgroup III as in Kabat et al. (supra). A "humanized" anti-system refers to a chimeric antibody comprising an amino acid residue from a non-human HVR and an amino acid residue from a human FR. In certain embodiments, a 'humanized antibody will comprise substantially all of at least 1 and typically 2 variable domains' wherein all or substantially all of the HVRs (eg, CDRs) correspond to HVRs of non-human antibodies, and all or Essentially all FRs correspond to the FR of human antibodies. The humanized antibody may optionally comprise at least a portion of the antibody value region derived from the human antibody. A "humanized form" of an antibody, such as a non-human antibody, refers to an antibody that has been humanized. The term "hypervariable region" or "HVR" as used herein refers to regions of the variable region of the antibody that are highly variable in sequence and/or form a structurally defined loop ("high change loop"). In general, the native four-chain antibody contains 6 HVRs; 3 in VH (HI, H2, H3) and 3 in VL (LI, L2, L3). The HVR typically comprises an amino acid residue from a hypervariable loop and/or from a "complementarity determining region" (cdR), the complementarity determining region having the highest sequence variability and/or involvement in antigen recognition. Exemplary hypervariable loops are present in amino acid residues 26-32 (L 1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-158864. Doc • 22- 201215618 101 (H3). (Chothia and Lesk, J. Μο/· 5ζ·ο/· 196:901-917 (1987)). Exemplary CDRs (CDR-L1, CDR-L2, CDR-L3, CDR-HI, CDR-H2, and CDR-H3) are present in amino acid residues 24-34 of L, amino acid residues 50 of L2. 56. Amino acid residues 89-97 of L3, amino acid residues 31-35B of HI, amino acid residues 50-65 of H2, and amino acid residues 95-102 of H3. (Kabat et al., "Segwences ο/' 〇/

Immunological Interest, 5th Edition Public Health Service, National Institutes of Health, Bethesda, MD (1991)). In addition to CDR1 in VH, CDRs typically comprise an amino acid residue that forms a hypervariable loop. The CDR also contains "specificity determining residues" or "SDR" as residues that contact the antigen. The SDR is included in the region of the CDR called the abbreviated-CDR or a-CDR. Illustrative &-匚011 (&-CDR-L1, a-CDR-L2 ' a-CDR-L3 ' a-CDR-Hl, a-CDR-H2 and a-CDR-H3) are present in the amine of LI Acidic acid residues 31-34, amino acid residues 50-55 of L2, amino acid residues 89-96 of L3, amino acid residues 31-35B of H1, amino acid residues 50 of H2 58 and H3 amino acid residues 95-102. (See Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)). Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al. (supra). An "immunoconjugate" is an antibody that binds to one or more heterologous molecules, including, but not limited to, a cytotoxic agent. "Individual/subject" is a mammal. Mammals include, but are not limited to, domesticated animals (eg, cows, sheep, cats, dogs, and horses), 158864.doc -23- 201215618 primates (eg, humans and non-human primates, such as monkeys), Rabbits and rodents (eg mice and rats). In some embodiments, the individual is a human. As used herein, "infant" means age from birth to no more than about! Individuals within the age range include infants up to approximately 12 months of age. An "isolated" antibody is an antibody that has been separated from components of its natural environment. In some embodiments, the antibody is purified by, for example, electrophoresis (eg, SDS-PAGE electrophoresis, isoelectric focusing (IEF) electrophoresis, capillary electrophoresis) or chromatography (eg, ion exchange or reverse phase HPLC). The purity is greater than %% or μ%. For a review of methods for assessing antibody purity, see, for example, _ grade, 丄 Chromatogr. B U%: 7947 (2QQ7). "Separated" nucleic acid refers to a nucleic acid molecule that has been separated from components of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in a cell that normally contains the nucleic acid molecule' but the nucleic acid molecule is present at a chromosomal location that is extrachromosomic or different from its natural chromosomal location. "Isolated nucleic acid encoding an anti-complex! antibody" means a nucleic acid molecule encoding an antibody heavy and light chain (or a fragment thereof) or a plurality of nucleic acid molecules or individual carriers, and is present in the host : This (etc.) nucleic acid molecule at medium = or multiple positions. An isolated nucleic acid encoding an anti-gH antibody refers to a nucleic acid molecule encoding an antibody heavy bond and light = (or one or more of its nucleic acid molecules 'including a single vector or individual, and is present in The nucleic acid molecule at or at a plurality of locations in the host cell. The term "monoclonal antibody" as used herein refers to a substantially homogeneous anti-158864.doc -24 - 201215618

An antibody obtained by a population of humans, that is, in addition to a possible variant antibody (for example, a variant containing a naturally occurring mutation or a variant produced in the production of a monoclonal antibody, which is usually present in a smaller amount) This population: Individual antibodies are identical and/or bind to the same epitope. Different from the usual pair. The multiple antibody preparations of the different antibodies of the determinant (antigenic determinant) are different, and the individual antibody of the early antibody preparation is directed against a single determinant on the antigen. Therefore, the modifier "single plant" # indicates that the resistance system is substantially homogeneous: the characteristics obtained by the body population, and should not be - required to produce antibodies by any particular party =. For example, monoclonal antibodies to be used in accordance with the present invention can be prepared by a variety of techniques including, but not limited to, fusion knob methods, recombinant DNA methods, phage display methods, and utilization of all or part of human immunoglobulins. Methods of transgenic animal species of protein loci, such methods and other exemplary methods of making monoclonal antibodies are described herein. "Naked antibody" refers to an antibody that does not bind to a heterologous moiety (e.g., a cytotoxic moiety) or a radioactive label. Naked antibodies can be present in pharmaceutical formulations. "Native antibody" refers to a naturally occurring immunoglobulin molecule having a different structure. For example, a native IgG antibody is about 15 Å, a heterotetrameric protein of dalton, consisting of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the (: terminal, each heavy chain has a variable region (VH) 'also known as a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CHI, CH2, and CH3). Similarly, From the n-terminus to the C-terminus, each light chain has a variable region (VL) 'also known as a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody can be based on its constant domain The amino acid sequence is classified into one of two types called κ and λ. 158864.doc 201215618 Drug Description 蚩 芈 f f ” ” Indications, use of hibiscus, information about warnings related to the use of such therapeutic products, dosage, dosing, combination therapy, contraindications and/or phase reference peptide sequence ^ "amino acid sequence - percentage of 'Sense' is in the case where the reference polypeptide sequence is aligned with the candidate sequence and, if necessary, the two gaps are introduced to achieve the maximum sequence--percentage percentage, and without any conservative ft substitutions as part of the sequence-sense, the candidate sequence The ratio of the amino acid residues of the amino acid reference amino acid residues in the reference polypeptide sequence is The purpose of determining the percent identity of the amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megahgn (DNASTAR) software. Those skilled in the art can determine any parameters suitable for the alignment sequence, including any algorithms that are high for achieving maximum alignment over the full length of the sequences being compared. However, for the purposes of this document, the sequence comparison computer program ALIGN is used. -2 to generate amino acid sequence identity percentage values. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and the source code has been included with the instruction manual at the US Copyright Office (u s.

Copyright Office) (Washington D.C., 20559) is filed with the copyright office in the United States copyright registration number TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California) or can be compiled from source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not change. 158864.doc -26 · 201215618 In the case of amino acid sequence comparison using AUGN-2, the amino acid sequence A is assigned to the amino acid sequence A, #, or amino acid sequence relative to the designated amino acid sequence B as follows - % (which may or may not specify amino acid sequence A for, with, or with respect to a given amino acid sequence 8 having or comprising an amino acid sequence identity:

L〇〇x score X/Y

Wherein X is the number of amino acid residues which are scored by the sequence alignment program a L J G N _2 in the alignment of A and B, and wherein ¥ is the total number of amino acid residues in 3. It will be appreciated that when 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 eight and eight will not be equal to the % identity of the amino acid sequence of B and A. All amino acid sequence identity % values used herein are obtained using the ALIGN-2 computer program as described in the previous paragraph, unless otherwise stated. The term "pharmaceutical formulation" refers to a formulation that is in a form that allows the biological activity of the active ingredient contained therein to be effective and that does not contain other components that have unacceptable toxicity to the individual to which the formulation will be administered. ""Pharmaceutically acceptable carrier" means a component of a pharmaceutical formulation that is not toxic to an individual other than the active ingredient. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers or preservatives. As used herein, treatment (and its grammatical variants) refers to a clinical intervention in an attempt to alter the individual being treated, but may be performed for prophylaxis or during the course of clinical pathology. The desired effects of treatment include, but are not limited to, preventing the occurrence or recurrence of the disease, alleviating the symptoms, attenuating the disease = any direct or indirect pathological consequences, preventing metastasis, and reducing the rate of disease progression. 158864.doc -27. 201215618 rate, improvement or Alleviate disease conditions and alleviate or improve prognosis. In some embodiments, the compositions of the invention are useful for delaying the progression of a disease or slowing the progression of a disease or reducing the morbidity of a disease or the severity of a disease condition. The term "variable region" or "variable domain" refers to a domain of an antibody heavy or light chain that binds to an antibody and an antigen. The variable domains of the heavy and light chains of the native antibody (VH and VL, respectively) typically have a similar structure' wherein each domain contains four conserved framework regions (FR) and three hypervariable regions (HVR). (See, for example, Kindt et al., / Magic; 6th Edition, W.H. Freeman and Co., page 91 (2007)) A single VH or VL domain may be sufficient to confer antigen binding specificity. In addition to this φ, an antibody that binds to a specific antigen can be isolated using a library derived from a VH or VL domain of an antibody that binds to the antigen, and a complementary VL· domain or VH domain. See, for example, Portolano et al., / 7 mm « « 〇 / · 150: 880-887 (1993); Clarkson et al, 352: 624-628 (1991). The term "vector," as used herein, refers to a nucleic acid molecule that is capable of proliferating another nucleic acid to which it is linked. The term includes a vector in the form of a self-replicating nucleic acid structure and a vector incorporated into the genome of the host cell into which it is introduced. Certain callers are capable of directing the performance of the nucleic acid to which they are operatively linked. Such vectors are referred to herein as "expression carriers." II. Compositions and Methods In one aspect, the present invention is based, in part, on the discovery of a single antibody that is neutralized by infection with HCMV infection. In some embodiments, provided with the complex! In the case of the combined antibody U, an antibody that binds to gH is provided. The antibodies of the present invention are useful, for example, for the prevention, inhibition, and/or treatment of infection, congenital 158864.doc •28·201215618 HCMV infection and patient infection caused by transplanted tissues infected with HCMV. Antibodies can also be used to diagnose HCMV infection. In one aspect, the invention is also based, in part, on the discovery of compositions comprising a combination of monoclonal antibodies that inhibit HCMV virus entry into all of the cell types of the placenta: endothelial cells, epithelial cells, monocytes/giant Phagocytes and fibroblasts, and reduce and/or inhibit the formation of HCMV resistant strains. In certain embodiments, methods of using such compositions are provided. The compositions of the present invention are useful, for example, for preventing, inhibiting, and/or treating HCMV infection, congenital HCMV infection, and patient infection caused by HCMV-infected transplanted organs or tissues that have been collected from patients previously or currently infected with HCMV. The composition can also be used to diagnose HCMV infection. A. Exemplary Anti-Complex I Antibodies In one aspect, the invention provides isolated antibodies that bind to Complex I. In certain embodiments, the anti-Complex I antibody specifically binds to a conformational epitope produced by association of UL128, UL130, UL131 and gH/gL or an epitope in an individual member of Recombination I . In some embodiments, the EC90 of the anti-Complex I antibody neutralizing HCMV is 0.7 pg/ml, 0.5 pg/ml, 0.3 pg/ml, 0.1 pg/ml, 0.09 pg/ml, 0.08 pg/ml, 0.07 Pg/ml, 0.06 pg/ml, 0.05 pg/ml, 0.04 pg/ml, 0.03 pg/ml, 0.02 pg/ml, 0.015 pg/ml, 0.012 pg/ml, 0.011 pg/ml, 0.010 pg/ml or 0.010 Below pg/ml. In other aspects, the anti-Complex I antibody specifically binds to Complex I on the surface of HCVM and neutralizes 50% HCMV at the following antibody concentrations: 0.05 pg/ml ' 0.02 pg/ml, 0.015 pg/ml, 0.014 Pg/ml, 0.013 158864.doc -29- 201215618 pg/ml, 0.012 pg/ml, 0.011 pg/ml, 0.010 pg/ml, 0.009 pg/ml, 0.008 pg/ml, 0.007 pg/ml, 0_006 pg/ml ' 0.005 pg/ml, 0.004 pg/ml, 0.003 pg/ml, 0.002 pg/ml, 0.001 pg/ml, 0.0009 pg/ml, 0.0008 pg/ml, 0.0007 pg/ml or 0.0007 pg/ml or less (eg in ΙΟ) .8 Μ, ΙΟ—9 Μ, ΙΟ-10 M, 10_11 Μ, 10·12Μ, 10·13Μ or l〇-13M below the antibody concentration). In one aspect, the invention provides an anti-Complex I antibody comprising at least 1, 2, 3, 4, 5 or 6 HVRs selected from the group consisting of: (a) comprising an amino acid sequence SEQ ID NO: 6 HVR-H1; (b) HVR-H2 comprising the amino acid sequence SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 8; (d) comprising an amine HVR-L1 of the acid sequence of SEQ ID NO: 9; (e) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 10-19; and (f) comprising the amino acid sequence SEQ ID NO: 20 HVR-L3. In one aspect, the invention provides an antibody comprising at least one, at least two or all three VH HVR sequences selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 6; (b) HVR-H2 comprising the amino acid sequence SEQ ID NO: 7; and (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 8. In another aspect, the invention provides an antibody comprising at least 1, at least 2 or all 3 VL HVR sequences selected from the group consisting of: (a) comprising an amino acid sequence of 8 £(^10 1^0: 9: 11 ¥ 11-1; (15) HVR-L2 comprising an amino acid sequence selected from the group consisting of 3 ugly 9 10 > 10: 10-19; and (c) comprising the amino acid sequence SEQ ID NO: 20 HVR-L3. 158864.doc • 30- 201215618 In one embodiment, the antibody comprises all three VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 6; HVR-H2 comprising the amino acid sequence SEQ ID NO: 7; and (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 8; and 3 VL HVR sequences selected from: (a) Amino acid sequence HVR-L1 of SEQ ID NO: 9; (b) HVR-L2 comprising the amino acid sequence SEQ ID NO: 10; and (c) HVR-L3 comprising the amino acid sequence SEQ ID NO: 20. In another embodiment, the antibody comprises all three VH HVR sequences selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 6; (b) comprising the amino acid sequence SEQ ID NO HVR-H2 of 7; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 8; and 3 VL HVR sequences selected from the group consisting of: (a) HVR-L1 comprising the amino acid sequence SEQ ID NO: 9; (b) HVR-L2 comprising the amino acid sequence SEQ ID: 11; and (c) comprising the amino acid sequence SEQ ID NO: 20 In another embodiment, the antibody comprises all three HVR sequences selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 6; (b) comprising an amino acid sequence HVR-H2 of SEQ ID NO: 7; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 8; and 3 VL HVR sequences selected from: (a) comprising the amino acid sequence SEQ ID NO: HVR-L1 of 9; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 12; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In another embodiment, The antibody comprises all three VH HVR sequences selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 6; (b) HVR-H2 comprising the amino acid sequence SEQ ID NO: 7; (c) comprising aminoguanidine 158864.doc -31 - 201215618 Sequence SEQ ID NO: 8 HVR-H3; and 3 Vl HVR sequences selected from: (a) comprising an amino acid sequence SEQ ID NO: 9 HVR-L1; (b) HVR-L2 comprising the amino acid sequence SEQ ID NO: 13; and (c) comprising the amino acid sequence SEQ ID NO: 20 HVR-L3. In another embodiment, the antibody comprises all three VH HVR sequences selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 6; (b) comprising the amino acid sequence SEQ ID NO: HVR-H2 of 7; and (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 8; and 3 VL HVR sequences selected from the group consisting of: (a) comprising the amino acid sequence SEQ ID NO: HVR-L1; (b) HVR-L2 comprising the amino acid sequence SEQ ID NO: 14; and (c) HVR-L3 comprising the amino acid sequence SEQ ID NO: 20. In another embodiment, the antibody comprises all three VH HVR sequences selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 6; (b) comprising the amino acid sequence SEQ ID NO: HVR-H2 of 7; and (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 8; and 3 VL HVR sequences selected from the group consisting of: (a) comprising the amino acid sequence SEQ ID NO: HVR_L1; (b) HVR-L2 comprising the amino acid sequence SEQ ID NO: 15; and (c) HVR-L3 comprising the amino acid sequence SEQ ID NO: 20. In another embodiment, the antibody comprises all three VH HVR sequences selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 6; (b) comprising the amino acid sequence SEQ ID NO: HVR-H2 of 7; and (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 8; and 3 VL HVR sequences selected from the group consisting of: (a) comprising the amino acid sequence SEQ ID NO: HVR-L1; (b) HVR-L2 comprising the amino acid sequence SEQ ID NO: 16; and (c) HVR-L3 comprising the amino acid sequence 158864.doc-32-201215618 column SEQ ID NO: 20. In another embodiment, the antibody comprises all three VH HVR sequences selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 6; (b) comprising the amino acid sequence SEQ ID NO: HVR-H2 of 7; and (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 8; and 3 VL HVR sequences selected from the group consisting of: (a) comprising the amino acid sequence SEQ ID NO: HVR-L1; (b) HVR-L2 comprising the amino acid sequence SEQ ID NO: 17; and (c) HVR-L3 comprising the amino acid sequence SEQ ID NO: 20. In another embodiment, the antibody comprises all three VH HVR sequences selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 6; (b) comprising the amino acid sequence SEQ ID NO: HVR-H2; and (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 8; and 3 VL HVR sequences selected from the group consisting of: (a) comprising the amino acid sequence SEQ ID NO: HVR-L1; (b) HVR-L2 comprising the amino acid sequence SEQ ID NO: 18; and (c) HVR-L3 comprising the amino acid sequence SEQ ID NO: 20. In another embodiment, the antibody comprises all three VH HVR sequences selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 6; (b) comprising the amino acid sequence SEQ ID NO: HVR-H2 of 7; and (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 8; and 3 VL HVR sequences selected from the group consisting of: (a) comprising the amino acid sequence SEQ ID NO: HVR-L1; (b) HVR-L2 comprising the amino acid sequence SEQ ID NO: 19; and (c) HVR-L3 comprising the amino acid sequence SEQ ID NO: 20. In some embodiments, the antibody comprises all three VH HVR sequences selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 6; (b) package 158864.doc -33-201215618 amine-containing HVR-H2 of SEQ ID NO: 7; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 8; and 3 VL HVR sequences selected from the group consisting of: (a) comprising an amino acid The sequence HVR-L1 of SEQ ID NO: 9; (b) the first amino acid comprising the HVR-L2 and the light chain variable region framework FR3 of the amino acid sequence SEQ ID NO: 21; and (c) comprising an amine group Acid sequence HVR-L3 of SEQ ID NO:20. In certain embodiments, any one or more of the amino acids of the anti-Complex I antibody provided above are substituted at the following HVR position: at 11 --L2 (SEQ ID NO: 10) t: position 4, 5, 11 and 12. In certain embodiments, the substitution is a conservative substitution as provided herein. In certain embodiments, any one or more of the following substitutions can be made in any combination: in HVR-L2 (SEQ ID NO: 57): D4E, D4T, D4S, G5A, D11E, D11T, D11S, and G12A. All possible combinations of the above substitutions are encompassed by the common sequence of SEQ ID NO:21. In any of the above embodiments, the anti-Complex I antibody is humanized. In one embodiment, the anti-Complex I antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework. In another embodiment, the anti-Complex I antibody comprises an HVR as in any of the above embodiments, and further comprising FR1 sequence SEQ ID NO: 22, FR2 sequence SEQ ID NO: 23, FR3 sequence SEQ ID NO: 24 and FR4 sequence VH of SEQ ID NO:25. In other embodiments, the anti-Complex I antibody comprises an HVR as in any of the above examples, and further comprising FR1 sequence SEQ ID NO: 22, FR2 sequence SEQ ID NO: 27, FR3 sequence SEQ ID NO: 28 and FR4 Sequence VH of SEQ ID NO:29. In other embodiments, the anti-Complex I antibody comprises an HVR as in any of the above examples, as in 158864.doc-34-201215618, and further comprising FR1 sequence SEQ ID NO: 30, FR2 sequence SEQ ID NO: 3 1 , FR3 Sequence SEQ ID NO: 32 and FR4 sequence SEQ ID NO: 25 VH. In other embodiments, the anti-Complex I antibody comprises an HVR as in any of the above examples, and further comprising FR1 sequence SEQ ID NO: 33, FR2 sequence SEQ ID NO: 23, FR3 sequence SEQ ID NO: 34 and FR4 Sequence VH of SEQ ID NO:25. In another embodiment, the anti-Complex I antibody comprises an HVR as in any of the above embodiments, and further comprising FR1 sequence SEQ ID NO: 35, FR2 sequence SEQ ID NO: 36, FR3 sequence SEQ ID NO: 37 and VL of the FR4 sequence of SEQ ID NO:38. In other embodiments, the anti-Complex I antibody comprises an HVR as in any of the above examples, and further comprising the FR1 sequence SEQ ID NO: 39 ' FR2 sequence SEQ ID NO: 40, FR3 sequence SEQ ID NO: 41 and FR4 VL of the sequence SEQ ID NO:42. In other embodiments, the anti-Complex I antibody comprises an HVR as in any of the above examples, and further comprising FR1 sequence SEQ ID NO: 43, FR2 sequence SEQ ID NO: 44, FR3 sequence SEQ ID NO: 41 and FR4 VL of the sequence SEQ ID NO:42. In any of the above antibodies, the VL FR3 sequence may be substituted with a sequence selected from SEQ ID NO: 67 or SEQ ID NO: 68. In another aspect, the anti-Complex I antibody comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96 with the amino acid sequence SEQ ID NO: 46 or SEQ ID NO: 47. %, 97%, 98°/〇, 99% or 100% sequence identity heavy chain variable domain (VH) sequences. In certain embodiments, the sequence apos has at least 90%, 91%, 92%, 93%, 941⁄4, 95°/ relative to reference 158864.doc -35 - 201215618. The 96%, 97%, 98%, or 99% homologous VH sequence contains a substitution (e.g., a conservative substitution), an insertion or a deletion, but the anti-complex 1 antibody comprising the sequence retains the ability to bind to complex I. In certain embodiments, in SEQ ID NO: 45 or SEQ ID NO: 46 or SEQ ID NO: 47, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted. In some embodiments 'replacement, insertion or deletion occurs in the outer region of the HVR (i.e., in the FR). In a specific embodiment, the VH comprises 1, 2 or 3 HVRs selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 6, and (b) comprising the amino acid sequence SEQ ID NO: 7 HVR-H2, and (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 8. In another aspect, an anti-Complex I antibody is provided, wherein the antibody comprises at least 90%, 91%, 92% '93%, 94 with the amino acid sequence SEQ ID NO: 48 or SEQ ID NO: 49 % '95%, 96% '97%, 98%, 99°/◦ or 100% sequence identity of the light chain variable domain (VL). In certain embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 960/〇, 97%, 98%, or 99%-dependent VL sequences relative to a reference sequence An anti-Complex I antibody comprising a substitution (eg, a conservative substitution), an insertion or a deletion, but comprising the sequence retains the ability to bind to Complex I. In certain embodiments: in SEQ ID NO: 48 or SEQ ID NO: 49, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted. In some embodiments, a substitution, insertion or deletion occurs in the outer region of the HVR (i.e., in the FR). In a particular embodiment, the VL comprises 1, 2 or 3 HVRs selected from the group consisting of: (a) HVR-L1 comprising the amino acid sequence SEQ ID NO: 9; (b) I58864.doc-36- 201215618 HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-19; and (c) HVR-L3 comprising the amino acid sequence SEQ ID NO: 20. In another aspect, an anti-Complex I antibody is provided, wherein the antibody comprises VH as in any of the examples provided above, and Vl in any of the examples provided above. In one embodiment, the antibody comprises the VH and VL sequences set forth in SEQ ID NO: 45 and SEQ ID NO: 49, respectively, including post-translational modifications of the sequences. In one embodiment, the antibody comprises the VH and VL sequences set forth in SEQ ID NO: 46 and SEQ ID NO: 49, respectively, including post-translational modifications of the sequences. In another embodiment, the antibody comprises the VH and V1 sequences of SEQ ID NO: 47 and SEQ ID NO: 49, respectively, including post-translational modifications of the sequences. In another embodiment, the antibody comprises the VH and V1 sequences of SEQ ID NO: 45 and SEQ ID NO: 48, respectively, including post-translational modifications of the sequences. In another embodiment, the antibody comprises the sequence of ¥1 and 乂1^, respectively, in SEQ ID > 10:46 and 8 £(^10>10:48, including post-translational modifications of the sequences. In one embodiment, the antibody comprises the VH and V1 sequences of SEQ ID NO: 47 and SEQ ID NO: 48, respectively, including post-translational modifications of the sequences. In another aspect, the invention provides An antibody against which the anti-Complex I antibody competes and/or binds to the same epitope as the anti-Complex I antibody provided herein. For example, in certain embodiments, a competition with an anti-Complex I antibody is provided and/or An antibody that binds to the same epitope as the anti-Complex I antibody, the anti-Complex I antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 45-47 and comprising an amino acid sequence of SEQ ID NO: 48 or SEQ ID NO In another aspect, the present invention provides an antibody which binds to the same epitope as an anti-Complex 1 antibody, the epitope comprising an amino group corresponding to an amine group selected from the group consisting of Acidic amino acid: glutamic acid at position 47 of the amino acid of SEQ ID N: 203;卩ID NO: an amino acid at position 51 of the amino acid of 203; aspartic acid at position 46 of SEQ ID NO: 203 and combinations thereof. The corresponding amino acid constituting the epitope may be The approximate position in the UL13 1 amino acid sequence is similar, but can be attributed to the difference in the amino acid sequence of UL 13 1 between various HCMV strains. In another aspect, the present invention provides a complex with HCMV An antibody that binds to a polypeptide of I, wherein the polypeptide comprises the amino acid sequence SRALPDQTRYK YVEQLVDLTLNYHYDAS (SEQ ID NO: 194). In another aspect, the invention provides a same epitope as the anti-Complex I antibody provided herein. In other aspects, the invention provides an antibody that binds to the same epitope as the anti-Complex I antibody provided herein, having an EC90 of 0.7 pg/ml, 0.5 pg/ml, 0.3 pg/ml, 0.1 pg/ Ml, 0.09 pg/ml, 0.08 pg/ml, 0.07 pg/ml ' 0.06 pg/ml, 0.05 pg/ml, 0.04 pg/ml, 0.03 pg/ml ' 0.02 pg/ml, 0.015 pg/ml, 0.012 pg/ Ml, 0.011 pg/ml, 0.010 0 L / 1111 or 〇.〇1〇48/11 [11 or less. In other aspects, the invention provides An antibody that binds to the same epitope as the anti-Complex I antibody provided herein and neutralizes 50% of HCMV at the following antibody concentrations: 0.05 pg/ml, 0.02 gg/ml, 0.015 pg/ml, 0.014 pg/ml, 0.013 pg/ml, 0.012 pg/ml, 0.011 pg/ml, 0.010 pg/ml, 0.009 pg/ml, 0.008 pg/ml, 0.007 pg/ml, 0.006 pg/ml, 0.005 pg/ml, 158864.doc -38 - 201215618 0.004 pg/ml, 0.003 pg/ml, 0.002 pg/ml, 0.001 pg/mi, 0.0009 pg/m b 0.0008 pg/m b 0.0007 pg/mi or 0.0007 gg/ml or less (eg in ΙΟ·8 Μ, 10·9 M, l〇·10 Μ, 10·" M, 10.12 M, l〇_13 M or 1 (at an antibody concentration of T13 M or less). In another aspect of the invention, the anti-Complex I antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric antibody, a humanized antibody or a human antibody. In one embodiment, the anti-complex is "filled with an antibody fragment, such as an Fv, Fab, Fab', scFv, bifunctional antibody or F(aly) 2 fragment. In another embodiment, the antibody is a full length antibody, For example, a full IgGl antibody or other antibody class or isotype as defined herein. In another aspect, the anti-complex antibody according to any of the above examples may have any of the characteristics as described in Section -7 below. One or any combination of features. B. Exemplary Anti-gH Antibodies In one aspect, the invention provides isolated antibodies that bind to gH. In certain embodiments, the anti-gH antibody specifically binds to the antigen of gH And neutralize HCMV 'EC90 is 0.8 pg/nU, 〇.7 μ§/ιη1, 〇6 μ§Λη1, 〇5 pg/m Bu0·4 pg/m 〇·3 pg/mh 〇2 ton岫卜〇"^/m卜〇〇9

Kg/nd, 0.08 _ml, 0.07 _ml, 〇 〇 6 tons (five), 〇 〇 5 Kg/rni, 0.04 pg/ml, 0.03 盹 (five), 〇 ^ 2 ^/m丨, 〇 〇1

Pg/mbu 0.015盹/(6), 〇.〇1〇 ^/m丨 or 〇〇1〇(4) below the claw. In some embodiments, the anti-gH antibody specifically binds to the epitope of §11/dimer produced in baculovirus 'IC5(^Q()i to 〇ΗnM. In the embodiment, IC5〇 can be 〇.〇ι ηΜ, 〇·〇2 —ν 158864.doc •39- 201215618 nM, 0.03 touch, 0.04 nM, 0.05 nM, 0.06 nM, 0.07 nM, 0.08 nM, 0.09 should 0.1 nM, 0.11 nM, 0.12 nM, 0.13 nM, 0.14 vesicle, 0.15 nM, 0.16 nM or 0-17 nM. In other embodiments, the antibody binds to gH on the surface of HCMV and neutralizes 50% of HCMV at the following antibody concentrations : 0.1 pg/ml, 0.09 pg/ml, 0.08 pg/mi, ο·.? pg/ml, 0.06 | ig/ml, 0.05 | ig/ml, 0.04 pg/ml, 0.03 pg/mi, 0.02 pg/ml , 0.015 pg/ml, 0.014 pg/ml, 0.013 pg/mi, 0.012 pg/ml, 0.011 pg/ml, 0.010 Kg/ml, 0.009 pg/ml, 0.008 pg/ml, 0.007 pg/ml, 0.006 Pg/ml , 0.005 pg/ml, 0.004 pg/ml, 0.003 pg/ml, 0.002 pg/m, o.ooi eg/ml4〇0 (H pg/ml or less (for example, i〇·9 Μ, ΙΟ·1.μ, ΙΟ · 丨1 Μ, ΙΟ·12 Μ, ΙΟ·13 M or 10·丨3 M below the antibody concentration). In one aspect, the invention provides an anti-gH antibody comprising at least 1, 2, 3, 4, 5 or 6 HVRs selected from the group consisting of: (a) comprising an amino acid sequence SEQ ID NO: HVR-H1 of 71; (b) HVR-H2 comprising an amino acid sequence selected from SEQ ID NO: 72, 73 or 74; (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 75; d) HVR-L1 comprising the amino acid sequence SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence SEQ ID NO: 77; and (f) comprising the amino acid sequence SEQ ID NO: 78 HVR-L3. In one embodiment, the invention provides an antibody comprising at least 1, at least 2 or all 3 VH HVR sequences selected from: (a) comprising an amino acid sequence SEQ ID NO: 71 HVR-H1; (b) HVR-H2 comprising the amino acid sequence SEQ ID NO: 72; and (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 75 158864. doc • 40-201215618. In another embodiment, the antibody comprises at least 1, at least 2 or all 3 VH HVR sequences selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 71; (b) comprising Amino acid sequence HVR-H2 of SEQ ID NO: 73; and (c) HVR-H3 comprising the amino acid sequence SEQ ID NO:75. In another embodiment, the antibody comprises at least 1, at least 2 or all 3 VH HVR sequences selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 71; (b) comprising Amino acid sequence HVR-H2 of SEQ ID NO: 74; and (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 75. In another aspect, the invention provides an antibody comprising at least 1, at least 2 or all 3 VL HVR sequences selected from: (a) HVR-L1 comprising the amino acid sequence SEQ ID NO: 76 (b) HVR-L2 comprising the amino acid sequence SEQ ID NO: 77; and (c) HVR-L3 comprising the amino acid sequence SEQ ID NO: 78; and comprising SEQ ID NO: 72, SEQ ID NO: 73 or HVR-H2 of the amino acid sequence of SEQ ID NO: 74. In another aspect, the invention provides an antibody comprising (a) a VH domain comprising at least 1, at least 2 or all 3 VH HVR sequences selected from: (i) comprising an amino acid sequence SEQ ID NO HVR-H1 of 71; (ii) 11乂11-112 comprising an amino acid sequence selected from SEQ ID NO: 72, SEQ ID NO: 73 or SEQ ID NO: 74, and (丨丨〇 comprises a selected from 8£()10 1\[〇: HVR-H3 of the amino acid sequence of 75; and (b) a VL domain comprising at least 1, at least 2 or all 3 VL HVR sequences selected from: (i HVR-L1 comprising the amino acid sequence SEQ ID NO: 76, (ii) HVR-L2 comprising the amino acid sequence SEQ ID NO: 77, and (c) comprising the amino acid sequence SEQ ID NO: 78 158864.doc •41 - 201215618 HVR-L3. In another aspect, the invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 71; (b) comprising Amino acid sequence 8 〇 10 1 ^ 0: 72 of 11 乂 11-112; ((:) contains amino acid sequence 3 £ (5 10 NO: 75 of HVR-H3; (d) contains amino acid sequence HVR-L1 of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence SEQ ID NO: 77; and (0 comprising selected from 3 卩1 1^〇: The amino acid sequence of 78 is 11¥11-1^3. In another aspect, the invention provides an antibody comprising: (a) an HVR comprising the amino acid sequence SEQ ID NO: 71 - (H) HVR-H2 comprising the amino acid sequence SEQ ID NO: 73; (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 75; (d) comprising the amino acid sequence SEQ ID NO : 76 of 11 ¥ 11-1 ^ 1; (6) contains amino acid sequence 8 £ (^10 1 ^ 0: 77 of 11 ¥ 11-1 ^ 2; and (f) comprises selected from SEQ ID NO: 78 In another aspect, the invention provides an antibody comprising: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 71; (b) comprising an amine group Acid sequence SEQ ID NO: 74 HVR-H2; (c) HVR-H3 comprising the amino acid sequence SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence SEQ ID NO: 76; ) HVR-L2 comprising the amino acid sequence SEQ ID NO: 77; and (f) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 78. In certain embodiments, any one or more of the amino acids of the anti-gH antibody provided above are substituted at the HVR position: in HVR-H2 (SEQ ID NO: 91): positions 6 and 8. In certain embodiments, the substitution is a conservative substitution as provided herein. In certain embodiments, any one or more of the following substitutions can be made in any combination: in HVR-H2 (SEQ ID ΝΟ··91): 158864.doc -42- 201215618 D6S, D6T, D6N, D6Q, D6F, D6M, D6L and T8R. All possible combinations of the above substitutions are encompassed by the common sequence of SEQ ID NO:93. In any of the above embodiments, the anti-gH antibody is humanized. In one embodiment, the anti-gH antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework. In another embodiment, the anti-gH antibody comprises HVR as in any of the above examples, and further comprising FR1 sequence SEQ ID N〇:79, FR2 sequence SEQ ID NO:80, FR3 sequence SEQ ID NO:81 and FR4 Sequence VH of SEQ ID NO:82. In other embodiments, the anti-gH antibody comprises HVR as in any of the above examples, and further comprising SEQ ID NO: 83, FR2 sequence SEQ ID NO: 84, FR3 sequence SEQ ID NO: 85 and FR4 sequence SEQ ID NO: VL of 86. In another aspect, the anti-gH antibody of the invention comprises at least 90°/〇, 91%, 92%, 93%, 94%, 95%, 96%, 97 with the amino acid sequence SEQ ID NO:92. %, 98%, 99% or 100% sequence identity but wherein the amino acid at position 54 is Asn(N) and/or the heavy chain variable domain in which the amino acid at position 56 is Asn(R) ( VH) sequence. In certain embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the VH sequence is contained relative to the reference sequence. Substitutions (eg, conservative substitutions), insertions or deletions, but the anti-gH antibodies comprising the sequence retain the ability to bind to gH. In certain embodiments, in SEQ ID NO: 92, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted, but wherein the amino acid at position 54 is Asn(N) and/or The amino acid at position 56 is Asn(R). In some embodiments, substitutions, insertions, or deletions occur in the outer region of the HVR (i.e., in the FR). Depending on the case, the anti-Lu 11 antibody is included in the VH sequence of 8 £(^1〇]^0:87, 8 £(5 1〇]^0:88 or 8 ugly (^1〇NO:89, including Post-translational modification of the sequence. In a particular embodiment, the VH comprises 1, 2 or 3 HVRs selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 71, (b) ) comprising HVR-H2 selected from the group consisting of SEQ 10 1^0:72, 8 £(^10 1^0:73 and 8 ugly (5 10 1^0:74 amino acid sequence, and (c) comprising an amine group The acid sequence SEQ ID NO: 75 of HVR-H3. In another aspect, the anti-gH antibody of the invention comprises at least 90%, 91%, 92%, 93%, 94% of the amino acid sequence SEQ ID NO: a light chain variable domain (VL) of 95%, 96%, 97%, 98%, 99% or 100% sequence identity. In certain embodiments, at least 90%, 91% relative to a reference sequence , 92%, 93%, 94%, 95%, 96%, 97% '98% or 99% of the VL sequence contains a substitution (eg, a conservative substitution), an insertion or a deletion, but contains the anti-gH of the sequence. The antibody retains the ability to bind to gH. In certain embodiments, in SEQ ID NO: 90, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted. In some embodiments, the substitution, insertion or deletion occurs in the outer region of the HVR (ie, in the FR). As the case may be, the anti-gH antibody is included in the VL sequence 歹 ij in SEQ ID NO: 90, including the sequence Post-translational modification. In a particular embodiment, VL comprises 1, 2 or 3 HVRs selected from the group consisting of: (a) HVR-L1 comprising the amino acid sequence SEQ ID NO: 76; (b) comprising an amine HVR-L2 of the SEQ ID NO: 77; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78. In another aspect, the anti-gH antibody of the invention comprises as provided above 158864.doc -44-201215618 The VH of the embodiment and the VL of any of the above provided examples. In one embodiment, the antibody comprises VH of SEQ ID NO: 87 and SEQ ID NO: 90, respectively. VL sequences, including post-translational modifications of their sequences. In another embodiment, the antibodies comprise the VH and VL sequences of SEQ ID NO: 88 and SEQ ID NO: 90, respectively, including post-translational modifications of the sequences. In another embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 89 and SEQ ID NO: 90, respectively, including post-translational modifications of the sequences. Aspect, the present invention provides an anti-gH provided herein, one kind of antibody that competes with and / or provided with an anti-gH antibody herein binds to the same epitope of an antibody. For example, in certain embodiments, an antibody that competes with an anti-gH antibody and/or binds to an anti-gH antibody comprising an amino acid sequence comprising SEQ ID NO: 87, 88 is provided. Or a VH of 89 and a VL comprising the amino acid sequence SEQ ID NO:90. In another aspect, the invention provides an antibody that binds to the same epitope as an anti-gH antibody, the epitope comprising an amino acid corresponding to an amino acid selected from the group consisting of the amine of SEQ ID NO: The tryptophan acid at position 168; the aspartic acid at position 446 of the amino acid of SEQ ID NO: 1; the proline at position 171 of the amino acid of SEQ ID NO: 1, and combinations thereof. The corresponding amino acid constituting the epitope may be at approximately the same position in the gH amino acid sequence, but may be attributable to differences in the amino acid sequence of gH between the various HCMV strains. In other aspects, the invention provides an antibody that binds to the same sputum determinant as the anti-gH antibody 158864.doc-45-201215618 provided herein, in the range of 〇1 nM to 〇17 nM. In various embodiments, lew can be 017 „ elbow or 017 ηΜα under 'eg, 0.16 ηΜ, 0·15 nM, 〇.l4 ηΜ, 〇13 ηΜ, 0.12 ηΜ, 0.11 ηΜ, 0.10 ηΜ, 0.09 ηΜ, (j og ηΜ, 〇〇7 囊, 0·06 ηΜ, 0,05 ηΜ, 0.G4 ηΜ, 〇·〇3 ηΜ, 0.02 ηΜ, 0.01 ηΜ or 0.01 ηΜ or less. For example, in some embodiments, An anti-gH antibody that binds to HB1 (the VH sequence comprising SEQIE) N0:89 and VL sequence SEQ ID:90) and 1 (:5〇 is 〇17 ηΜ or 0.17 ηΜ or less (eg 0.16 ηΜ, 0.15 ηΜ, 0.14 ηΜ, 0.13 ηΜ, 0.12 ηΜ, 0.11 ηΜ, 0.10 ηΜ, 〇·〇9 ηΜ, 0.08 ηΜ, 0.07 ηΜ ' 0.06 ηΜ ' 0.05 ηΜ ' 〇.〇4 ηΜ ' 0.03 ηΜ > 〇.〇2 The EC90 of ηΜ, 0.01 ηΜ or 〇·〇1 ηΜ) or neutralizing HCMV infection is 0.8 pg/ml, 0.7 pg/m 〇·6 pg/nU, 〇·5 pg/m 卜 0.4 pg/ml, 0.3 Pg/ml, 0.2 pg/ml, 0.1 pg/ml, 〇〇9 μ8/ηι1, 〇〇8 pg/ml, 0·07 pg/ml, 0.06 pg/mi, 〇·〇5 pg/ml, 〇〇 4 pg/ml, 0.03 pg/ml, 0.02 pg/ml An antibody of 0. 01 μ§/πιι, 〇〇15 pg/ml, 0.010 pg/ml or 0.010 pg/mi or less. In other aspects, the invention provides the same antigenic binding as the anti-gH antibody provided herein. An antibody that neutralizes 5 % of HCMV at the following antibody concentrations: 0.1 pg/mi, 〇.〇9 pg/mi, 〇, 〇8 pg/ml, 0.07 pg/ml, 0_06 pg/ml, 〇· 〇5 pg/ml, 〇.〇4 pg/ml, 0.〇3 pg/rril, 0.02 pg/ml, 0.015 pg/ml, 0.014 pg/ml, Ο.Ο13 pg/ml, 0.012 pg/ml, 0.011 Pg/ml, (K010 pg/mi, 〇.〇〇9 pg/ml, 0.008 pg/ml, 0.007 pg/ml, 0.006 pg/ml, 0.005 I58864.doc -46- 201215618 pg/ml, 0.004 pg/ml , 0.003 pg/ml, 〇·〇〇2 pg/ml, 0.001 pg/ml or 0.001 pg/ml or less (for example, at 1〇·8μ, 10-9M, 10·10Μ, 1 (Γ11 Μ, 1 (Γ12 Μ , 1 〇 13 Μ or 10-13 Μ below the antibody concentration). In another aspect of the invention, the anti-gH antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric antibody, a humanized antibody or a human antibody. In one embodiment, the anti-gH antibody is an antibody fragment, such as an Fv, Fab, Fab, scFv, bifunctional antibody or F(ab,) 2 fragment. In another embodiment the antibody is a full length antibody, such as an intact IgG 1 antibody or other antibody class or isotype as defined herein. In another aspect, the anti-gH antibody according to the above examples may be combined with any one of the features described in Sections 1-7 below or any combination of features. Antibody Affinity In certain embodiments, the dissociation constant (Kd) of an antibody of the invention as provided herein is $1 μΜ, $100 nM, S10 nM, SI nM, $0.1 nM, 50.01 nM or 50.001 nM (eg i〇-8 ^ ^ or 1〇-8 M or less, for example, from 10 8 10 to 10 13 Μ, for example, from 1〇·9 μ to 1 〇·13 Μ). In the examples, Kd was measured by the Fab format of the relevant antibody and its radiolabeled antigen binding assay (RIA) as described for the antigens described below. Fab is equilibrated by labeling the antigen with a minimum concentration (Ι25ι) in the presence of a titration series of unlabeled antigens, and then the bound antigen is captured by an anti-Fab antibody coated plate to measure the solution binding affinity of the Fab to the antigen. (See, for example, Chen et al., j M〇/price 〇 / 293:865 881 (1999)). To establish the assay conditions, micr〇titer® multiwell plate 201215618 (Thermo Scientific) was coated overnight with 50 mM sodium carbonate (pH 9.6) containing 5 pg/ml anti-Fab antibody (Cappel Labs), and then at room temperature ( Block with 2% (w/v) bovine serum albumin in PBS for about 2 to 5 hours at about 23 °C. In a non-adsorbing plate (Nunc #269620), mix 1 μpM or 26 pM [1251]-antigen with serial dilutions of the relevant Fab (eg with Presta et al, Cawcer Res. 57: 4593-4599 (1997) The anti-VEGF antibody Fab-12 was evaluated. The relevant F ab is then incubated overnight; however, the incubation can last for a longer period of time (e.g., about 65 hours) to ensure equilibrium is achieved. Thereafter, the mixture is transferred to a capture plate for incubation at room temperature (e.g., 1 hour). The solution was then removed and the plate was washed 8 times with PBS containing 0.1% polysorbate 20 (TWEEN-20®). When the plate was dry, 150 μΐ scintillator (MICROSCINT-20tm; Packard)' per well was added and the plate was counted for 10 minutes on a TOPCOUNTtm gamma counter (Packard). The concentration at which each Fab is produced is less than or equal to 20% of the maximum binding is selected for competitive binding assays. According to another embodiment, the Kd system uses a surface plasmon resonance assay using BIACORE®-2000 or BIACORE®-3000 (BIAcore, Inc., Piscataway, NJ) at 25 ° C with a fixed antigen CM5 wafer, Measured under about 10 reaction units (RU). Briefly, according to the supplier's instructions, ethyl-iT-(3-didecylaminopropyl)-carbodiimide hydrochloride (EDC) and hydroxybutylimine (NHS) activation Carboxydenylated dextran biosensor wafer (CM5, BIACORE, Inc.). The antigen was diluted to 5 pg/ml (about 0.2 μM) with 10 mM sodium acetate (pH 4.8), followed by injection at a flow rate of 5 μl/min to achieve about 10 reaction units (RU) of the coupled protein. After the injection of the antigen, 1 Μ ethanolamine was injected to block the unreacted group. In the kinetics 158864.doc -48 - 201215618, PBS (PBST) containing 0.05% polysorbate 20 (TWEEN-20tm) surfactant was injected at 25 ° C at a flow rate of about 25 μΐ / min. Two-fold serial dilutions of Fab (0.78 nM to 500 nM). The association rate was calculated by simultaneously fitting the association and dissociation sensor maps using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2). kQn) and the dissociation rate 汴. "). The equilibrium dissociation constant (Kd) is calculated as the ratio kcff/ku. See, for example, Chen et al., J. Μο/. 5ζ·ο/· 293:865-881 (1999). If the association rate exceeds 106 M·1 s·1 as determined by the above surface plasmon resonance assay, the association rate can be determined by using a fluorescence quenching technique which measures the presence of increasing concentrations of antigen. Increase or decrease in fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm bandpass) of 20 nM anti-antigen antibody (Fab form) at 25° (: 6868) , as measured in a spectrometer, such as a stop-flow equipped spectrophometer (Aviv Instruments) or an 8000 Series SLM-AMINCOtm spectrophotometer (ThermoSpectronic) with a mixed colorimetric tube. 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 and other fragments described below. For a review of certain antibody fragments, see Hudson et al, Mel 9: 129-134 (2003). For a review of scFv fragments, see, for example, Pluekthiin, The Pharmacology of Monoclonal Antibodies, Vol. 13 3, Rosenburg and Moore, 158864.doc -49-201215618 (Springer-Verlag, New York), pp. 269-3 1 5 ( 1994); see also WO 93/16185; and U.S. Patent Nos. 5,571,894 and 5,587,458. For a discussion of Fab and F(ab')2 fragments comprising rescue receptor binding epitope residues and having an increased in vivo half-life, see U.S. Patent No. 5,869,046. A bifunctional antibody is an antibody fragment which has a bivalent or bispecificity with two antigen binding sites. See, for example, EP 404,097; WO 1993/01161; Hudson et al, Med. 9: 129-134 (2003); and Hollinger et al, Pr〇c. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Trifunctional and tetrafunctional antibodies are also described in Hudson et al, 9: 129-134 (2003). A single domain antibody is an antibody fragment comprising all or part of a heavy chain variable domain or all or part of a 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, e.g., U.S. Patent No. 6,248,516 B1). Antibody fragments can be produced by a variety of techniques including, but not limited to, protein hydrolyzing intact antibodies and by recombinant host cells (e.g., E. coli (five co/z) or phage), as described herein. , Dispersing and Humanizing Antibodies In certain embodiments, the antibodies provided herein are chimeric antibodies. Some of the chimeric antibodies are described, for example, in U.S. Patent No. 4,8,6,567; and Morrison et al, 5W.t/a, 81:6851-6855 (1984). In one example, the chimeric antibody comprises a non-human variable region (eg, variable 158864.doc 201215618 derived from a mouse, atmosphere, hamster, rabbit, or non-human primate (such as a monkey)) human sputum region . In another example, the chimeric antibody is a "class swap"antibody' wherein the class or subclass has been modified from a class or subclass of the parent antibody. Chelating antibodies include antigen-binding fragments thereof. In certain embodiments, the chimeric antibody is a humanized antibody. Generally, non-human steroids are humanized to reduce their immunogenicity to humans while preserving the specificity and affinity of the parental non-human organism. Generally, a humanized antibody comprises one or more variable domains' wherein the HVR (or portion thereof), e.g., CDr, is derived from a non-human antibody, and the FR (or a portion thereof) is derived from a human antibody sequence. Humanized antibodies will also include at least a portion of the human constant region as appropriate. In some embodiments, some of the residues in the 'humanized antibody are substituted, e.g., by the corresponding residues from a non-human antibody (e.g., an antibody from which the HVR residue is derived), for example, to restore or improve antibody specificity or affinity. Humanized antibodies and methods for their preparation are reviewed, for example, in Almagro and Fransson, Front. 13: 1619-1633 (2008) and are further described, for example, in Riechmann et al, iVaiwre 332:323-329 (1988); Queen Etc., #加, / deal 5W. 86:10029-

10033 (1989); U.S. Patent Nos. 5,821,33, 7, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Me/Office Hearts 36:25-34 (2005) (Describe SDR (a-CDR) transplantation); Padlan, Mo/. Immunol. 28:489-498 (1991) (description "resurfacing"); Dall'Acqua et al, Methods 36: 43-60 (2005) (Description of "FR Reorganization"); and Osbourn et al., 36: 61-68 (2005) and Klimka et al., Br. J. Cancer, 83: 252-260 (2000) (description of FR reorganization "guided selection (guided selection) Selection)" 158864.doc -51 - 201215618 law). Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best-fit" approach (see, for example, Sims et al., J. /wmwwo/. 151:2296 (1993) a framework region derived from the common sequence of human antibodies of a particular light chain or heavy chain variable region subgroup (see, eg, Carter et al, Proc. Natl. Acad. Sci. USA, 89: 4285 (1992); and Presta Et al., "WW, 151: 2623 (1993)); human maturation (somatic mutation) framework or human germline framework (see for example Almagro and

Fransson, Fro Price. Price still cz. 13:1619-1633 (2008)); and the framework regions produced by screening FR libraries (see for example Baca et al., 乂 5b/. c/zem. 272: 10678-10684 (1997) and Rosok et al, J. C/2 (iv). 271:22611-22618 (1996))-4. Human antibodies In certain embodiments, the antibodies provided herein are human antibodies. Human antibodies can be produced using a variety of techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Cwrr. Opk. The corpse / 5: 368-74 (2001) and Lonberg, Ci/rr. :45〇_ 459 (2008). Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or have human variable regions in response to antigen challenge. Intact antibodies. These animals usually contain all or part of the human immunoglobulin locus that replaces the endogenous immunoglobulin locus or is present extrachromosomally or randomly integrated into the animal's chromosome. In these transgenic mice The endogenous immunoglobulin locus usually does not live. I58864.doc -52 - 201215618. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, 23: 1117-1 125 (2005). See also eg U.S. Patent Nos. 6,075,181 and 6,150,584, the disclosure of which are incorporated herein by reference to U.S. Patent No. 5,770, 429, to the disclosure of U.S. Patent No. 5,770,429, to the disclosure of U.S. Patent No. 7, 041, 870, to KM MOUSE®, and to the beauty of VELOCIMOUSE® technology. U.S. Patent Application Publication No. US 2007/0061900. Human variable regions derived from intact antibodies produced by such animals can be further improved, for example, by combining with different human constant regions.

Human antibodies can also be prepared by fusion-based methods. Human myeloma and mouse-human heteromyeloma cell lines for producing human monoclonal antibodies have been described. (See, for example, Kozbor ·/· Tmmwwo/., 133: 3001 (1984); Brodeur et al, Monoclonal Antibody Production Techniques and Applications, pp. 5 1-63 (Marcel Dekker, Inc., New York, 1987); and Boerner Et al., /_ 147: 86 (1991)). Human antibodies produced by human B cell fusion tumor technology are also described in Li et al, iVoc. iVa " JcW. 5W. C/Sd, 103: 3557-3562 (2006). Other methods include, for example, the methods described in U.S. Patent No. 7,189,826 (which describes the production of a single human 18]^1 antibody from a fusion tumor cell line) and Ni,26(4):265-268 (2006) ( Describe human-human fusion tumors). Human fusion tumor technology (Trioma technology) is also described below: Vollmers and Brandlein, //Vsio/og;; 20(3): 927-937 (2005) and Vollmers and

Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3)·Λ85-91 (2005). % 158864.doc -53- 201215618 Human antibodies can also be produced by isolating Fv pure lineage variable domain sequences selected from human-derived phage display libraries. These variable domain sequences can then be combined with the desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below. 5. Antibodies obtained from the library The antibodies in the compositions of the invention can be isolated by screening for antibodies having the desired activity in the combinatorial library. For example, various methods are known in the art for generating phage display libraries and screening for antibodies having the desired binding characteristics in such libraries. Such methods are reviewed, for example, in Hoogenboom et al, Methods Mo/ecw/ar Bz'o/ogy 178: 1-37 (edited by O'Brien et al., Human Press, Totowa, NJ, 2001) and are for example in the following Further description: McCafferty et al, iVaiMre 348:552-554; Clackson et al, iVaiwre 352: 624-628 (1991); Marks et al, 乂Mol. Biol. 222: 581-597 (1992); Marks and Bradbury,

Mei/zoi/s /w Mo/ecw/ar 248:161-175 (edited by Lo, Human)

Press, Totowa, NJ, 2003); Sidhu et al., Mo/. Price/. 338(2): 299-310 (2004); Lee et al., /. Mo/. 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 some phage display methods, the lineages of the VH and VL genes are separately selected by polymerase chain reaction (PCR) and randomly recombined into a phage library, which can then be followed by Winter et al., 乂. and ev. /mmwwo /., 12: Screening of antigen-binding phage in such phage libraries as described in 433-455 (1 994). 158864.doc -54- 201215618 Phage typically present in the form of a single-chain Fv (scFv) fragment or an antibody fragment in the form of a Fab fragment. Libraries from immunized sources provide antibodies with high affinity for the immunogen without the need to construct fusion tumors. Alternatively, the natural lineage can be selected (eg, from human selection) to provide antibodies against a wide range of non-autoantigen and autologous antigens from a single source without any immunization, as by Griffiths et al., 乂12: 725-734 (1993). Finally, natural libraries can also be synthesized by colonizing unrearranged V gene segments from stem cells and using PCR primers containing random sequences to encode highly variable CDR3 regions and achieving in vitro rearrangement, such as by Hoogenboom and Winter. , «/. Mo/. Price/., 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, 2005/01 19455, 2005/0266000, 2007/0117126, 2007 / 0160598, 2007/0237764, 2007/0292936 and 2009/0002360. An antibody or antibody fragment isolated from a human antibody library is considered herein to be a human antibody or a human antibody fragment. 6. Multispecific Antibodies In certain embodiments, the antibodies provided herein are multispecific antibodies, such as bispecific antibodies. A multispecific antibody is a monoclonal antibody having binding specificity for at least two different sites. In certain embodiments, one of the binding specificities is for Complex I or gH and the other binding specificity is for any other antigen. In certain embodiments, one of the binding specificities is for Complex I and the other binding specificity is for gH. In certain embodiments, the bispecific 158864.doc • 55-201215618 antibody binds to two different epitopes of complex I or gH. Bispecific antibodies can also be used to localize cytotoxic agents to cells having complex I or gH on the cell surface. Bispecific antibodies can be prepared as full length antibodies or antibody fragments. Techniques for preparing multispecific antibodies include, but are not limited to, recombinantly co-presenting two immunoglobulin heavy-key linkages with different specificities (see Milstein and Cuello, 305: 537 (1983)); WO 93/ 08829; and

Traunecker et al., M. M50 «/· 10: 3655 (1991)); and "knob-in-hole" engineering (see, for example, U.S. Patent No. 5,73, 168). Multispecific antibodies can also be prepared by engineering an electrostatic steering effect to prepare antibodies to heterodimeric molecules (WO 2009/089004 A1); cross-linking two or more antibody bit fragments (see for example U.S. Patent No. 4,676,980, and Brennan et al. 229:81 (1985)); use of a leucine zipper to produce a bispecific antibody (see, e.g., Kostelny et al, J. 148 (5). 1547 - 1553 (1992)) The use of "bifunctional antibody" technology to prepare bispecific antibody fragments (see, eg, Hollinger et al, 5^.. 90:6444-6448 (1993)); and the use of single-bond Fv (sFv) dimers (see for example Gruber et al., "/· /wwwwo/., 152:5368 (1994)); and preparation of trispecific antibodies as described, for example, in Tutt et al., /. 147: 60 (1991). Engineered antibodies (including "Octopus antibodies") having three or more functional antigen binding sites are also included herein (see, for example, US 2006/0025576 A1). 158864.doc -56- 201215618 The antibodies or fragments herein also include "dual-acting FAb" or "DAF" comprising an antigen binding site that binds to complex I or gH and another different antigen (see your J. aUS 2008/ 0069820). 7. Antibody Variants In certain embodiments, the amino acid sequence variants of the antibodies provided herein are encompassed. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. The amino acid sequence variant of the 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 obtain the final construct, with the proviso that the final construct has the desired characteristics 'e.g., antigen binding. a) Substitution, Insertion, and Deletion Variants In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Related sites induced by substitution mutations include HVr and Fr. Conservative substitutions are shown under the heading "Conservative substitutions" in Table 1. More substantial variations are provided under the heading "Exemplary Substitutions" in Table 1 and are further described below with respect to the amino acid side chain classes. Amino acid substitutions can be introduced into the relevant antibodies and screened for products having the desired activity, such as retained/improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. 158864.doc •57·201215618 Table 1 Exemplary substitutions of the original residues preferred substitutions Ala(A) Val; Leu; lie Val Arg(R) Lys; Gin; Asn Lys Asn(N) Gin; His; Asp, Lys; Arg Gin Asp (D) Glu ; Asn Glu Cys ( C ) Ser ; Ala Ser Gln ( Q ) Asn ; Glu Asn Glu ( E ) Asp ; Gin Asp Gly ( G ) Ala Ala His ( H ) Asn ; Gin ; Lys ; Arg Arg Ile(I) Leu ; Val ; Met ; Ala ; Phe ; Leucine Leu Leu ( L ) leucine ; lie ; Val ; Met ; Ala ; Phe lie Lys ( K ) Arg ; Gin ; Asn Arg Met(M) Leu ; Phe ; lie Leu Phe ( F ) Trp ; Leu ; Val ; lie ; Ala ; Tyr Tyr Pro ( P ) Ala Ala Ser ( S ) Thr Thr Thr ( T ) Val ; Ser Ser Trp ( W ) Tyr; Phe Tyr Tyr(Y) Trp ; Phe ; Thr ; Ser Phe Val(V) lie ; Leu ; Met ; Phe ; Ala ; ortho-leucine Leu Amino acid can be grouped according to the shared side chain properties: (1) Hydrophobic Sex: leucine, Met, Ala, Val, Leu, lie; (2) Neutral hydrophilicity: Cys, Ser, Thr, Asn, Gin; (3) Acidity: Asp, Glu; (4) Qualitative: His, Lys, Arg; (5) Residues affecting chain orientation: Gly 'Pro; (6) Aromatic: Trp, Tyr, PheA non-conservative substitution will result in the conversion of one of these categories into another category. One type of substitution variant involves the substitution of one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). In general, the variants obtained with the -58-158864.doc 201215618 step-by-step study will improve in some organisms I1 (such as increased affinity, reduced immunogenicity) relative to the parent antibody. (eg, improved) and/or will have certain biological properties that are substantially retained by the parent antibody. An exemplary substitution variant is an affinity matured antibody that can be conveniently produced, for example, using phage-based affinity maturation techniques, such as the techniques described herein. Briefly, one or more residues are mutated and a variant antibody is presented on the phage and screened for a variant antibody having a particular biological activity (e. g., binding affinity). Alterations (e. g., substitutions) can be made in the HVR, e.g., to improve antibody affinity. These changes can be made in the HVR "hot spot (h〇tsp〇t)" (ie, the residue encoded by the codon that is subjected to high frequency mutations during the somatic maturation process) (see for example Chowdhury, Mei/zoA Μο/. Βζ • ο/· 207: 179-196 (2008)) and/or SDR (a-CDR) were performed and the resulting variation was tested for binding affinity. It has been described, for example, in Hoogenboom et al., Heart/(10) m: 1-37 (〇, Brien et al., ed., Human Press, T〇t〇wa, NJ, (2001)) by constructing and reselecting from a secondary library. Come to affinity maturity. In some embodiments of affinity maturation, diversity is introduced into a variable gene selected for maturation by any of a variety of methods, such as error-prone PCR, strand shuffling, or oligonucleotide site-directed mutagenesis. A secondary library is then generated. The library is then screened to identify any antibody variants with the desired affinity. Another method of introducing diversity involves an HVR targeting approach in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutation induction or modeling. CDR-H3 and CDR-L3 are especially targeted. 158864.doc -59· 201215618 In certain embodiments, substitutions, insertions, or deletions can occur within one or more HVRs as long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, t' can be made in the subject to not substantially reduce the conservative change in binding affinity (e.g., conservative substitution as provided herein). These changes can be made outside the HVR "hotspot" or SDR. In the variant vh& VL sequence provided above, the implementation of each HVR has not changed or contains at most! One, two or three amino acid substitutions. One method suitable for identifying residues or regions of an antibody that are susceptible to mutation-induced targeting is known as "alanine scanning mutation induction" as described by Wells (1989) 244:1, 81-1,85. In this method, a residue or a set of target residues (eg, charged residues such as arg, asp, his, lys, and gh) are identified and neutralized or negatively charged with an amino acid (eg, alanine or The polyalanine) substitution determines whether the interaction of the antibody with the antigen is affected. The substitution can be introduced at the position of the amino acid which shows a functional sensitivity to the initial substitution. Alternatively or additionally, the crystal structure of the antigen-antibody complex is used to identify The point of contact between the antibody and the antigen. These contact residues and adjacent residues can be targeted or eliminated as substitution candidates. The variant can be screened to determine if it contains the desired properties. Amino acid sequence inserts include length An amino- and/or carboxyl-terminal fusion in the range of one residue to a polypeptide comprising one hundred or more residues and an intrasequence insert having a single or multiple amino acid residues. Examples of inserts include antibodies having a thiol sulfhydryl residue at the terminal. Other insertion variants of the antibody molecule include antibody or c-terminus with an enzyme (for example, for ADEPT) or increase serum half-life of the antibody. . B) the extent of glycosylation of antibody glycosylation variants In certain embodiments, provided herein the antibody is altered to increase or decrease the fusion polypeptide 158864.doc • 60- 201215618 thereof. Addition of a glycosylation site to an antibody or deletion of a glycosylation site by an antibody can be conveniently accomplished by altering the amino acid sequence to create or remove one or more glycosylation sites. When the antibody comprises an Fc region, the carbohydrate to which it is attached can be altered. Native antibodies produced by mammalian cells typically comprise a branched biantennary oligosaccharide, which is typically joined to the Asn297 of the ch2 domain of the Fc region by an N-linkage. See, for example, Wright et al, 7757(7//15:26-32 (1997). Oligosaccharides may include various carbohydrates such as mannose, N-ethyl glucosamine (GlcNAc), galactose, and sialic acid. And trehalose linked to GlcNAc in the "backbone" of the biantennary oligosaccharide structure. In some embodiments, the oligosaccharides in the antibodies of the invention may be modified to produce antibody variants having certain improved properties. In one embodiment, an antibody variant having a carbohydrate structure lacking trehalose linked (directly or indirectly) to the Fc region is provided. For example, the amount of trehalose in the antibody can range from 1% to 80%, 1 % to 65%, 5% to 65% or 20% to 40%. As described, for example, in WO 2008/077546, all sugar structures (eg, complex, hybrid, and high mannose structures) are attached by attachment to Asn 297. The average amount of trehalose in the sugar chain at Asn297 was calculated to determine the amount of trehalose as measured by MALDI-TOF mass spectrometry. Asn297 means located at about position 297 in the Fc region (Eu number of the Fc region residue) Aspartate residue; however, due to minor sequence changes in the antibody , Asn297 also three '158864.doc •61 - 201215618

It is possible to locate approximately 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. Such trehalylation variants may have improved ADCC function. See, for example, U.S. Patent Publication No. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications relating to "trehaloselation" or "hypoglycemic" 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 2004/01 10282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; W02005/053 742; W02002/031140; Okazaki et al., 乂尬/. 5,.〇/· 336:1239-1249 (2004); Yamane-Ohnuki et al., Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing de-fucosylated antibodies include Lecl3 CHO cells lacking protein fucosylation (Ripka et al, Jrc/z. 249: 533-545 (1986); US patent application

Requests US 2003/0157108 A1, Presta, L; and WO 2004/056312 Al, Adams et al, especially in Example 11) and gene knockout cell lines, such as the α-1,6-trehalyltransferase gene CHO cells are knocked out (see, for example, Yamane-Ohnuki et al, 87: 614 (2004); Kanda, Υ· et al, Bioeng., 94(4): 680-688 (2006); and W02003/085107). Further provided are antibody variants having a oligosaccharide, such as a biantennary oligosaccharide in which the Fc region of the antibody is ligated by GlcNAc. Such antibodies may be 158864.doc • 62- 201215618 Allogeneic may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003/011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibody variants in which at least one galactose residue in the oligosaccharide is attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, 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 an antibody provided herein, thereby producing an Fc region variant. The Fc region variant may comprise a human Fc region sequence comprising an amino acid modification (e.g., a substitution) at one or more amino acid positions (e.g., a human IgGl, IgG2, IgG3 or IgG4 Fc region). In certain embodiments, the invention encompasses antibody variants having some, but not all, of the effector functions that make the antibody a candidate for a variety of applications in which the half-life of the antibody is greater in vivo. ® is important, and certain effect functions such as complement and ADCC are unnecessary or harmful. In vitro and/or in vivo cytotoxicity assays can be performed to confirm reduction/depletion of CDC and/or ADCC activity. For example, an Fc receptor (FcR) binding assay can be performed to ensure that the antibody lacks FcYR binding (and thus may lack ADCC activity) but retains FcRn binding ability. Primary cells that mediate ADCC NK cells exhibit only Fc (RIII, whereas monocytes exhibit Fc (RI, Fc (RII and Fc (RIII. The expression of FcR on hematopoietic cells is outlined in Ravetch and Kinet, Annu Rev. Immunol. Non-limiting examples of in vitro assays for assessing ADCC activity of related molecules are described in U.S. Patent No. 5,500,362 (Table 3, pp. 464, pp. 464, pp. 464864.doc -63-201215618). See, for example, Hellstrom, I. et al., Proc. t/M 83:7059-7063 (1986)) and

Hellstrom, I et al., 5W. CAS^ 82: 1499-1502 (1985); 5,821,337 (see Bruggemann, M. et al., /. Mec? 166:1351-1361 (1987)). Alternatively, non-radioactive assays can be employed (see, for example, ACTITM non-radioactive cytotoxicity assays for flow cytometry (Cell Technology, Inc, Mountain View, CA); and CytoTox 96® non-radioactive cytotoxicity assays (Promega, Madison, WI)). Effector cells suitable for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively or additionally, the ADCC activity of the relevant molecule can be assessed in vivo, for example, in an animal model, such as the animal model disclosed in Clynes et al, ZVoc. Nat'l Acad. Sci. USA 95:652-656 (1998). A Clq binding assay can also be performed to confirm that the antibody is unable to bind Clq and thus lacks CDC activity. See, for example, the Clq and C3c binding ELISAs in WO 2006/029879 and WO 2005/100402. To assess complement activation, CDC assays can be performed (see, for example, Gazzano-Santoro et al., /. TrnmMwo/. Mei/zoc/i 202: 163 (1996); Cragg, MS et al, 101: 1045-1052 (2003) ; and Cragg, MS and MJ Glennie, Blood 103:273 8-2743 (2004)). FcRn binding and in vivo clearance/half life assays can also be performed using methods known in the art (see, for example, Petkova, SB et al, Int'l. Immunol. 18(12): 1759-1769 (2006)). Reduced antibodies include one or more substituted antibodies of Fc region residues 238, 265, 269, 158864. doc-64. 201215618 270, 297, 327 and 329 (U.S. Patent No. 6,737,056). These Fc mutants include a Fc mutant having a substitution at two or more of the amino acid positions 265, 269, 270, 297, and 3 27 'including the substitution of residues 265 and 297 to alanine. DANA" Fc mutant (US Patent No. 7,332,581). Certain antibody variants with improved or reduced binding to FcR have been described. (See, e.g., U.S. Patent No. 6,737,056; WO 2004/056312; and Shields et al., 乂 5/0/.c/7. 9(2): 6591-6604 (2001)) 某些 In some embodiments, Antibody variants comprise an Fc region having a substitution at one or more of the amino acid substitutions of the ADCC, such as at positions 298, 333 and/or 334 of the Fc region (the EU numbering of the residues). In some embodiments, 'changes in Clq binding and/or complement dependent cytotoxicity (CDC) are produced in the Fc region, such as, for example, U.S. Patent No. 6,194,551, WO 99/51642, and Idusogie et al., */. 164: 4178-4184 (2000). Increased half-life and the neonatal Fc receptor (FcRn) responsible for the transfer of maternal IgG to the fetus (Guyer et al, 乂 1 17:587 (1976) and Kim et al, J. /www(10)/. 24:249 (1994) A combination of improved antibodies is described in US 2005/0014934 A1 (Hinton et al.). The antibodies comprise an Fc region having one or more substitutions in which the modified Fc region binds to FcRn. Such Fc variants include Fc variants 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, 158864.doc -65- 201215618 3 82, 413, 424 or 434, for example, Fc region residue 434 is substituted (U.S. Patent No. 7,371,826). See also, Duncan and Winter, 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and \\^0 94/29351. d) Cysteine engineered antibody variants In certain embodiments, it may be desirable to produce a cysteine engineered antibody, such as "thioMAb", in which one or more residues of the antibody are half Cyst acid residue substitution. In a particular embodiment, the substituted residue is present at a reachable site of the antibody. By substituting their residues with cysteine, the reactive thiol group is thereby localized to the accessible site of the antibody and can be used to bind the antibody to other moieties such as a drug moiety or a linker-drug moiety. An immunoconjugate is produced as described further herein. In certain embodiments, any one or more of the following residues may be substituted with a cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and S400 (EU) of the heavy chain Fc region Numbering). Cysteine engineered antibodies can be produced as described, for example, in U.S. Patent No. 7,521,541. e) Antibody Derivatives In certain embodiments, the antibodies provided herein can be further modified to contain other non-protein portions known in the art and readily available. Portions suitable for the derivatization of antibodies include, but are not limited to, water soluble polymers. Non-limiting examples of water soluble polymeric materials include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidine _, poly], 3_dioxolane 'poly_1'6_three 158864.doc • 66 - 201215618 a mixture of aerane ethylene/maleic anhydride, polyamino acid (homopolymer or none) Gauge/, polymer) and dextran or poly(N_vinylpyrrolidone) polyethylene glycol, propanol homopolymer, polyglycidyl/epoxy copolymer, polyoxyethylene Polyols (such as glycerin), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde has advantages in manufacturing due to its stability in water. The polymer can be in any knife 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 derivatization: ® can be determined based on considerations including, but not limited to, the specific properties or functions of the antibody to be modified, and whether the antibody derivative will be used for determination. Therapy under conditions, etc. In another embodiment, a combination of an antibody and a non-protein moiety that can be selectively heated by exposure to radiation is provided. In one embodiment, the non-proteinaceous moiety is a carbon nanotube (Kam et al, Proc. #加/&&&&&&&&&&&&&&&&& Radiation can have any wavelength and includes, but is not limited to, not damaging normal cells but heating the non-protein portion to a wavelength that can kill the temperature of cells adjacent to the antibody-non-protein portion. C. Recombinant Methods and Compositions Antibodies can be produced using recombinant methods and compositions as described, for example, in U.S. Patent No. 4,816,567. In one embodiment, an isolated nucleic acid encoding an anti-Complex I antibody or an anti-gH antibody described herein is provided. The nucleic acid may encode an amino acid sequence comprising VL and/or an amino acid sequence comprising a VH of an antibody (e.g., a light chain and/or a heavy chain of an antibody). In another embodiment, one or more vectors (e.g., expression vectors) comprising the nucleic acid are provided. Host cells comprising this nucleic acid are provided in another embodiment 158864.doc-67-201215618. In one such embodiment, the host cell comprises (eg, has been transformed as follows): (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising an anti-Wei amino acid sequence and comprising an antibody vh, or (2) a first vector comprising a nucleic acid encoding an amino acid sequence comprising the antibody VL, and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the antibody VH. In one embodiment, cells, such as Chinese hamster ovary (CHO) cells or lymphocytes (e.g., γ〇, NS0, Sp20 cells). In one embodiment, a method of making an anti-Complex I antibody or an anti-gH antibody, wherein the method comprises culturing a sputum cell comprising a nucleic acid encoding the antibody as provided above under conditions suitable for expression of the antibody And recovering the antibody from the host cell (or host cell culture medium) as appropriate. For recombinant production of an anti-Complex I antibody or an anti-gH antibody, a nucleic acid encoding an antibody, e.g., as described above, is isolated and inserted into one or more vectors for further selection and/or expression in the host cell. Such nucleic acids can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of specifically binding to genes encoding the heavy and light chains of the antibody). Host cells suitable for the selection or expression of an antibody-encoding vector include prokaryotic or eukaryotic cells as described herein. For example, antibodies can be produced in bacteria, particularly when glycosylation and Fc effect functions are not required. For the presentation of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in the large intestine rod 158864.doc -68-201215618 bacterium ). After performance p said that the antibody can be isolated from the soluble fraction from the bacterial cell paste and can be further purified. In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeast are hosts suitable for the selection or expression of antibody-encoding vectors, including glycosylation pathways that have been "humanized" & Fully human glycosylated forms of fungi and yeast strains. See Gerngr〇ss, 22: 1409-1414 (2004) and Li et al., 绐 μ 24:210-215 (2006). Host cells suitable for the expression of glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plants and insect cells. A number of baculovirus strains that can be used in conjunction with insect cells have been identified for use in transfecting grass worms (filling ffugiperda). Plant cell cultures can also be used as hosts. See, for example, U.S. Patent Nos. 5,959,177, 6,040,498, 6,42,548, 7,125,978, and 6,417,429, the disclosure of which is incorporated herein by reference. Cells can also be used as hosts. For example, mammalian cell strains suitable for growth in suspension may be suitable. Further examples of mammalian host cell strains are SV40 transformed monkey kidney CV1 cell line (COS-7); human embryonic kidney cell line (293 or 293 cells such as, for example, Graham et al., J. Ge« KzW. 36: 59 (1977); young hamster kidney cells (BHK); mouse podocytes (TM4 cells as in, for example, Mather, 5/〇/· 158864.doc-69-201215618 23:243-251 (1980) Said); monkey kidney cells (CVI); African green monkey kidney cells (VERO-76); human cervical cancer cells (HELA); canine kidney cells (MDCK); buffalo rat liver cells ( BRL 3 A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumors (MMT 060562); TRI cells, such as, for example, Mather et al., see 7. Jcad. Scz.. 383:44 -68 (1982); MRC 5 fine-moon pack; and FS4 cells. Other suitable mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al, Proc. iVai/. Acad. Sci. 77:42 16 (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, for example, Yazaki and Wu, Mei/zoA Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 ( 2003). D. Assays The anti-Complex I antibodies or anti-gH 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 antigen binding activity of an antibody of the invention is tested, for example, by known methods such as ELISA, Western blots and the like. In another aspect, a competition assay can be used to identify antibodies that compete with the anti-Complex I antibodies described herein for binding to Complex I. In another aspect, a competition assay can be used to identify antibodies that compete with the anti-gH antibodies described herein for binding to gH. 158864.doc -70-201215618 In certain embodiments, the competing antibody binds to the same epitope of gH or complex I (e.g., a linear epitope or a conformational epitope). A detailed exemplary method for locating the epitope to which the antibody binds is provided by Morris (1996) "Epitope Mapping Protocols" 'Methods k Mo/ecw/ar price o/og_y volume 66 (Humana Press, Totowa, NJ) In an exemplary competition assay, the immobilized complex I or gH is incubated in a solution comprising a first labeled antibody and a second unlabeled antibody that bind to complex I or gH, respectively, and the second unlabeled The ability of the antibody to compete with the first antibody for binding to complex I or gH. The second antibody can be present in the fusion tumor supernatant. As a control, the immobilized complex I or gH was incubated in a solution containing the first labeled antibody but not the second unlabeled antibody. After incubation under conditions allowing the binding of the first antibody to complex I or gH, excess unbound antibody is removed and the amount of label associated with immobilized complex I or gH is measured. If the amount of the label associated with the immobilized complex I or gH in the test sample is substantially reduced relative to the control sample, then the second antibody is indicated to compete with the first antibody for binding to complex I or gH. See Harlow and Lane (1988) Antibodies: A Laboratory Manual % \A (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY) ° Competition assays can also be used as described above, using complex I or complex II gH And/or other members transfected and expressed on the cell surface by the FACS of the gH and/or cells of the other members. Alternatively, ELISA using gH and/or reconstituted complex I or complex II can also be used in the 158864.doc -71 - 201215618 competition assay. Anti-gH antibodies and anti-complex I antibodies were further described in the Examples using FACS and ELISA. 2. Activity assays In a single aspect, a test for identifying a biologically active anti-complex j antibody is provided. Biological activity may include, for example, specific binding to a conformational epitope produced by association of Ul 12 8 , UL 13 0, UL 131 and gH/gL; or specific binding to an epitope within a single protein of Complex I; And HCMV, EC9 〇 is 0.7 | ig / ml or less than 0.7 pg / ml. In some embodiments, the 'EC9〇 is 0.5 pg/ml or less than 0.5 pg/ml. In other embodiments, the ECpo is 0.3 pg/ml or less than 0.3 pg/ml. In other embodiments, the EC90 is 0.1 pg/ml or less than 1 pg/mi. In other embodiments, ε^9〇 is 0.08 pg/ml or less and 0.08 pg/ml or less. In other embodiments, the Ec9〇 is 0.06 pg/ml or less and 0.06 pg/ml or less. In other embodiments, the Ec9〇 is 0.04 pg/ml or less than 〇4 pg/ml. In other embodiments, the EC9 〇 is 0.02 pg/ml or less than 0.02 pg/ml. In other embodiments, the Ec9〇 is 0.015 pg/ml or less than 0.015 pg/ml. In other embodiments, Ec9〇 is 0.012#邑/1111 or 0.012 48/1111 or less. In other embodiments, ^9〇 is 0.011 pg/ml or 0.011 pg/ml or less. In other embodiments, the Ec9〇 is 0.010 pg/ml or less and 0.010 pg/ml or less. Compositions comprising antibodies having such biological activity are also provided. In one aspect, k is used to identify a bioactive anti-gH antibody assay. Biological activity may include, for example, neutralization of HCMV, EC90 of 1 pg/ml, 0.9 μδ/ml, 0.8 pg/ml, 〇·7 ng/m dip. 6 μ§/ηι〇 5 ^/ml, 0.4 pg/ Ml, 0.3 pg/ml, 0.2 pg/ml, 〇1 μ§Λη1, 〇〇9 158864.doc •11- 201215618

Pg/ml '〇·〇8 pg/ml, 〇·07 pg/ml, 〇 K6 Kg/m Bu 0.04 pg/ml or 0.04 pg/mi or less. The IC50 of the anti-gH antibody in the composition of the present invention and the gH/gL-mer expressed in the baculovirus is 〇.17 nM4〇17 nM or less, for example, 〇16 尔, 0.15 nM, 0.14 nM, 〇.13 nM, 〇12 touch, 〇ιι nM, (Uo nM, 〇.G9 nM, G (10) nM, g Q7 nM, _ _, 〇 _ 〇 5 nM, 0.04 nM, 0.03 nM, 〇〇 2 nM, 〇〇 1 side or 〇〇i

Below nM. Compositions comprising antibodies having such in vivo and/or in vitro biological activity are also provided. In certain embodiments, the biological activity of an antibody of the invention is tested. For an illustrative description of this assay, see Example 3. E. Immunoconjugates The invention also provides compositions comprising an immunoconjugate comprising an anti-complex ruthenium antibody or an anti-§11 antibody and an immunosuppressive agent, such as a chemotherapeutic agent or a drug , growth inhibitors, toxins (eg, protein Wuxin, bacterial 'fungi, enzymatically active toxins of plant or animal origin; or fragments thereof), or radioisotopes. In one embodiment, the immunoconjugate is an antibody-drug conjugate (ADC), wherein the antibody binds to one or more drugs including, but not limited to, the following: maytansinoid (see U.S. Patent No. 5 2 〇8 〇2〇, 5,416,064 and European patent EP 〇425 235 B1); auristatin, such as monoterpene auristatin (m〇n〇methylauristatin) drug part DE and DF (MMAE and MMAF) (See U.S. Patent Nos. 5,63 5,483 and 5,780,588 and 7,498,298); dolphin toxin 158864.doc -73-201215618 (dolastatin); calicheamicin or its derivatives (see US patent) Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001 and 5,877,296; Hinman et al., Cawcer et al. 53:3336-3342 (1993) And Lode et al, Cancer Res. 58: 2925-2928 (1998)); anthracycline, such as daunomycin or doxorubicin (see Kratz et al, CwrreW Med) C/zew. 13:477-523 (2006) ; Jeffr Ey et al,

Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., 16:717-721 (2005); Nagy et al., /Voc. 7V"a" 97:829-834 (2000) ;

Dubowchik et al., 5/oorg. Met/· C/zew· Leiiers 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and US Patent No. 6,630,579 ;methotrexate; vindesine; taxane, such as docetaxel, paclitaxel, larotaxel, tesaloxime Tesetaxel) and ortataxel; trichothecene; and CC1065. In another embodiment, the immunoconjugate comprises an antibody as described herein and an enzymatically active toxin or fragment thereof, including but not limited to, a diphtheria A chain, a non-binding active fragment of diphtheria toxin, an exotoxin ( Exotoxin) A bond (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, Modicin 158864.doc •74- 201215618 (modeccin)A chain, α - sarcin, Aleurites fordii protein, dianthin protein, Phytolaca americana protein (pAPI, PAPII and PAP-S), momordica charantia inhibitor, hemp Curcin, crotin, sapa〇naria 〇fficinaiis inhibitor, gelonin, mit 〇 ii ii ii ii rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest rest gel gel Combination of phen〇mycin, en〇mycin and trichothecene.

In a further addition, an immunoconjugate comprises an antibody as described herein that binds to a radioactive atom to form a radioconjugate. A variety of radioisotopes can be used to generate radioconjugates. Examples include At2丨丨, f3! ', 9〇,

Radioactive isotopes of Re186, Re188, Sm153 Βι212, p32 'pb2i2&Lu. When the radioconjugate is used for detection, it may contain radioactive atoms for scintigraphy studies, such as Ji 99〇1 or 1123; for nuclear magnetic resonance (nmr) imaging (also known as magnetic resonance imaging, mri) Spin label, such as again iodine _ 123, 姨-131, marriage - ill, Weng 10 r mountain 1, μ 1 _ ^ u 1 mouse-19, carbon-13, nitrogen-15, oxygen-17, chaos, fierce or iron . Combinations of antibodies and cytotoxic agents can be prepared using a variety of bifunctional protein couplers, such as N-butylenediamine _3_(2"biti-monothio)propionate (SPDP), Butadiene imino group _4_(N-m-butyleneimine methyl) ring & burned 1-曱酉 曱酉 g ( SMCC), iminothiolane (IT), sub a difunctional derivative of an amino ester (such as diimidodipic acid dihydrogenate hydrochloride), an active vinegar (such as dibutyl succinimide octane vinegar), an aldehyde (such as valeraldehyde) Bis-azido compounds (such as bis(p-azidobenzoquinone 158864.doc -75-201215618) hexamethylenediamine), double nitrogen derivatives (such as bis-(p-diazetyl) Ethylenediamine), diisocyanate (such as toluene 2,6-diisocyanate), and bis-active fluorine compound (such as I,5-difluoro-2,4-dinitrobenzene). For example, it can be like Vitetta The ricin immunotoxin is prepared as described in 238:1098 (1987). Carbon-labeled 1-isothiocyanobenzoyl-3-methyldiethylidamine pentaacetic acid (MX-DTPA) a kind of radioactive nucleotide Combination of an exemplary chelating agent. See WO94 / 11026. Linker may facilitate release of the cytotoxic drug in the cell "of the cleavable linker." For example, an acid labile linker, a peptidase sensitive linker, a photolabile linker, a dimer linker or a linker containing a disulfide can be used (Chari et al., Cancer Λα. 52:127- 131 (1992); U.S. Patent No. 5,208,020). The immunoconjugates or ADCs herein are expressly encompassed, but not limited to, prepared with cross-linking reagents including, but not limited to, the following commercially available (e.g., commercially available from Pierce Biotechnology, Inc., Rockford, IL., USA). These combinations: BMPS, EMCS, GMBS, HBVS, LC SMCC, MBS 'ΜΡΒΗ, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, thio-EMCS, thio-GMBS, thio-KMUS, thio- MBS, thio-SIAB, thio-SMCC and thio-SMPB, and SVSB (butyl succinimide-(4-vinyl fluorene) benzoate). F. Methods and Compositions for Diagnosis and Detection In certain embodiments, any anti-Complex I antibody and/or anti-gH antibody or composition comprising such antibodies as provided herein are suitable for use in detecting organisms The presence of complex I and/or gH in the sample. As used herein, the term "detection" 201215618 covers 疋 or qualitative detection. In certain embodiments, the biological sample comprises cells or tissues' such as the placenta, kidney' heart, lung, liver, pancreas, intestine, thymus, bone, tendon, cornea, skin, heart valve, and vein. In addition, an antibody-containing composition can be used to detect HCMV in endothelial cells, epithelial cells, fibroblasts, and macrophages. In one embodiment, an anti-Complex I antibody and/or an anti-gH antibody for use in a diagnostic or detection method is provided. In another aspect, a method of detecting the presence of complex I and/or gH in a biological sample is provided. In certain embodiments, the method comprises reacting a biological sample with an anti-complex antibody and/or an anti-gH antibody as described herein, allowing the anti-complex Σ antibody to bind to complex I and/or the anti-antibody to bind to gH Contact under conditions, and to detect whether a complex is formed between the anti-complex "fill" and complex I and/or between the anti-gH antibody and gH. This method can be an in vitro or in vivo method. In one embodiment, the anti-Complex I antibody or the anti-gH antibody or the anti-complex 丨 antibody is combined with an anti-antibody for selection for selection with an anti-Complex I antibody or an anti-antibody or anti-Complex I antibody in combination with an anti-gH antibody. Treated individuals, for example, when complexes I and gH are biomarkers for selecting a patient. Exemplary conditions that can be diagnosed using the compositions of the invention include HCMV sensitivities such as HCMV infection from the transplanted organ or tissue 'congenital HCMV infection, hcmv infection during pregnancy, and HCMV infection in children, infants, and adults. In certain embodiments, 'providing a composition comprising a labeled anti-complex Ϊ antibody and/or an anti-gH antibody. (but Not limited to) directly detected markers or moieties (such as fluorescent labels, chromogenic markers, electron-dense markers, luminescent labels and radioactive labels), and for example via enzymatic or molecular interactions Indirect detection of parts (such as enzymes or ligands). Exemplary labels include, but are not limited to, radioisotopes 32p, i25l ', and 13|] [; fluorophores, such as rare earth chelates or luciferins (flu〇rescein) and its derivatives; rhodamine and its derivatives; dansyi; umbemferone; iuceriferase, such as firefly luciferase and Bacterial luciferase (U.S. Patent No. 4,737,456); luciferin; 2,3-dihydropyridazinedione; horseradish peroxidase (HRp); alkaline phosphatase; _-galactosidase; glucoamylase · lysozyme; sugar oxidase, such as glucose oxidase, galactose oxidase and glucose-6-phosphate dehydrogenase; heterocyclic oxidase, such as uricase and jaundice Oxidase; with hydrogen peroxide Coupling of enzyme precursors such as HRP, lactoperoxidase or microperoxidase; biotin/avidin; spin labeling; phage labeling; stable free radicals and analogues thereof G. Pharmaceutical Formulations A pharmaceutical formulation, such as an anti-Complex I antibody or an anti-gH antibody or an anti-complex described herein, in combination with an anti-gH antibody, by mixing the specific antibody having the desired purity with a Or a variety of pharmaceutically acceptable carriers, optionally selected from the P/zar Hall, 16th edition, 〇s〇1, A (1980)), in the form of a lyophilized formulation or an aqueous solution. As described herein, the anti-complex I antibody and the anti-gH antibody can be formulated as a single combined pharmaceutical formulation or a separate pharmaceutical formulation. Pharmaceutically acceptable carriers are generally non-toxic to the recipient at the dosages and concentrations employed and include, but are not limited to, buffers, 158864.doc -78 - 201215618 such as phosphates, citrates and other organic acids Antioxidants, including ascorbic acid and guanidine thioglycol; preservatives (such as gasified octadecyldimethylbenzylidene; hexamethonium chloride; benzalkonium chloride) Benzothonium chloride; phenol; butanol or phenyl decyl alcohol; alkyl p-hydroxybenzoate, such as methyl or propylparaben; catechol; Phenol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 1 residue) polypeptide; protein such as serum albumin, gelatin or immunoglobulin; hydrophilic polymer, such as Polyvinylpyrrolidone; amino acids such as glycine, glutamic acid, aspartame, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, Mannose or dextrin; chelating agent, such as EDT A; a sugar such as sucrose, mannitol, trehalose or sorbitol; a salt-forming relative ion such as sodium; a metal complex (such as a Zn-protein complex); and/or a nonionic surfactant, Such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein additionally include interstitial drug dispersing agents such as soluble neutral-active hyaluronidase glycoprotein (sHASEGP), such as the human soluble PH-20 hyaluronan glycoprotein, such as rHuPH20 (HYLENEX®) , Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use (including rHuPH20) are described in U.S. Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, sHASEGP is combined with one or more other glycosaminoglycanases (such as chondroitinase). Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958, 158,864. 79-201215618. Aqueous antibody formulations include the formulations described in U.S. Patent Nos. 6,171,586 and WO2006/044908, and the formulations of w〇2〇〇6/〇449〇8 include histidine acetate buffers. In addition to the anti-Complex I antibody and/or the anti-gH antibody, the formulations herein may also contain the active ingredients necessary for the particular indication being treated, preferably the active ingredients which do not adversely affect each other. . For example, additional ganciclovir, foscarnet, valganciclovir and cidofovir may be required. These active ingredients are suitably present in combination in an amount effective to achieve the intended purpose. The active ingredient may be coated in microcapsules prepared by, for example, coacervation techniques or by interfacial polymerization (for example, hydroxymercapto cellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively); colloidal state Drug delivery systems (eg, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions. This technique is disclosed in d•SWewces, 16th edition, 〇s〇l, a_, (1980). Sustained release formulations can be prepared. Suitable examples of sustained release formulations include solid hydrophobic polymeric semipermeable matrices containing antibodies in the form of shaped articles such as films or microcapsules. Formulations intended for in vivo administration are generally sterile. Sterility can be easily achieved, for example, by filtration through a sterile filtration membrane. H. Therapeutic Methods and Compositions Any of the compositions comprising an anti-complex Ϊ antibody and/or an anti-gH antibody provided herein can be used in a method of treatment. In one aspect, a composition comprising an anti-complex "filled or anti-158864.doc-80-201215618 gH antibody or anti-complex I antibody and an anti-gH antibody" for use as a medicament is provided. In other aspects, provided A composition comprising an anti-Complex I antibody or an anti-gH antibody or an anti-Complex I antibody and an anti-gH antibody for use in the treatment of HCVM infection. In certain embodiments, an anti-Complex I antibody comprising a therapeutic I method is provided Or a composition of an anti-gH antibody or an anti-complex I antibody and an anti-gH antibody. In certain embodiments, the invention provides an anti-complex I antibody or anti-gH for use in a method of treating an individual having an HCMV infection A composition of an antibody or an anti-complex I antibody and an anti-gH antibody, the method comprising administering to the individual an effective amount of a composition comprising an anti-Complex I antibody and/or an anti-gH antibody. In other embodiments, the invention A composition for use in a method of preventing, inhibiting, or treating a HCMV infection of a congenital HCMV infection or a tissue or organ transplant recipient of a transplanted tissue, organ or donor, or having been infected with HCMV. In such an embodiment Organization or device The transplant recipient is seronegative for HCMV infection. In other embodiments, the transplant recipient or individual has previously been infected with HCMV and is at risk of HCMV reactivation and infection. In some embodiments, the method additionally comprises administering to the individual or transplant The recipient is administered an effective amount of at least one other therapeutic agent, such as described below. In other embodiments, the invention also provides methods for treating an infant infected with HCMV or an infant exposed to HCMV during pregnancy. A composition comprising an anti-Complex I antibody or an anti-gH antibody or an anti-Complex I antibody and an anti-gH antibody, the method comprising administering to the infant an effective amount of a composition comprising an antibody of the invention or a combination thereof. The present invention provides a composition comprising an anti-Complex I antibody or an anti-gH antibody or an anti-Complex I antibody and an anti-gH antibody for use in the treatment, inhibition or prevention of HCMV infection in an individual at risk of infection. According to any 158864. Doc -81 - 201215618 The "individual" of the above embodiment is preferably human. In another cancer sample, the invention provides the use of a composition comprising an anti-complex antibody and/or an anti-gH antibody or an anti-complex I antibody and an anti-gH antibody for the manufacture or preparation of a medicament. In one embodiment, the agent is used to treat, prevent or inhibit HCMV infection. In another embodiment, the agent is for treating, preventing, or inhibiting HCMV infection, comprising administering to the individual having the HCMV infection an effective amount of the agent. In other embodiments, the agent is for use in a method of preventing, inhibiting, or treating a HCMV infection of a congenital HCMV infection or a tissue or organ transplant recipient of a transplanted tissue, organ, or donor that has or is owed to HCMV infection. In one such embodiment, the tissue or organ transplant recipient is seronegative for HCMV infection. In other embodiments, the transplant recipient or individual has previously been infected with HCMV and is at risk of HCMV reactivation and infection. In certain embodiments, the agent additionally comprises an effective amount of at least one other therapeutic agent, such as described below. In another embodiment, the medicament is for treating, inhibiting or preventing Hcmv infection in an individual at risk of infection, comprising administering to the individual an effective amount of an agent to inhibit or prevent HCMV infection. In other embodiments, the agent is for treating an infant infected with 11 (:) infection or an infant exposed to HCMV during pregnancy, comprising administering to the infant an effective amount of a composition comprising an antibody of the invention or a combination thereof. An "individual" according to any of the above embodiments may be a human. In another aspect, the invention provides a method of treating, preventing or inhibiting HCM: Infection. In one embodiment, the method comprises administering to the individual an effective amount A composition comprising an anti-complex antibody and/or an anti-gH antibody. In other embodiments t, the invention provides a prophylactic, inhibitory or therapeutic congenital 158864.doc -82 - 201215618

A method of HCMV infection or HCMV infection of a transplanted tissue, organ or donor with or with a hcMV-infected tissue or organ transplant recipient comprising administering to the individual or transplant recipient an effective amount of an antibody comprising an anti-complex and A composition of an anti-gH antibody. In one such embodiment, the tissue or organ transplant recipient is seronegative for HCMV infection. In other embodiments, the transplant recipient or individual has previously been infected with HCMV and is at risk of HCMV reactivation and infection. In one such embodiment, the method further comprises administering to the individual an effective amount of at least another therapeutic agent as described below. In other embodiments, the invention provides a method of treating, inhibiting, or preventing an infant infected with HCMV or an infant exposed to HCMV during pregnancy, comprising administering an antibody of the invention or a combination thereof Composition. An "individual" according to any of the above embodiments may be a human. In another aspect, the invention provides a method of inhibiting or preventing HCMV infection in an individual at risk of infection. In one embodiment, method package 3 administers to the individual an effective amount of a composition comprising an anti-Complex 1 antibody and/or an anti-sense antibody to inhibit or prevent HCMV infection. In the embodiment, the individual is a human. In other embodiments, the transplanted organ or tissue can be any organ or tissue that can be implanted from one to the second individual. For example, the transplanted 7 can be: (but not limited to) heart, kidney, liver, lung, sputum, intestine or chest, for example, the transplanted tissue can be (but is not limited to) the hand, the cornea, Skin, face, Lange island, bone marrow, stem cells, whole blood, small blood = serum, blood cells, blood vessels, heart valves, bones, osteophytes, cartilage 'ligaments, tendons, muscle lining. 158864.doc • 83- 201215618 In another aspect, the invention provides, for example, for use in any of the above methods of treatment comprising any of the anti-complexes provided herein! Groups of antibodies and/or anti-gH antibodies: pharmaceutical and pharmaceutical formulations. In one embodiment, the pharmaceutical formulation comprises any of the anti-Complex I antibodies and/or anti-gH antibodies and pharmaceutically acceptable carriers provided herein. In another embodiment, a pharmaceutical formulation comprises any of the anti-Complex I antibodies and/or anti-gH antibodies provided herein and at least one other therapeutic agent, such as described below. The antibodies in the compositions of the invention may be used in therapy alone or in combination with other agents. For example, an antibody of the invention can be co-administered with at least one other therapeutic agent. In certain embodiments, the additional therapeutic agent is ganciclovir, valganciclovir, Foscarnet, and/or cidofovir. In other embodiments, the additional therapeutic agent is an additional therapeutically isolated antibody. The combination therapies described above encompasses combination administration (where two or more therapeutic agents are included in the same or separate formulations); and separate administration, in which case administration of the antibody composition of the invention This can be done before, concurrently with, and/or after administration of the additional therapeutic agent and/or adjuvant. The compositions of the present invention (and any other therapeutic agents) can be administered by any suitable means, including parenteral, intrapulmonary, and intranasal administration, and if necessary, for topical treatment, including intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. Administration can be carried out in part by any suitable route, e.g., by injection (e.g., intravenous or subcutaneous injection), depending on whether the administration is short-term or long-term. Various dosing schedules include, but are not limited to, single administration or multiple administrations over multiple time points, bolus administration and pulse infusion are encompassed herein. 158864.doc -84- 201215618 The compositions of the present invention will be formulated, administered and administered in accordance with good medical practice. Factors considered in this case include the treatment of '', σ*, the specific condition, the particular mammal being treated, the individual patient's clinical & Λ 玛 、, the cause of the disease, the site of the drug delivery, the method of administration, The time of administration is other factors known to Jiu Jiji. The composition is not required, but optionally formulated with one or more of the agents used in the prevention or treatment of the condition. The effective amount of such other agents will depend on the amount of antibody present in the formulation, the type of disorder, or other factors discussed in the type of treatment. Such agents are usually administered in the same dosages and with administration routes as described herein, or at any of the dosages described herein: from 1% to 99%, or in any dosage and by empirical/clinical determination as appropriate. use. For the prevention or treatment of a disease, the appropriate dose of the antibody contained in the composition of the invention (when used alone or in combination with one or more additional therapeutic agents) will be the type of disease to be treated, the type of antibody, the severity of the disease, and the course of the disease. Administration of the antibody to achieve prophylactic or therapeutic purposes, prior therapy, clinical history of the patient, response to the antibody, and judgment of the attending physician. The antibodies included in the compositions described herein are suitable for administration to a patient once or over a range of treatments. Depending on the type and severity of the disease, for example, by one or more separate administrations or by continuous infusion, each from about μg/kg to 15 mg/kg (eg (M mg/kg_1〇mg/kg)) The antibody can be the initial candidate dose for administration to a patient. Depending on the factors mentioned above, a typical per dose of bismuth can range from about 1 pg/kg to 100 mg/kg or more. For repeated administrations over several days or longer, depending on the condition, the treatment will usually continue until the symptoms of the disease are inhibited. An exemplary dose of each of the anti-158864.doc -85 - 201215618 is about 0.05 mg / From kg to about 1 mg/kg. Therefore, one or more of 0.5 mg/kg, 2 mg/kg, 4 q mg/kg or 10 mg/kg (or any combination thereof) can be administered to the patient or Multiple doses. These doses may be administered intermittently, for example weekly or every 3 weeks (eg, such that the patient receives from about 2 to about 20 or, for example, about 6 doses of the antibody). The initial higher loading dose can be administered (loading Dose), followed by one or more lower doses. The process of this therapy is monitored by conventional techniques and assays. Any of the above formulations or treatments can be performed using an immunoconjugate of an antibody described herein in place of an anti-complex Ϊ antibody and/or antibody, or in addition to an anti-complex I antibody and/or an anti- §] antibody An immunoconjugate of an antibody described herein can be used. I. Preparations In another aspect of the invention, an article of manufacture comprising a substance suitable for treating, preventing, and/or diagnosing the above conditions is provided. The article comprises a container And a label or package insert located on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, 1 solution bags, etc. The containers may be formed from materials such as glass or plastic. The containers may be contained separately or together. A composition of another combination of compositions that treats, prevents, and/or diagnoses a condition and can have a sterile access port (e.g., the container can be an intravenous solution bag or vial having a stopper pierceable by a hypodermic needle). The active agent in the composition is an antibody of the invention. The label or the pharmaceutical label indicates that the composition is used to treat the selected condition. Further, the article may comprise (4) A fourth device, wherein the composition comprises an antibody of the invention; and a first combiner comprising a combination, wherein the composition comprises another cytotoxic agent or other 158864.doc-86 - 201215618 therapeutic agent. The article of manufacture in this embodiment may further comprise a package insert which means that the composition is not useful for treating a particular condition. Alternatively or additionally, the article may further comprise a pharmaceutically acceptable buffer (such as bacteriostatic water for injection ( A second (or third) container of BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. It may further include other materials that are desirable from a commercial and user standpoint' including other buffers, diluents, filters, needles, and syringes. It is to be understood that any of the above products may include an immunoconjugate of an antibody described herein in place of an anti-complex 1 antibody and/or an anti-gH antibody, or in addition to an anti-complex I antibody and/or an anti-gH antibody. An immunoconjugate of an antibody as described herein. III. Examples The following are examples of methods and compositions of the present invention. It will be appreciated that various other embodiments may be implemented in the light of the general description. Materials and Methods Virus growth. Human fetal lung fibroblasts (MRC5) cultured under subculture® 7-14, except in DMEM culture (American Type Culture Collection >ATCC; Manassas, VA) VR1814 (Ravello Lab, Fondazione IRCCS Policlinic) was propagated in p〇 human umbilical vein endothelial cells (HUVEC) (Lonza; Basel, Switzerland) cultured under subculture 4-6 as described.

San Matteo, Pavia Italy), and the concentrated supernatant was resuspended in complete medium and frozen. Complete medium supplemented with 10% fetal bovine serum, penicillin/streptomycin 'L-calic acid (all 158864.doc •87·201215618 from Invitrogen; Carlsbad, CA) and 20 mM HEPES ( Cellgro; Manassas, VA) DMEM. MRC5 and HUVEC cells and human retinal pigment epithelial cells (ARPE-19) (ATCC-described culture), monocyte-derived macrophages (MDM), and cytotrophoblast cells as placental epithelial cells in 96-well plates (cytotrophoblast) is tested. MDM was isolated from whole blood using the RosetteSep Human Monocyte Enrichment Mix (Stemcell Technologies, Vancover, BC, Canada) as per the instructions. Monocytes were then stimulated with 0.1 pg/ml lipopolysaccharide (LPS) (Invivogen) and grown overnight in DMEM. Platelets and unbound cells were washed with PBS prior to infection. Cytotrophoblast cells were isolated from a 19-week placenta (Pereira Lab, UCSF, using the protocol from Librach et al., 1991, «/CF 1 13:437-449) and seeded in 96-well tissue culture plates. The cytotrophoblast cell marker cytokeratin 7 (CK7) (Dako) of the cytotrophoblast cell preparation was assayed and found to be more than 90% positive at the onset of infection. The following HCMV strains were obtained from Dr. Jay Nelson (University of Oregon Health and Science University (OHSU); Portland, OR): Adinis, Brown, Cano, Davis, Dement, Grunden, Harris, Keone, Lysistrata, NewRock, Phoebe, Powers, Salvo, Schmoe, Simpson and Watkins ° The following HCMV strains were obtained from Dr. Sunwen Chou (OHSU): C079, C323, C327, C336, C352, C353 and C3 59. The thawed virus is added to MRC5 fibroblasts and allowed to grow until 1% CPE is visible (about 1 〇-12 days after infection). After 3 days, the cells were scraped off and the supernatant was collected and concentrated by ultracentrifugation at 158864.doc -88 - 201215618. Dilutions of each strain were used to infect fresh fibroblasts in 96-well plates. The virus was infected for 18 hours, after which the cells were 100°/. Ethanol fixed. Mab810 (an anti-IE antibody) (Millipore; Billerica, ΜΑ) was used for sputum staining and immunofluorescence analysis was performed. The titer is calculated and used to determine the amount of virus necessary to achieve the neutralization assay's infection rate (MOI). Basically, neutralization tests are generally performed as in Abai et al., 2007, J. Twww(10)/Mei/zoc??, 3 22:82-93, with the exception that the assay is performed in DMEM (Gibco) and by the above The immunofluorescence is described for detection. Briefly, antibodies are serially diluted and mixed with the virus diluted in complete medium such that the final virion concentration when mixed with the medium or non-inhibitory antibody results in about 1 infectious virus per cell (ΜΟΙ = 1). The antibody was mixed with virus and incubated for 1 hour at 37 degrees, followed by addition to confluent monolayers of MRC5, ARPE-19, HUVEC or monocyte-derived macrophages (MDM). The virus was infected for 18 hours, after which time the cells were fixed with 100% ethanol. Cells were blocked in PBS containing 2% BSA and then stained with anti-HCMV IE antibody Mab810 (Millipore) or rabbit anti-HCMV IE (Johnson Lab, Oregon Health Sciences University). The cells were washed with PBS and incubated with appropriate AlexaFluor 488 and Hoechst stains (Invitrogen). Data containing two wells of the indicated antibody concentration were averaged and compared to infection in the absence of antibody (set to 100%). Cells were imaged and counted using ImageXpress® MicroTM and MetaXpress® (Molecular Devices). The data was logarithmically transformed, corrected, plotted and calculated using Prism (GraphPad Software, La Jolla, CA) EC50 and 158864.doc -89- 201215618 EC90. The EC90 value was calculated from the best fit curve using the EC50 curve fitting algorithm. The detection range is 100-6.5 χΙΟ 5 infectious virus particles per well. Verification verification was observed between experiments, especially in the case of different viral infection rates. Amplification and clustering of clinical virus strains. The clinical HCMV strain (from Oregon Health Sciences University) was grown on fibroblasts, the supernatant was collected, and concentrated using ultracentrifugation. DNA was isolated from infected cells using the DNeasy blood and tissue kit (Qiagen). HCMV gene primers were designed using an alignment of HCMV strains that were not restricted by patent rights. Conserved regions separated by less than 500 bases were selected. Sequences from clinical strains were viewed using Sequencher® and translated using MacVector. The tree is constructed by ClustalW and aligned in the Jalview alignment editor and using nearest neighbor consistency %. Protein is expressed by baculovirus. In order to detect the expressed protein, rabbit polyclonal antibodies were produced by standard procedures. Each rabbit was immunized with a peptide corresponding to the HCMV protein. Each peptide is as follows: gH_871 HPHHEYLSDLYTPCSSSGRRDHSLERLTR (SEQIDNO: 195) »gH_977 CPHVWMPPQTTPHDWKGSHTTSGLHRPH (SEQ ID NO: 196) > gL_873 CGLPPELKQT1RVNLPAHSRYGPQAVDAR (SEQIDNO: 197) > UL128_988VGLDQYLESVKKHKRLDVCRAKMGYMLQ (SEQIDNO: 198) > UL128_989RQWHNKLTSCNYNPLYLEADGRIR (SEQIDNO: 199) > UL130_892 RDYSVSRQVRLTFTEANNQTYTFCraPNCSEQ JD NO: 200) > UL130_892SPWFILTANQNPSPPWSKLTYPKPHDC (SEQ ID NO: 201), and UL131 993 TAEKNDYYRVPHYWDACSRALPDQTRYK (SEQ ID NO: 202) » 158864.doc • 90-201215618 Serum was purified by capture on a peptide-binding column and subsequent dissociation. For the secreted protein, a baculovirus construct of the extracellular domain of each HCMV protein was prepared. Each of the HCVM extracellular domains was fused to the baculovirus signal sequence and the 6x-His tag on the C-terminus. The baculovirus expression vector is used to infect SF9 or Tini insect cells. Proteins were collected and subjected to gel filtration and examined by acrylamide gel electrophoresis and coomassie staining. Confluence contains all five proteins (gH, gL, UL128, UL130 and UL131). The gB trimer construct was produced by fusing gB S64-K115 with Q499-E655. When expressed by infected insect cells, the construct produces a gB protein that is not membrane anchored, as expected to form a trimer, binds to neutralizing and non-neutralizing gB antibodies, and may be in its pre-fusion format . When gH and gL are co-expressed, the resulting gH/gL protein binds to HB1 and recognizes the following antibodies that are both non-configuration and conformational gH epitopes: MSL-109, rabbit anti-gH, rabbit anti-gL (from David Johnson, OHSU, Ryckman et al., /. P7ro/. 82:60-70 (2008)), rabbit anti-gH_977 and rabbit anti-gL_873. Insect cells are co-infected with gH, gL, UL128, UL130 and UL131 to produce a small amount of binding to hu8G8 and non-configuration and conformational antibodies (including rabbit anti-gH, anti-gL, anti-UL128, anti-130, anti-131 and the above-mentioned rabbit polyclonal antibody ) a heterogeneous protein. The pRK-CMV vector was constructed. For the surface expression of the full-length viral glycoprotein, three different types of plastids were constructed. Individual HCMV genes were amplified from start to finish. gH, gL, gB were amplified from genomic DNA, and UL128, UL130, UL131 were amplified from cDNA and first cloned using PCR Blunt II TOPO (Invitrogen). Subsequently, the gene was cloned into the sequence of "cleavage of 2A peptide from 158864.doc 91 201215618" (Szymczak et al., Α^3ί 22:589-94 (2004)) to encode each HCMV gene and the last 3 gene. The gene for eGFP is isolated from the Genentech Mammalian Expression Vector (pRK-tk-Neo). Three plastids were constructed, one with gB and eGFP, one with gH, gL and eGFP, and one with UL128, UL130, UL131 and eGFP. The plastids were transfected into human embryonic kidney (HEK)-293T cells (American Type Culture Collection, ATCC; Manassas, VA) using Lipofectamine 2000 (Invitrogen; Carlsbad, CA).

Cytogam® (HIG) reduction. HEK-293T cells were treated with lipofectamine 2000 (Invitrogen) with gB/eGFP or gH/gL/eGFP and UL128/UL130/UL131/eGFP or mock for HIG to neutralize the components of the virus into epithelial cells. Transfected and incubated for 48 hours. Cells were dissociated using Accutase (Sigma), assembled, and divided into 12 aliquots. Cytogam® was diluted to 20 pg/ml in PBS and 0.5°/calf serum albumin (BSA) and incubated for 1 hour in a suspension containing 3×107 transfected cells. Cytogam® was then continuously transferred to 3 χ 107 fresh aliquots of transfected cells. Subculture to new cells was performed until the greatest specific loss of antibody was observed (6 passages). An ELISA assay was performed to detect the reduction of certain HCMV specific antibodies. The Maxisorp (NUNC) plate was coated with PBS containing purified gB, gH/gL, or gH/gL/UL128/UL130/UL131 produced by baculovirus and/or lysate of transfected HEK293T cells. Detection was determined by goat anti-human IgG Fcy (Jackson Laboratory, Bar Harbor, ME) in combination with horseradish peroxidase. The lower limit of detection is 0.08 pg/ml. The resulting HIG is then concentrated using a 100 kD molecular weight cutoff concentrator (Centricon) -92- 158864.doc

S 201215618 for use in the neutralization assay described above. An affinity reduction column is generated in the following manner. Protein (1-2 mg soluble gB or gH/gL) was dialyzed extensively against PBS and added to approximately 1 ml of Sterogene ALD Superflow resin equilibrated in PBS. Sodium cyanohydride (0.2 ml of a 1 Torr solution) was added to chemically couple the protein to the aldehyde containing resin and the reaction was allowed to proceed overnight at 4 °C. Individual resins were loaded into the tubule string and washed extensively with PBS to remove any unbound protein. 2 mg of Cytogam® was loaded onto the column in a volume of 800 μΐ and washed with PBS at a flow rate of 0.4 mL/min. Unbound protein was collected in several 0.5 ml aliquots and concentrated in a rotary concentrator at a molecular weight of 5000 Daltons to concentrate to approximately 100 μM, respectively. Samples were sterile filtered and stored at 4 °C until assayed. FACS. The previously described pRK-CMV vector was transfected into HEK293T cells either alone or at a ratio of gH/gL of 50:50 using UL128-131 using lipofectamine 2000 (Invitrogen). After 48 hours, cells were dissociated using Accutase (Sigma). All primary or secondary antibodies (Jackson Labs) were cultured and washed in PBS, 2% FCS, 0.2% sodium azide (FACS buffer). After staining, the cells were fixed in FACS buffer containing 2% polyfurfural. Fluorescence analysis was performed using a FACS Calibur 4 (Beckton Dickinson) and data was processed using FlowJo software (Tree Star Inc.). Resistant virus mutants are produced. To generate a viral mutant that is resistant to the antibodies described herein, the HCMV strain VR1814 was subjected to Genentech's antibody MSL-109 at a suboptimal concentration (Aulitzky et al., /./«/Here <^· D/t 163:1344-47 (1991)), in the presence of HB1, hu8G8 on epithelial cells 158864.doc -93- 201215618 or in the presence of a combination of HB1 and hu8G8 in ARPE 19 cells (American Type Culture Collection, ATCC) ; grown in Manassas, VA). The experiment was started in a 24-well plate in which the antibodies at EC50, 2x EC50 or EC90 each corresponded to 3 wells and the infection magnification (MOI) was 0.5. One week, one-half of each well volume was subcultured to new cells and the antibody concentration was increased 1.5-fold or remained stable. Typically, as of the ninth generation, the mutant appears as a single plaque. These viruses are grown in such a way that the antibody concentration is increased to the final concentration of l〇x EC90. Subsequently, the mutants were stocked and analyzed for resistance to HB1 and hu8G8 by neutralization assay as described above. The entire process was started 4 times for ARPE-19 cells (3 wells per antibody concentration) and only with HB1 and MSL 109 (hu8G8 does not neutralize the virus on MRC5 cells). In order to generate other resistance mutations, the extracellular virus was treated with AA-ethylnitrosourea (ENU, Sigma-Aldrich; St. Louis, MO) or UV (254λ Stratalinker, Stratagene; Santa Clara CA) and allowed to be at 24 ARPE-19 or MRC5 cells were infected in well form (24 wells per treatment) or 96 well format (72 wells per treatment). After infection (under MOI 1 or 2), the medium is treated with HB1 (under EC100) or hu8G8 (under EC100) or a combination of the two antibodies (each at EC50), orciclovir (GCV, Complete medium replacement of Sigma-Aldrich). Each week, the supernatant is subcultured to fresh cells while increasing the concentration of antibody or GCV. The growing virus was transferred to larger wells and stored after 2-3 months. The whole process starts twice each time. Order glycoprotein. DNA was isolated from control or mutant virus-infected cells or supernatant (DNA blood/tissue extraction kit, Qiagen; Valencia, CA). According to the National Center for Biotechnology Information (National Center for 158864.doc -94- 201215618

The alignment of the HCMV strains AD169, FIX, TB40E, Toledo and Towne sequences obtained in the Biotechnology Information, NCBI) database was designed to target primers spanning the conserved sequences of the genes. Glycoproteins from the start codon of each clinical virus strain to base 2196 (only the stop codon is lacking) were amplified. Glycoprotein B was amplified from the start to base 2686 (only the stop codon was lacking). UL128, UL130 and UL131 are each amplified according to the cDNA sequence obtained from Akter et al., "/. F/ro/. 84:1117-22 (2003) from the beginning to the end. The polymerase chain reaction (PCR) product is sequenced using a dye terminator reaction and the sequences are aligned and trimmed (sequencer). The re-enactment of the mutation. The pRK-CMV-expressing plastid containing the gH/gL gene or the UL128/UL13 0/UL131 gene as described above was modified to replace a single mutation found in each of the resistant mutants. Each gH/gL plastid was transfected (Lipamine 2000, Invitrogen; Carlsbad, CA) into HEK 293T cells (ATCC) for 2 days, and then by fluorescence activated cell sorting as described above (FACS) Analysis of the ability of surface-expressed HCMV proteins to bind to control anti-gH antibody 10F8 or HB1. Each UL128/UL130/UL131 plastid was co-transfected with the gH/gL plastid for 2 days, and then the ability of the surface-expressed protein to bind HB1, hu8G8 and control rabbit anti-UL131_993 antibody was evaluated. Analysis and images were generated using FlowJo (Treestar; Ashland, OR).

Analyze virus entry. Stocks of resistant and control virus strains (parallel passage on ARPE-19 cells in the absence of antibodies) were grown and supernatants (pure) were collected. Quantitative PCR (qPCR) was performed to obtain pp65 DNA pp65F TCGCGCCCGAAGAGG (SEQ ID NO: 189), pp65R CGGCC GGATTGTGGATT (SEQ ID NO: 190), Taqman probe CACCGA 158864. doc - 95 - 201215618 CGAGGATTCCGACAACG (SEQ ID NO: 191) . To determine the number of replicates, a standard curve was obtained by pl65 into Zero Blunt PCR Cloning (Invitrogen). The dilution of the virus based on the replica number was infected with ARPE-19 and MRC5 cells for 18 hours, followed by fixation and observation. The number of infectious particles per DNA copy was calculated and compared to the virus strains that were subcultured without antibodies and plotted using Excel version 14.1.2 (Microsoft; Redmond, WA). Example 1 - Generation of anti-Complex I antibody and anti-gH antibody Anti-Complex I murine mAb 8G8 was produced. Two groups of Balb/c mice (10 per group) were immunized with intact UV-inactivated (3000 mJ) HCMV (viral strain VR1814) at a concentration of 1χ106 pfu per mouse, twice a week for a total of SC /IP injection 7 times. In the first group of animals, each mouse was infused with RIBI adjuvant and subsequently injected with PBS containing HCMV. In the second group of animals, the animals were not perfused and then injected with RIBI adjuvant containing HCMV. The test blood of the immunized mice was subjected to serum sample titration by ELIS A and virus neutralization assay as described above. The mice in the top 5 reactivity were selected to produce fusion tumors. Two groups of fusions were performed using lymphocytes from the nodules and inguinal nodules and mouse myeloma cell line X63-Ag8.653. The fused cells were plated in 96-well tissue culture plates (58 plates) and fusion tumor selection was started using HAT medium supplement (Sigma, St. Louis, Μο.) 1 day after fusion. A total of 738 IgG+ fusion tumors were screened using virus neutralization assays on epithelial cells as described above. The HCMV strain VR1814 was tested for EC50 (pg/ml) of the resulting antibody against various cell types and compared to MSL-109 (an anti-gH antibody) and is shown in Table 2. The monoclonal antibody 8G8 was screened for the most potent neutralizing antibody and was selected for humanization and further characterization. Table 2

EC50(pg/ml) : HCMV strain VR1814 Cell type Target epithelial endothelial fibroblast MSL-109 gH 0.1642 0.0764 0.3890 Murine 8G8 complex I 0.0014 0.0007 N/A Rat 5H3 gH 1.15 1.42 17.76 Rodent 10F8 gH 0.1 0.1 1.11 Murine 15H2 gH 0.12 0.11 1 Murine 354.1 Complex I 0.03 0.07 N/A Humanization and analysis of murine 8G8 mAb. The murine fusion tumor 8G8 was humanized by standard CDR grafting using the λ3 or λ4 light chain (Fig. 2) and the VH1, VH3 or VH7 heavy chain framework (Fig. 1). For comparison, the common human lambda germline sequence of λ3 and λ4 is shown in Figure 2. A neutralization assay was performed to compare the combination of the 8G8 human/murine chimeric antibody (QE7/C2) with the 8G8 VH1, VH3 or VH7 humanized heavy chain and the 8G8 λ3 or λ4 light chain. The λ4 variant but not the λ3 variant was found to neutralize HCMV (Fig. 3). HVR-L2 of mutation λ4 as shown in Figure 4 introduces substitution at amino acid 50C, 50D, 56, and amine group at amino acid 57 (first amino acid of FR3) (according to Kabat numbering) Acid substitution to provide stability to the antibody. The various mutations were lightly linked in combination with the 8G8 human VH1 chain and tested for antibodies as described above and in assays. Antibodies with a single amino acid substitution showed good neutralizing activity (i.e., Al, E1, ΤΙ, A2, E2, and T2) (Fig. 5). Similarly, all antibodies containing two amino acid substitutions showed good neutralizing activity (i.e., SGSG and TGDA). A single mutant SG was included as a comparative control and it also showed good neutralizing activity. (Figure 6). 158864.doc -97- 201215618 The humanized 8G8 λ4 antibody sequence is shown in Figure 7 (hu8G8A4 FW). Figure 8 shows the sequence of the humanized 8G8 VH1 sequence (hu8G8.VH1) and Figure 9 shows the sequence of the humanized 8G8 VH3 sequence (hu8G8.VH3). Figure 10 shows the humanized 8G8 λ4 antibody sequence in which the first two amino acids (QP) have been modified to allow the polypeptide to start with serine (Q is deleted and L is mutated to S) and the amino acid 36 retains the murine amine group. Acid (Υ). The polypeptide sequence of this antibody is shown as a λ4 8G8 graft. A representative nucleic acid sequence encoding a polypeptide is shown below the polypeptide sequence. The affinity of the anti-gH antibody is mature. The synthesis of antibody sequences of the variable heavy and variable light chain sequences of MSL-109, as disclosed in PCT Publication No. WO 94/1 6730, published on Aug. 4, 1994, which is hereby incorporated by reference in its entirety. Single antibody MSL-109. The amino acid sequence of the MSL-109 VH and VL chains is shown in Figure 11 (VL: SEQ ID NO: 90; VH: SEQ ID NO: 92). The MSL-109 anti-system is based on an IgGl framework containing heavy chain VH3 and light chain Vk2. Recombinant DNA encoding this antibody was cloned into CHO cells. The antibody MSL-109 was affinity matured by randomization of the complementarity determining regions (CDRs) followed by phage display with a progressively limiting concentration of the biotinylated gH/gL selection conjugate. Localization of CDRs by randomization of oligonucleotides using the "NNK" codon, where N is any of the four natural nucleotides, and K is 50% thymine and 50% guanine. The NNK codon can encode any of the 20 natural amino acids. Libraries of light and heavy chains were prepared separately, and each of the three CDRs of each chain was simultaneously randomized. This produces a pure line with 0 to 3 random amino acid changes in each chain with up to 1 mutation in each CDR. The phage Fab fragment was presented as a 158864.doc-98-201215618 and the library was prepared by standard methods. Combining the pure line' and then competing with 10〇nM gH/gL or MSL-109 IgG to reduce by culturing a phage display library with 1 and 0·1 nM biotinylated gH/gL in successive rounds of selection The combination of pure affinity and gH/gL with lower affinity. The bound pure lines were captured on neutravidin or streptavidin coated ELISA plates, washed and lysed in 1 mM HCl for 1 hr at room temperature. The lysed phage were neutralized with 1 μl volume of 1 μ Tris (pH 8.0) and used to infect E. coli to achieve amplification for the next round of selection. The pure line sequence from the second round of selection determines the frequent mutations in the selected phage. A pure line with a favorable mutation was tested by competitive phage ELIS A. The IgG and Fab fragments of the mutant MSL-109 with individual or combined mutations in the heavy chain Kabat positions 53 and 55 were expressed and tested for in vitro neutralization of CMV. Amino acid substitution at amino acid 53 alone or in combination with an amino acid substitution at amino acid 55 (replacement of T55 with R or κ) (with s, I, N, Q, F, M, L) , G, H, K, W, Y, V or A substitution D53) provides antibodies with improved neutralizing properties (Figures 12B and 12C). A schematic of some of these variations is shown in Figure 12A. In addition, the amino acid N52 in MSL-109 can be replaced by S. This substitution does not affect potency but allows S in position 5 3 to have no glycosylation at position 5 2 . The heavy chain variable sequence has 89 possible combinations (SEQ ID NOS: 87, 88, 89 and 96-182) with various amino acid substitutions at position 55 of the amino acid 53 and/or amino acid. The common sequence is provided as SEq m n〇:94. The affinity of the Fab fragments of these anti-gH antibodies for gH/gL dimers produced in baculovirus was measured in a phage-present ELIS A assay. In particular, the phage pure lines presenting the βL 158864.doc -99-201215618 MSLd09 variant Fab fragment were incubated with serially diluted gH/gL and incubated for 1 hour at room temperature. Unbound phage were detected by incubating the mixture in the gH/gL coated ELISA plate wells for 10 minutes at room temperature. The plates were washed with PBS-T and incubated with anti-M13 HRP conjugate for 30 minutes, followed by washing and color development with TMB to detect phage bound to immobilized gH/gL. The IC50 was calculated by nonlinear regression, i.e., 50% of the phage-gH/gL mixture was free. The IC50 is in the range of 0.01-0.1 nM. The individual affinities of the selected variants are shown in Table 3. Table 3 Variant phage ELIS A ICs〇(nM) H2 single mutant WT (MSL-109) 0.53 H2-D53L 0.02 H2-D53M 0.05 H2-D53N 0.06 H2-D53S 0.1 H2-D53T 0.06 H2 double mutant H2-T55R 0.17 H2-D53F/T55R 0.01 H2-D53L/T55R 0.02 H2-D53M/T55R 0.07 H2-D53N/T55R(HB1) 0.05 H2-D53Q/T55R(HB2) 0.01 H2-D53S/T55R 0.03 H2-D53T/T55R 0.03 Amazing The amino acid change at the VH2 HVR produces antibodies with significantly higher binding and neutralization capabilities. For example, HB1 (D53N/T55R) has a 10-fold increase in affinity for gH/gL compared to MSL-109, as shown by phage ELISA (Table 3). Compared to the parental MSL-109 antibody, when expressed as a Fab fragment in E. coli, HB1 (D53N/T55R) inhibits 158864.doc •100-201215618 HCMV into ARPE-19 cells by about 40 times more potently. (ie 'EC50=0.15 nM vs. 6.2 nM), as indicated by the neutralization assay (Fig. 12B) ° In addition, when HB_ cells are expressed in full-length IgG, 'HB1 (D53N/T55R) enters ARPE for HCMV The inhibition in -19 cells was about 6 times more potent as shown by the neutralization assay (Table 4, Figure 12C). The EC50 and EC90 (pg/ml) of the HB1 antibody in the neutralization assay (1 representative experiment) for various cell types were shown in Table 4 below compared to the MSL 109 antibody. Table 4 Epithelial endothelial endothelial MDM MDM fibroblast fibroblast EC50 EC90 EC50 EC90 EC50 EC90 EC50 EC90 MSL-109 0.3 2 0.48 2.9 0.04 0.42 0.73 4.8 HB1 0.05 0.41 0.03 0.28 0.03 0.19 0.11 0.77 Example 2 - Antibody Functional Study Comparison 1 ^1 (0531^/丁5 511) and 1111808 and 1110 block the ability of HCMV viruses to enter epithelial cells, endothelial cells, macrophages, and fibroblasts in a neutralization assay. The EC50 of hu8G8 for epithelial cells was 0.006 pg/ml (0.2 nM), the EC50 for endothelial cells was 0.004 pg/ml (0.3 nM), and the EC50 for monocytes was 0.001 eg/ml (0.006 nM). In terms of HCMV in neutralizing each of these cell types, hu8G8 is at least 8-fold more potent than HB1. However, as expected, hu8G8 did not block the entry of the virus into the fibroblasts, while HB 1 blocked the virus from entering the fibroblasts with an EC50 of 0.11 pg/ml (0.7 nm) (see Figure 13). It has been reported that 'HIG can prevent HCMV fetal infections and/or diseases when administered to pregnant women with primary HCMV infection (Nigro et al., 2005)' indicates that CMV-specific antibodies can confer protection to developing fetuses. Neutralization test 101 · 158864.doc 201215618 When assessed, HIG was found to neutralize the virus into all test cell types, but the potency was much less than either monoclonal antibody (see Figure 13). This relatively low performance is attributed to the multi-plant nature of HIG with only a small fraction of proteins with anti-CMV neutralizing activity. Example 3 - HIG Subtraction Study In order to identify neutralizing antibody components in high immunoglobulin, HEG anti-gB antibody or anti-complex I was attenuated by HEK293T cells transfected with gB or complex I by 6 consecutive incubations. (gH/gL/UL 128/UL130/UL 13 1) Antibody. Cytogam® (HIG) reduction was performed according to the above method. Analysis of the adsorbed serum showed 〇°/ compared to the control cells. , there is > 95 ° /. Antibodies reactive with cells transfected with gB are adsorbed by this procedure, as determined by a purified gB ELISA. However, compared to 0% for control cells, only about 45% of antibodies reactive with cells transfected with complex I have been adsorbed, such as by solubilization from transfected HEK293T cells as described above. The product was assayed by ELISA. The subtracted HIG is then used in a neutralization assay to determine the effect of depletion on preventing the entry of the virus into epithelial cells. Serial dilutions of the adsorbed HIG preparation were used in the neutralization assay described above as compared to the simulated adsorption of HIG. The results of these experiments are shown in Figure 14. Antibodies against gB did not appear to contribute significantly to HIG's ability to neutralize epithelial cells, whereas antibodies against complex I appeared to contribute significantly to HIG neutralizing activity. Removal of the complex I-specific antibody reduced the HIG neutralizing capacity (EC50) by about 85% when tested on epithelial cells. The elimination of HIG for fibroblasts is not possible because of the extremely high concentration required to detect 158864.doc -102- 201215618. HIG has an EC50 of about 500 pg/ml for this cell type. Since UL128, UL130 and UL131 proteins are not required for entry into fibroblasts, gB or gH/gL expressed by baculovirus in combination with the column as described above is used for specific protein/complexation from HIG. An antibody with specificity. In the case where the anti-gB antibody was nearly completely attenuated (the 95% reduction of the gB antibody on the gB column was 0% reduction of the gB antibody on the gH/gL column), no neutralization change was observed. However, an EC50 reduction of 65 was observed with most anti-gH/gL antibodies reduced (84% reduction of gH/gL antibody on gH/gL column for 0% reduction of gH/gL antibody on gB column) °/. (See Figure 14). From this data, it is concluded that the major neutralizing anti-system in HIG is directed to the gH/gL/UL128/UL13 0/UL131 complex. In particular, the complex I neutralizing antibody is a major neutralizing antibody against epithelial cell entry in HIG. In addition, gH/gL antibodies in HIG have a major role in inhibiting viral entry into fibroblasts. These experiments show that the anti-gB antibody has little effect in HIG neutralization, and adsorbs HIG by using baculovirus gB, gH/gL and gH/gL/UL128/UL130/UL131, and about 1% by ELISA. The HIG has gB reactivity, while about 0.1-0.2% is reactive with complex I or gH/gL. Knowing the concentration of complex-specific antibodies in HIG, their complex-specific antibody neutralization potency can be corrected by determining the complete HIG neutralization efficiency based on the percentage of IgG actually associated with the complex that leads to neutralization. To calculate (for example, for fibroblasts, 810 pg/ml x 0· 1-0.2 = 0.8-1.6), as shown in Table 5 below. 158864.doc -103 - 201215618 Table 5 EC9〇bg/ml) Neutralizing agent Target Epithelial cells Endothelial cells Macrophage Fibroblasts HCMV-HIGt HCMV + Unknown 0.01-0.02 0.01-0.02 0.004-0.01 0.8-1.6 HB1 SH 0.4 0.28 0.19 0.78 HB2 gH 0.41 0.44 0.21 0.78 HCMV-HIG HCMV + unknown 8.0 11.6 3.8 810 Humanized 8G8 complex with VH1 0.02 0.04 0.010 n/a Humanized 8G8 complex with VH3 I 0.010 0.7 0.010 n/a 卞The EC90 value was adjusted according to the concentration (0.1-0.2%) of the gH/gL/UL 12 8/UL13 O/UL13 1 antibody in HIG. As shown above in Table 5, the combination of HB1 and humanized 8G8 (VH1 or VH3) was able to approximate the neutralizing potency of HIG for all cell types tested in the neutralization assay. Cells were infected at the following HCMV infection rate (MOI): epithelial cells ΜΟΙ = 1, endothelial cells ΜΟΙ = 1, macrophage MOI = 0.5 and fibroblasts ΜΟΙ = 1. HB1 and HIG (as corrected for the amount of HIG specific for complex I) inhibit similar potency against fibroblast infection, but do not provide sufficient efficacy for epithelial cells, endothelial cells or macrophages . Humanized 8G8 (VH1) and (VH3) and HIG (as calibrated according to the amount of HIG with complex I specificity) have similar neutralizing potency with respect to epithelial cells, endothelial cells and macrophages. However, it failed to neutralize infection with fibroblasts. Thus, for all cell types tested, the combination of antibodies provides neutralization of HCMV similar to HIG neutralization of HCMV (adjusted for complex I-specific antibodies). The ability of HB1 and hu8G8 with VH1 and HCMV to enter all of the various cell types was again tested in the neutralization assay and compared to the HIG calculations and the actual neutralizing potency of 158864.doc -104 - 201215618. Cells were infected with the following HCMV MOI: epithelial cells ΜΟΙ = 1, endothelial cells MOI = 0.25, macrophages ΜΟΙ = 0.25 and fibroblasts ΜΟΙ = 0.8. The results of this experiment are shown below in Table 6. The average EC90 obtained in this experiment and the results shown in Table 5 are shown below in the shaded boxes in Table 6. Table 6 EC9〇bg/ml) Neutralizing agent Target epithelial cells Endothelial cells Giant blast cell fibroblast HCMV-HIG 卞HCMV 0.01-0.02 0.007-0.014 0.01-0.02 0.4-0.7 +Unknown 0.01-0.02 0.01-0.02 0.01-0.02 0.6-1.2 book 1 gH 0.18 0.08 0.14 0.25 0.29 0.18 0.17 0.52 HCMV-HIG HCMV 10.2 6.7 10.9 370 + unknown 9.1 9.1 7.4 590 Humanized 8G8 complex with VH1 I 0.02 0.008 0.008 0.02 0.009 0.01 n/a fHIG according to gH/ Adjustment of the contribution of gL/UL128/UL130/UL131 antibodies 0 Example 4 - Neutralized HCMV clinical isolates of gH, gL, UL128, UL130 and more than 20 clinical isolates obtained from 2 laboratories of Oregon Health Sciences University The UL13 1 gene is sequenced and compiled with other publicly available sequences. The publicly available sequences are produced by strains derived from the United States, Europe, and Japan. The cells infected with each virus strain were dissolved and DNA was extracted using a DNA blood/tissue extraction kit (Qiagen; Germantown, MD). The primers for the conserved sequence 158864.doc -105 - 201215618 were designed based on the alignment of the AD169, FIX, TB40E, Toledo and Towne sequences available in the National Biotechnology Information Center database. The glycoprotein gH of each clinical strain from the start codon to base 2196 (only the stop codon is lacking) was amplified. The polymerase chain reaction (PCR) product was sequenced using a dye terminator reaction at Genentech. The sequences are aligned and trimmed (sequencer). Other gH sequences were obtained from the NCBI database by using a registration number from Chou et al., Infect. Dis. 166:604-7 (1992) and then obtaining a "correlation sequence". In total, after removal of the signal peptide, clusters (ClustalW, European Institute of Bioinformatics (EBI); Cambridgeshire, England) were derived from the bilirubin sequences of 57 strains, and the average distance was used to compare the percentages according to the percent identity (JalView) Waterhouse et al., 2009). The sequencing results indicated a 1% change in UL128, UL130 and UL131 sequences between clinical isolates (after removal of the signal peptide). The results of this study are consistent with the findings in Europe that UL128, UL130 and UL131 are highly conserved among pregnant women with primary HCMV infection (Baldanti et al., Jrc/2. K/ro/. 151:1225-33 ( 2006)). In all strains, gH is at least 95% at the protein level (after removal of the signal peptide). Construct a phylogenetic tree with 2 different branches (data not shown). This tree is consistent with the previous report of the gH protein sequence divided into two phylogenetic groups (Chou, /. /77/eci_Db. 166:604-7 (1992)). According to the literature, the HCMV isolates in the two branches are not geographically distinct (i.e., the virus strain isolated in the sputum is found in two branches) (Pignatelli, 乂 Gen. Virol. 84:647-655 (2003)) ° The ability of HB1 (D53N/T55R) to neutralize the infectivity of different groups of HCMV clinical isolates to fibroblasts was tested. Table 7 shows the utility of HB 1 compared to HIG 158864.doc -106 - 201215618. It was found that HB1 can be the same as or better than HIG (when corrected according to the amount of HIG specific for gH/gL/UL128/UL130/UL131) and HIG neutralizing each of the HCMV strains representing the maximum gH sequence diversity. The results of neutralization assays using HCMV strains Dement, Adinis and VR1814 at various MOIs in various experiments are also shown in Table 7 below.

Table 7 Viral strain name (branched number) HB1 (D53N/T55R) E090 (pg/ml) HIG EC90 (pg/ml)* HIG EC90^g/ml) Cano (1) 0.27 0.3-0.7 355 Keone(l) 0.12 0.1- 0.2 104 NewRock(l) 0.18 0.12-0.24 119 TR(1) 0.59 0.3-0.7 350 Brown (2) 0.76 0.4-0.9 442 Dement(2) 0.78 0.8-1.6 80 0.08 0.15-0.3 154 Adinis(2) 2.0 0.74-1.5 233 0.08 0.1-0.2 120 Grunden(2) 0.08 0.14-0.28 137 Harris (2) 0.32 0.3-0.6 305 Phoebe(2) 0.04 0.1-0.2 115 VR1814(2) 0.08 0.1-0.3 790 0.78 0.8-1.6 0.25 0.4-0.7 370 *EC90 value according to HCMV-HIG The concentration of gH/gL/UL128/UL130/UL131 antibody (0.1-0.2%) was adjusted. Example 5 - Specificity of antibodies The antigen specificity of HB1 and hu8G8 was evaluated. A plastid containing a viral glycoprotein is constructed such that each protein is expressed in equal stoichiometry by separating each gene with "self-cleavage 2 A peptide" (Szymczak et al., Biotechnol. 22:589-94 (2004)). The plastid contains the full-length gene of gB/eGFP, gH/gL/eGFP or UL128/UL130/UL131/eGFP (from cDNA selection). 158864.doc -107· -0 201215618 The body was transfected into human embryonic kidney (HEK)-293T cells (American Type Culture Collection, ATCC; Manassas, VA) using lipofectamine 2000 (Invitrogen; Carlsbad, CA). The CMV glycoprotein is expressed at its surface. After 2 days, the cells were dissociated and stained with saturated primary antibody HB1, hu8G8, anti-gB, affinity purified rabbit anti-UL131_933 or affinity purified rabbit anti-gH_977. Cells were stained with appropriate secondary antibodies in combination with allophycocyanin (APC, Jackson ImmunoResearch; West Grove, PA). The camping light of individual cells was measured using a FACSCalibur (BD Biosciences; San Jose, CA) and analyzed using FlowJo software (Tree Star; Ashland, OR). GFP-positive cells (cells expressing CMV transgenes) were selectively mapped to demonstrate antibody binding. As shown in Figure 15, HB1 reacts with cells expressing a complex of gH/gL or gH/gL alone and UL128/UL130/UL131. Hu8G8 only reacted with cells expressing gH/gL/UL128/UL130/UL131 (Fig. 15) and did not react with cells expressing gH/gL or gH/gL/gO alone (data not shown). Neither antibody reacts with cells expressing gB. Therefore, HB 1 recognizes the epitopes present on the gH/gL complex and the gH in complex I. The hu8G8 antibody binds to an antigenic determinant within the five envelope proteins forming complex I, but does not bind to gH/gL/gO or gH/gL alone. Example 6 - Evaluation of Synergism or Antagonism HB 1 and hu8G8 were tested in combination in a virus neutralization assay to determine if there was a difference in potency when the two antibodies were combined. Since antibodies have different targets and are presumed to block the entry of viruses independently, it is assumed that the effects of HB 1 and hu8G8 are additive. Therefore, the application of Bliss Independent Party 158864.doc • 108· 201215618 (combination reaction C with two single compounds of effect A and B is C=A+B-AxB). To this end, HB1 and hu8G8 were mixed at a 1:1 ratio and tested in a series of dilutions in a virus neutralization assay performed on epithelial cells and the EC50 was calculated as described above. HB1 did not augment or attenuate the efficacy of hu8G8 on epithelial cells and the 1:1 curve accurately overlaps the simulated Bliss independence curve, indicating additive rather than synergistic effects (see Figure 16 and Table 8). Also, as expected, hu8G8 did not alter the efficacy of HB1 on fibroblasts because hu8G8 did not block HCMV entry into fibroblasts (data not shown). Therefore, at a 1:1 ratio, HB 1 and hu8G8 did not show any antagonistic or synergistic effects. Table 8 mAB EC5〇bl/ml for epithelial cells alone HBl 0.063 alone hu8G8 0.0080 HBl:hu8G8, 0.0060 at 1:1 simulated Bliss independence 0.0069 To assess whether HB1 and hu8G8 show synergy over a wide range of ratios For action or antagonism, a series of "checkerboard" dilutions across a range of EC50 values are used for neutralization assays. Each antibody was diluted as indicated in Table 9 below, while the virus concentration was constant. The percentage of infected cells for epithelial cells (corrected against antibody-free controls) is shown in Table 9 below for various combinations of antibody concentrations: • tmi 158864.doc -109- 201215618 Table 9 hu8G8 hu8G8 hu8G8 hu8G8 hu8G8 hu8G8 hu8G8 hu8G8 hu8G8 HB1 10 μ^ηιΐ 2 pg/ml 0.4 pg/ml 0.08 μ^ιπΐ 0.016 μ_1 0.0032 μβ/ηιΐ 0.00064 0.000128 Ug/ml ua/ml 0 pg/ml HB1 10 pg/ml 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 HB1 2 pg/ml 0.00 0.00 0.00 0.00 0.00 0.00 0.56 0.17 0.00 HB1 0.4 pg/ml 0.23 0.00 0.28 0.47 0.32 2.08 3.57 2.94 3.97 HB1 0.08 pg/ml 0.29 0.15 0.15 0.15 1.91 13.53 26.76 25.26 26.66 HB1 0.016 gg/ml 0.00 0.48 0.42 0.59 3.29 39.70 61.94 67.60 61.94 HB1 0.0032 pg/ml 0.37 0.71 1.06 0.29 7.23 46.22 80.96 93.01 97.34 HB1 0 pg/ml 0.64 0.33 0.14 0.63 5.50 53.93 83.51 91.95 100.00 Shadow = concentration of each antibody partially neutralized. Using the neutralization assay as described above, the EC50 of HB1 and hu8G8 was determined in the presence of another antibody at 0.8, 0.016, 0,0032 pg/ml. The results of these experiments are shown in Table 10 below and Table 11 and Figure 17. Table 10 - hu8G8 potency antibody at different HB1 concentrations and EC50 (pg/mL) concentration of hu8G8 HB1 ' 0.0037 HB1 at 08 pg/ml 0.0047 HB1 at 016 pg/ml, 0.0028 HBl at 0032 gg/ml, 0.0031 at 0 pg/ml Table 11 - HB1 potency antibody at different hu8G8 concentrations and EC5 〇hg/mL for concentration HB1 hu8G8, 0.035 hu8G8 at 0032 pg/ml, 0.043 1111808 at 6064 pg/ml, at 000128 4§/1111, 0.041 hu8G8, 0.030 at 0 pg/ml. There is no evidence of synergy or antagonism after comparing the efficacy of each antibody alone with the combination of various ratios 158864.doc -110· 201215618 . For example, after comparing the performance curve of hu8G8 with the efficacy curve of hu8G8 and 0.08 pg/ml HB1 (infected with 1% of infection in the absence of titration antibody), we found that the curves overlap (see Figure 17). Also, in the presence of various concentrations of hu8G8, each HB1 potency curve overlaps (relative to 100% infection correction) (see Figure 17). Therefore, there is no evidence of synergistic or antagonistic effects between antibodies at a wide range of ratios. Example 7 - Evaluation of virus resistance produced Although human CMV has a relatively low mutation rate (compared to hepatitis virus C (HCV) or human immunodeficiency virus (HIV)), the virus was evaluated. The ability to escape HB 1 or hu8G8 or both by generating resistance mutations. The virus is grown in the presence of suboptimal concentrations of HB1 (or MSL-109) or hu8G8, or both HB1 and hu8G8 antibodies. As the virus is subcultured to new cells every week (about 50% of each round is subcultured to new cells), the concentration of each antibody is gradually increased. A mutant virus resistant to each individual antibody was observed, but no mutant conferred resistance to the combination. All resistant virus mutations occur from a single plaque. A mutant that confers resistance to neutralization caused by HB 1 appears (see Fig. 18). However, as indicated by the neutralization assay, these mutants are still sensitive to hu8G8, which has an EC50 similar (see Figure 18 and Table 12 and Table 13). 158864.doc -111 - 201215618 Table 12 - HCMV mutants with resistance to HB1 appearing HB1 EC50~g/ml) No Ab control 0.04 HB1-mutant virus 1 0.21 HB1-mutant virus 2 No neutralizing HB1-mutant virus 3 0.07 HB1-mutant virus 4 200 HB1-mutant virus 5 no neutralizing HB1-mutant virus 6 no neutralization Table 13-HCMV HB1 resistance mutant remains sensitive to hu8G8 neutralization hu8G8 EC50 (pg/ml) Dataset 1 data Set 2 No Ab control 0.008 0.0005 HB1-mutant virus 1 0.010 0.0006 HB1-mutant virus 2 0.008 0.006 HB1-mutant virus 3 0.001 0.0001 HB1-mutant virus 4 No detectable 0.0001 HB1-mutant virus 5 No detectable 0.001 HB1-mutant virus 6 0.001 not measured

In addition, mutants which confer resistance to neutralization by hu8G8 appear, and these mutants are still sensitive to HB1, and HB1 has an EC50 similar (see Figure 19 and Table 14 and Table 15). Table 14 - HCMV mutants appearing resistant to hu8G8 hu8G8 EC5〇hg/ml) No Ab control 0.002 hu8G8-mutant virus 1 no neutralization hu8G8-mutant virus 2 0.25 hu8G8-mutant virus 3 no neutralization

Table 15 - HCMV hu8G8 resistant mutants are still sensitive to HB1 neutralization HB1 EC50_ml) No Ab control 0.22 hu8G8-mutant virus 1 0.18 hu8G8-mutant virus 2 0.07 hu8G8-mutant virus 3 0.06 158864.doc -112-

S 201215618 To understand the molecular properties of resistance to HB 1 and hu8G8 antibodies, gB, gH, gL, UL128, UL130 and UL131 from each resistant strain were sequenced. Compared to the VR1814 and D1 strains (VR1814 is subcultured on epithelial cells without antibody pressure), all strains resistant to HB1 have a single non-conservative amino acid mutation in gH, and No other mutations were found in other glycoproteins (Table 16). Eleven individual strains producing resistance to HB1 were generated, covering only five different nucleotide mutations in only three amino acids. These amino acids were not found to be mutated in clinical strains that were sequenced or had published sequences. The mutations that responded to hu8G8 appeared less frequently, and only three strains were found to be resistant. Compared to the VR1814 and D1 strains, all three strains resistant to hu8G8 had a single non-conservative amino acid mutation in UL131, and no other mutations were found in other glycoproteins (see Table 16). When the mutant gH and UL1 3 1 sequences were compared with 60 available clinical strain sequences, none of the strains carried these mutations. Table 16 - Location of mutations that produce resistance

Resistant virus strain mutant protein residue change ΗΒ1-mutant 1 gH P171H ΗΒ1-mutant 2 gH W168C ΗΒ1-mutant 3 gH P171S ΗΒ1-mutant 4 gH D446N ΗΒ1-mutant 5 gH W168C ΗΒ1-mutant 6 gH W168R hu8G8-mutant 1 Ul131 Q47K hu8G8-mutant 2 Ul131 K51E Hu8G8-mutant 3 Ul131 D46N *- Mutant produced in epithelial cells** Mutants produced in fibroblasts when comparing HB 1 resistance The ability of the virus strain to infect cells with the D1 strain 158864.doc -113- 201215618, these resistant strains have deep entry defects (up to 20-fold reduction in efficiency), indicating that in vivo growth of these strains will Weaken (see Figure 20). When comparing the ability of hu8G8 resistant strains to cells infected with D1 strains, 'the resistant strains were found to be able to infect cells with specific efficiency; however, these strains grew extremely slowly, indicating a defect in production (data not shown) ). Further analysis is needed to understand the mechanism of this weakening. To determine whether these mutations affect the ability of HB1 and hu8G8 to bind to gH and UL131, respectively, site-directed mutagenesis induces complex I (gH/gL/UL128/UL130) for transient expression of resistant mutations on the surface of HEK-293T cells. /UL131) and FACS analysis of antibody binding was performed. Mutation of P171 (mutants 1 and 3: P171 mutated to Η or S) increased the resistance to HB1 by only 2 to 5 fold and the binding of this antibody to gH/gL did not change significantly. However, the mutations seen in HB 1-mutants 2, 5 and 6 (mutation of W168 to C or R) completely abolished the binding ability of HB 1 (see Figure 21). Furthermore, these viral mutants were not neutralized by HB1 (see Figure 18). Mutant 4 (D446N) showed an intermediate phenotype; it increased the resistance to neutralization by HB1 by a factor of 500 (see Figure 18), but binding to HB 1 was still detectable (see Figure 21). To determine how mutations in UL131 affect hu8G8 binding, transfection of HEK-293T cells with wild-type or mutant gH/gL/UL128/UL130/UL131 complexes and anti-gH (HBl and MSL) by FACS analysis -109), a combination of anti-UL131_993 and hu8G8 (see Figure 22). All three UL131 mutations eliminated the binding of hu8G8 to the gH/gL/UL128/UL130/UL131 complex. The HB 1 resistance mutation is localized to the structural model of HCMV glycoprotein (based on the recently analyzed structure of 158864.doc -114-201215618 HSV-2 gH and EBV gH) (Backovic et al., see 45, 197: 2263 5 -22640 (2010)). All mutant residues were mapped to the same side of gH (data not shown). The HB1 Fab is modeled on the gH structure. The occupied area of the HB 1 Fab covers all mutations, indicating that HB 1 binds to the epitope defined by such mutations. Similarly, the hu8G8 resistance mutations are in close proximity to each other (4 residues apart), and although the structure of UL 13 1 is unknown, both are localized to the putative alpha helix domain and predicted to be on the same side of the helix. Thus, along with the binding assay, the resistance mutations elucidated the epitopes on both the gH/gL/UL128/UL13 0/UL131 complex against both HB1 and hu8G8. Example 8 - Affinity analysis The affinity of both HB 1 and hu8G8 was determined by biacore and Scatchard analysis as described below. The affinity of HB1 for soluble gH/gL exhibited by baculovirus was determined by biacore analysis and was known to be 1 nM. In particular, surface plasmon resonance (SPR) measurements (Karlsson et al., 1991) were performed using a BIAcore 3000 instrument (GE Healthcare; Piscataway, NJ) to assess the secretion of gH/gL from HB1 binding baculovirus expression. ability. The SPR based biosensor reports a change in refractive index close to the surface. When a protein target ("ligand") is covalently immobilized on the surface of a sensor wafer, SPR can be used to monitor non-covalent interactions of binding partners ("analytes") injected on the surface; analyte binding The instantaneous measurement results can be used to determine the dynamics and affinity of the interaction. In the case of the 1:1 interaction of analyte B with immobilized ligand A 158864.doc 115. 201215618, the equilibrium is described using Equation 1: L· Λ _ ^οη Α Λ A + B^-r~&gt ;ΑΒ ^off In Equation 1, kQn is the association rate constant, kQff is the dissociation rate constant, and the equilibrium dissociation constant KD is determined by KD^koff/kcn. Equation 2 is used to determine the rate of formation of a 1:1 bound complex: ^-]=kon[Amkoff[AB] When expressed as an SPR signal (/?), Equation 2 can be written as Equation 3:

rjD

~^ = KonCHC + koff)R In Equation 3, C is the concentration of the free analyte and Rmax is the maximum analyte binding capacity of the surface. Similarly, for analyte B, which is capable of dimerization in solution to form two binding sites, the equilibrium can be described by Equation 4. A + B< konVkoffi > AB + B < kon2lkoff2 > AB2 The kinetic constant can be determined and used to calculate KD by measuring the concentration dependence of the binding rate and the dissociation rate in the absence of free analyte. The kinetics of binding were determined using an anti-Fc capture method for non-covalently immobilized HB1 followed by injection of different concentrations of gH/gL for SPR measurements. Docking CM5 biosensor wafers (BR 1000 14, CM5 Research Grade; BIAcore, Inc.) following instructions provided by the manufacturer, using an operating buffer (10 mM HEPES (pH 7.4), 150 mM NaCl, and 0.01% Polysorbate The alcohol ester 20) was perfused and corrected with 70% glycerol. As briefly summarized below, mouse monoclonal anti-human Fc antibody (human antibody capture kit, BR-1008-39, BIAcore, 158864.doc • 116- 201215618)

Inc.) is fixed on all four flow channels of the CM5 chip. Use N_ethyl hydrazine, _(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxybutylimine (NHS) (amine coupling kit) following the protocol described by the manufacturer , 811-^00-50; BIAcore, Inc.) and using a 7 minute activation time to activate the flow cell. The activated matrix was then reacted via amine δ /, capture antibody by injecting 60 μg of 25 pg/mL antibody diluted in 10 mM sodium acetate (pH 5.0) at a flow rate of 10 pL/min. At the end of the coupling injection, any remaining unreacted NHS groups were not activated by injection of 35 μΙ 1 Μ ethanolamine hydrochloride at a flow rate of 5 pL/miη. The amount of capture antibody covalently immobilized in this manner was estimated from the SPr signal before and after the coupling procedure and given a range of 8000-9500 RU on 4 flow channels. An Rmax value of less than about 100 (arbitrary SPR or resonance unit (RU)) is generally considered to provide a good signal to noise ratio without limiting the range of measurable kinetic constants. Initial experiments indicated that at a flow rate of 30 pL/min, a 60 μL injection of 〇·ΐ3 pg/mi HB1 resulted in the capture of sufficient HB 1 to observe a signal of approximately 50 RU after saturation with gH/gL. Therefore, this HB 1 concentration and injection protocol was used to determine the kinetic constant.

The bonding measurement is performed by capturing HB 1 on the flow cell 2 as described above, wherein the flow cell 1 is used as a reference. A concentration of gH/gL solution varying from 0.39 nM to 100 nM was prepared in the operating buffer in 2 fold increments. A sensor map of 6 Å of these solutions was injected on the surface of the sensor wafer at a flow rate of 3 〇 pL/min. The sensing wafer was maintained at 25 ° C and the dissociation was monitored for 10 minutes after the end of the injection. 30 3 M via injection between the binding cycles

MgC12 is used to regenerate the surface of the sensor wafer. This injection caused any remaining 158864.doc -117- 4^201215618 HBLgH/gL complex to dissociate from the capture antibody. Then capture HB1 on the flow rate (1) above to enter the lamp-binding cycle. A "blank" sensor map of the injection buffer on the sensor wafer was similarly collected. The observed sensor map is processed for kinetic analysis by first subtracting the signal of the measured reference groove. The ##υ° obtained by the regenerated portion of the curve is removed and the sensor map is then zeroed by subtracting the average ru value of the baseline before the analyte injection. Finally, the sensor map of the injected injection buffer was subtracted from the obtained curve containing the sand solution. The software supplied by the manufacturer was used to analyze the data according to a 1:1 Langmuir binding model or a mussel analyte model. Ί SPRk唬 increases with gH/gL concentration, indicating that HB captured by Fe is competent for antigen binding. The analysis of the data according to the i:i Langmuir binding model indicates that the apparent equilibrium dissociation constant (Kd) of 0.15 nM and the various kinetic inheritances shown in Table 17 are 'but' the curve is not well matched. The map has a relatively large χ2 value of 2.1. The observed sensor map is better described by the bivalent analyte KD model (χ2 = 0.4), which produces the apparent KD of 1 〇 nM and various kinetic constants shown in Table 18. Table 17 - Kinetic constants calculated using the 1:1 Langmuir binding model K^s·1) R/7Jitc(RU) Κ〇(ηΜ) 6.8X103 1.02X10·4 42 "oil — ~2Λ Table 18- Kinetic constant IWM-V1 calculated using the bivalent analyte KD model) Ko/yis'1) URU-Y1) Rmo^iRU) Kp(nlVi) y1 2.5χ105 2.5 χΚΓ4 0.174 0.166 65 1.0 0.4 Since biacore is not available for determination The affinity of hu8G8, so Ska's analysis is used as an alternative method. In this method, the sclerosting antibody is mixed with a line of 158864.doc-118·201215618 column unlabeled antibody dilutions and assayed for competition. The results were plotted using the fit algorithm of Munson and Rodbard to determine the affinity of the antibody (Figure 23). The mean Kd of HB1 was 1.27 nM and the average Kd of hu8G8 was 2.03 nM (Table 17). Affinity measurements of both gH/gL/UL128/UL130/UL131 complexes on both surface of adenoviral cells and HB1 and hu8G8 were also determined by Skacha analysis and found to be 1.27 nM and 2.03 nM, respectively. Specifically, HB1 and hu8G8 were mothified using the Iodogen method (Thermo-Fisher Scientific; Waltham, ΜΑ). The radiolabeled antibody was purified from free 125I-Na by gel filtration using a NAP-5 column. The specific activity of the purified hu8G8 antibody was 12.30 pCi/pg and the specific activity of the purified HB1 antibody was 14.66 pCi/pg. 50 μΐ competitive reaction mixture containing a fixed concentration of iodinated antibody and a decreasing concentration of unlabeled antibody

I placed in a 96-well plate. ARPE-19 cells transiently transfected with adenovirus expressing protein complex gH/gL/128/130/13 1 were detached from the flask using Sigma Accutase® solution (Sigma-Aldrich; St. Louis, MO) for multimerization Formaldehyde was fixed and washed with binding buffer (containing 2% FBS, 50 paws) \4 11 ££8 (?^[7.2) and 0.1% sodium azide]. The washed cells were added to a 96-well plate containing triplicate 50 pL of the competition reaction mixture at a density of 25,000 cells in 0.2 mL of binding buffer. The final concentration of the iodinated antibody in each of the competing reactions containing the cells is 1 〇〇 pM and the final concentration of the unlabeled antibody in the competing reaction containing the cells is different, starting at 500 nM and then by 1:2 Diluted to 10 concentrations, and included zero-added buffer-only samples. The cell-containing competitive reaction was incubated for 2 hours at room temperature, then transferred to Millipore Multiscreen filter plate 158864.doc -119-201215618 and washed 4 times with binding buffer to separate the free iodinated antibody from the bound iodinated antibody. The filter was counted on a Wallac Wizard 1470 gamma counter (PerkinElmer Life and Analytical Sciences; Wellesley, ΜΑ). Binding data were evaluated using New Ligand software (Genentech) using a fitting algorithm of Munson and Rodbard (y4 «fl/· Biochem., 7:22-39 (1980)) to determine the binding affinity of the antibodies. Table 19 HCMV anti-caries test K〇(nM) mean KD(nM)± SDa HB1 1 1.3 1.27 ±0.06 2 1.2 3 1.3 1 1.96 Hu8G8 2 2.06 2.03 ± 0.06 3 2.07 KD=equilibrium dissociation constant; SD=standard deviation

Example 9 - Analysis of the combination of hu8G8 and complex I

To further characterize the binding of hu8G8 to complex I, an ELISA assay was performed to test whether hu8G8 binds to the portion of UL13 1 containing the resistant mutation identified in Example 7. Specifically, the serine acid codon at position 41 to the serine codon at position 68 (SRALPDQTRY KYVEQLVDLT LNYHYDAS (SEQ ID NO: 194)) amplifies the DNA encoding UL131 and is ligated into the N-terminal His6 , GST and TEV cleavage sites (DNA654570) in a restricted independent colonization (RIC) vector. This portion of UL131 forms the putative alpha helix in the secondary structure of the protein. UL131 with mutation Q47K was also selected, which abolished the binding of hu8G8 to UL131 in the case of complex I (gH/gL/UL128/UL130/UL131). The sequence verified construct was grown in E. coli strain R〇setta2 (DE3). The culture of the bacterium was carried out overnight at 30 ° C in an LB medium containing 50 pg/ml of carbenicillin. At 〇D600 0.7, protein expression in 1-L cultures was induced overnight at 16 °C with 0.3 mM IPTG. The cells were collected and immediately transcribed by 100 mM Tris (pH 8.0), 500 mM NaCl, 5% glycerol (buffer A) containing no EDTA protease inhibitor bond (Roche).

Wave treatment and cell destruction to dissolve. The solubilized cells were briefly centrifuged at 1 rpm for 40 minutes and the clarified lysate was loaded on a gravity flow Ni chelate affinity column (Qiagen). The column was washed with 1 column volume buffer a and 10 column volumes of buffer A containing 50 mM imidazole. Protein with 1 〇〇 mM

Tris (pH 8.0), 500 mM NaCl, 5% glycerol, 500 mM pm were dissolved and immediately dialyzed into 50 mM Tris (pH 8.0), 200 mM NaCl, and 5% glycerin. The protein was further purified on a size exclusion chromatography column (S200 10/30, GE) with 25 mM Tris (pH 8.0), 200 mM NaCl and 5% glycerol. To determine the binding of hu8G8 to the UL131 protein fragment, Maxsorb £ [18 plates were coated overnight at 4° (with 108, 2〇〇11 per well or 4〇11§ in carbonate coating buffer). After washing 3 times with wash buffer (PBS containing 5% 5% Tween 20 [Sigma Chemical]), each well was assayed with a diluent (containing 0.5% BSA [Invitrogen; Carlsbad, CA]). Blocked for 1 hour. hu8G8 was incubated in assay diluent for 1 hour at 10 pg/ml or 1 pg/mi. After 3 washes, each well was bound to peroxidase-conjugated anti-human antibody (Jackson Immunolabs, Bar Harbor, ME) was incubated for 1 hour at 1:5000, or with horseradish peroxidase-conjugated anti-5HIS (Qiagen) for 1 hour at 1:500 or 1:5000. Experimental knot 158864.doc -121 - 201215618 The results are shown in Figure 24 and include data for ELISA plates coated with 200 ng of protein and incubated with 10 pg/ml hu8G8. Although described in considerable detail for purposes of clarity and description, by way of illustration and example The foregoing invention is not to be construed as limiting the scope of the invention. The disclosures of all of the patents and scientific literature cited are expressly incorporated herein by reference in their entirety in their entirety herein in the the the the the the the the the the the the the the the the the the the the Alignment with the amino acid sequence of the selected human heavy chain variable region: VH1 FW (SEQ ID NO: 52), human VH3 FW (SEQ ID NO: 53), and human VH7 FW (SEQ ID NO: 54). Amino acids are numbered according to Kabat numbering. Boxing of hypervariable regions (HVR). Circles indicate VL-VH interactions (Padl an (1994) Mo/, /mm w π 〇/. 31:169); double asterisks (one above the other) indicates the position of the Vernier (Foote and Winter (1992) J. Mol. Biol. 224:487) and the FW-CDR interaction (Padlan (1994) Mo/, 31:169) A single asterisk at positions 47, 64, 66, 68 indicates the Venier position (Foote & Winter (1992) J. Mol. Biol. 224: 487); a single asterisk at position 58 indicates FW-CDR interaction ( Padlan (1994) Mo/· Plant 31: 169) Figure 2 shows the light chain variable region (VL) of murine mAb 8G8 (SEQ ID NO: 51) and human light chain variable region: λ3 FW region (SEQ ID NO: 69) and human λ4 FW region (SEQ I The amino acid sequence of D NO: 55) is aligned. Amino acids are numbered according to the Kabat number. Frame the hypervariable region (HVR). Circles indicate VL-VH interactions (Padlan (1994) Mo/. 31:169); 158864.doc -122- 201215618 Double asterisks (one above the other) indicate the Venier position (!"〇0化和Winter (1992) J. Mol. Biol. 224:487) and FW-CDR interaction (Padlan (1994) Mo/, /mmwwo/. 31:169). A single asterisk at positions 47, 64, 66, 68 indicates the Venier position (Foote and Winter (1992) J. Mol. Biol. 224:487); a single asterisk at position 58 indicates FW-CDR interaction (Padlan) (1994) Mo/, /wmwwo/. 31:169) ° Figure 3 shows the results of the neutralization assay comparing the 8G8k3 variant with the 8G8X4 variant. Panel A: In the neutralization assay, a humanized 8G8X3 antibody with human VH1, VH3 or VH7 was used compared to the mouse/human chimeric 8G8 antibody (QE7/C2). Panel B: In the neutralization assay, a humanized 8G8X4 antibody with human VH1, VH3 or VH7 was used as compared to the mouse/human chimeric 8G8 antibody (QE7/C2). The EC50 values of the experiments are presented below the respective experiments. Figure 4 shows the mutated sequence in 8G8 HVR-L2. The amino acid sequence of the first amino acid of HVR-L2 and FR3 is shown (WT: SEQ ID NO: 57; A1: SEQ ID NO: 58; El: SEQ ID NO: 59; ΤΙ: SEQ ID NO: 60; A2: SEQ ID NO: 61; E2: SEQ ID NO: 62; T2: SEQ ID NO: 63; SG: SEQ ID NO: 64; SGSG: SEQ ID NO: 65; TGDA: SEQ ID NO: 66) . The numbers in the figure are based on the Kabat number. Figure 5 shows the results of a neutralization assay using various humanized 8G8 antibodies having a mutant HVR-L2 region containing a single amino acid substitution as shown in Figure 4. Figure A: Neutralization check. The HVR-L2 mutant antibodies all contain the human 8G8 VH1 chain. Panel B: EC50 values for the experiment. I58864.doc.123-201215618 Figure 6 shows the results of a neutralization assay using various humanized 8G8 antibodies having the mutant HVR-L2 region containing the two amino acid substitutions shown in Figure 4. Figure A: Neutralization check. The HVR-L2 mutant antibodies all contain the human 8G8 VH1 chain. Panel B: EC50 values for the experiment. Figure 7 shows the light chain variable region of murine mAb 8G8 (SEQ ID NO: 51) and the human light chain variable region λ4 FW (SEQ ID NO: 55) and the humanized light chain variable region of 8G8 on λ4 FW ( The amino acid sequence alignment of hu8G8A4 FW) (SEQ ID ΝΟ: 48). Amino acids are numbered according to the Kabat number. For the hypervariable zone (HVR) force frame. Circles indicate VL-VH interactions (Padlan (1994) Mo/, /w mw«o/· 31:169); double asterisks (one above the other) refer to non-Venil positions (Foote and Winter (1992) J Mol. Biol. 224:487) and FW-CDR interaction (Padlan (1994) Mo/. 3 1:169). A single asterisk at positions 47, 64, 66, 68 indicates the Venier position (Foote and Winter (1992) J. Mol. Biol. 224:487); a single asterisk at position 58 indicates FW-CDR interaction (Padlan) (1994) Mo/, 31:169). Figure 8 shows the heavy chain variable region of murine mAb 8G8 (SEQ ID NO: 50) and human heavy chain variable region VH1 framework (VH1 FW) (SEQ ID N〇: 52) and humanized weight of 8G8 on VH1 FW The amino acid sequence alignment of the chain variable region (hu8G8.VH1) (SEQ ID NO: 45). The amino acid is numbered according to the Kabat number. Frame the hypervariable region (HVR). The circle indicates the VL-VH interaction (Padlan (1994) Mo/· /wwmwo/. 31:169); the double asterisk (one above the other) indicates the Venier position (Foote and Winter (1992) J. Mol·Biol 224:487) and FW-CDR interaction (Padlan (1994) Mo/. 158864.doc -124· 201215618 /mmwnο/. 31:169). A single asterisk at positions 47, 64, 66, 68 indicates the Venier position (Foote & winter (!992) J. Mol. Biol. 224:487); a single asterisk at position 58 indicates FW-CDR interaction ( Padlan (1994) Mo/. 31:169). An exemplary nucleic acid sequence encoding hu8G8.VH1 (SEQ ID NO: 185) is also shown.

Figure 9 shows the heavy chain variable region of murine mAb 8G8 (SEQ ID NO: 50) and the human heavy chain variable region VH3 FW (SEQ ID NO: 53) and the humanized heavy chain variable region of 8G8 on VH3 FW ( The amino acid sequence alignment of hu8G8.VH3) (SEQ ID NO: 46). Amino acids are numbered according to the Kabat number. Frame the hypervariable region (HVR). Circles indicate VL-VH interactions (Padlan (1994) Mo/· 31:169); double asterisks (one above the other) indicate Venier positions (Foote and Winter (1992) J. Mol. Biol. 224:487 And FW-CDR interactions (Padlan (1994) //wwwwo/. 31:169) 单一 A single asterisk at positions 47, 64, 66, 68 indicates the Venier position (Foote and Winter (1992) J. Mol. Biol. 224:487); a single asterisk at position 58 indicates FW-CDR interaction (Padlan (1994) Mo/· 31:169) Figure 10 shows the light chain variable region of murine mAb 8G8 VL (SEQ ID ΝΟ: 51) and the light chain variable region of λ4FW region (SEQ ID NO: 55) and the humanized light chain variable region of 8G8 (λ4 8G8 graft) on λ4FW (wherein at amino acid 2 and 36 according to Kabat numbering) The amino acid sequence of the amino acid change (SEQ ID NO: 49) was introduced to align. Amino acids are numbered according to the Kabat number. Frame the hypervariable region (HVR). Circles indicate VL-VH interactions (Padlan (1994) Μσ/· /wwwwo/. 31:169); double asterisks (one above the other) indicate Pooh 158864.doc -125· 201215618 Location (Foote and Winter ( 1992) J. Mol. Biol. 224:487) and FW-CDR interaction (Padlan (1994) Mo/· /wimimo/· 31:169). A single asterisk at positions 47, 64, 66, 68 indicates the Venier position (Foote and Winter (1992) J. Mol. Biol. 224: 487); a single asterisk at position 58 indicates FW-CDR interaction (Padlan) (1994) Mo/, /mmwno/· 3 1:169). An exemplary nucleic acid sequence encoding a λ4 8G8 graft (SEQ ID NO: 186) is also shown. Figure 11 shows the alignment of the human antibody MSL-109 with the amino acid sequence of mAb ΗΒ1. Panel A: Alignment of MSL-109 VL (SEQ ID NO: 90) with affinity matured HB1 VL (also SEQ ID NO: 90 (100% cis-)); and circle B: human antibody MSL-109 VH (SEQ ID NO: 92) Aligned with the amino acid sequence of affinity matured 1^1 ¥11 (8 £ () 10!^0:89). Amino acids are numbered according to the Kabat number. Frame the hypervariable region (HVR). Figure 12A shows the amino acid sequence of HVR-H2 (SEQ ID NO: 91) and IGHVSdPOUSEQ ID (93) from MSL-109 and the various amino acid substitutions made. Figure 12A and Figure 12C show the results of 2 different neutralization assays performed using antibodies containing the mutated HVR-H2 region. Both the Fab (Fig. 12B) and mAb (Fig. 12C) neutralization assays are shown. The IC50 is provided in nM units. Fig. 13 shows the results of a comparison between the ability of the antibody containing λ4 8G8 graft and hu8G8.VH1 (hereinafter referred to as "hu8G8") and HB1 and HIG to prevent infection of epithelial cells and fibroblasts.

Figure 14 shows the results of virus neutralization assays on epithelial cells and fibroblasts using depleted high immunoglobulin (HIG). HIG anti-gB 158864.doc -126- 201215618 specific antibody, anti-complex I specific antibody, anti-gH/gL antibody, or simulated subtraction was used as a control. Figure 15 shows the results of FACS analysis aimed at determining the antigen specificity of HB1 and hu8G8 antibodies compared to known anti-gB, anti-gH and anti-UL131 antibodies. APC intensity on the X-axis indicates antibody binding. The y-axis plots the proportion of cells at a given intensity, expressed as a percentage of the maximum number of cells at any intensity. Figure 16 shows the results of a neutralization assay in which hu8G8 was mixed with HB1 at a 1:1 ratio and tested for its ability to inhibit HCMV-infected epithelial cells in a series of dilutions. The combination of the two antibodies has an additive effect and exhibits a Bliss independent equation (the combined reaction C of the two single compounds with effects A and B is C = A + B - AxB). Figure 17 shows the results of neutralization assays for determining HB1 potency at different hu8G8 concentrations or hu8G8 potency at different HB1 concentrations. Figure 18 shows the results of the neutralization assay for the HB 1 resistant HCMV mutant. Panel A shows the results of neutralization assays using HB1 antibodies. Panel B shows the results of neutralization assays using the hu8G8 antibody. The HB 1 resistant HCMV mutant is still sensitive to hu8G8 neutralization. Figure 19 shows the results of the neutralization assay for the hu8G8 resistant HCMV mutant. Panel A shows the results of neutralization assays using HB1 antibodies. Panel B shows the results of neutralization assays using the hu8G8 antibody. The hu8G8 resistant HCMV mutant is still sensitive to HB 1 neutralization. Figure 20 shows that HCMV strain (WT) D1 (VR1814 which grows in parallel when a resistant strain is produced) is compared to various HB1 resistant virus mutant pairs 158864.doc -127 - 201215618 dermal cells and fibroblasts The virus enters relevant information. Figure 21 shows the ability of the HB1 antibody to bind to the gH/gL of the cell surface containing the point mutation imparting resistance in gH, as determined by FACS analysis. Different anti-gH antibodies were used as positive controls for cell surface expression. The X-axis is the GFP intensity, which is an indicator of HCMV glycoprotein performance. The y-axis is the APC signal, which indicates antibody binding. Figure 22 shows the ability of the hu8G8 antibody to bind to the complex I of the cell surface containing the point mutation conferring resistance in complex I, as determined by FACS analysis. Anti-UL13 1 antibody and anti-gH antibody were used as positive controls for cell surface expression. The X-axis is the GFP intensity, which is an indicator of HCMV glycoprotein expression. The y-axis is the APC signal, which indicates antibody binding. Figures 23A and 23B show the results of a Scala analysis aimed at determining the binding affinity of hu8G8 and HB1 for their antigens. The results were plotted using the proposed algorithm of Munson and Rodbard. The y-axis plots the concentration ratio of the bound 1251 labeled antibody to the total antibody. The total antibody was calculated based on the concentration of the 125 conjugated antibody and the unlabeled antibody. Figure 24 shows measurement of hu8G8 and positive control antibody (anti-HIS) with a peptide fragment of UL13 1 (amino acid 41 (Ser) to amino acid 68 (Ser) of SEQ ID NO: 194) (SRA-helix WT) or ELISA assay results containing the corresponding fragment of the amino acid substituted Q47K (SRA-helix Mut) binding. 158864.doc •128- 201215618 Sequence Listing <110>US-based Nandek Company <120> Antibody Composition and Method of Use

<130> P4680Ri^O <140> 100135366 <1^> 2011-09-29 <150> 61/504,056 <151> 2011-07-01 <150> 61/387,735 <151> 2010-09-29 <150> 61/387,725 <151> 2010-09-20 <160> 209 <170> Patentln version 3.5

<210> 1 <211> 743 <212> PRT <213> Human Cell Huge Virus <400>

Met Atg Pro Gly Leu Pro Pro Tyr Leu Thr Val Phe Thr Val Tyr Leu 1 5 10 15

Leu Ser His Leu Pro Ser Gin Arg Tyr Gly Ala Asp Ala Ala Ser Glu 20 25 30

Ala Leu Asp Pro His Ala Phe His Leu Leu Leu Asn Thr Tyr Gly Arg 35 40 45

Pro He Arg Phe Leu Arg Glu Asn Thr Thr Gin Cys Thr Tyr Asn Ser 50 55 60

Ser Leu Arg Asn Ser Thr Val Val Arg Glu Asn Ala lie vSer Phe Asn 65 70 75 80

Phe Phe Gin Ser Tyr Asn Gin Tyr Tyr Val Phe His Met Fro Arg Cys 85 90 95

Leu Phe Ala Gly Pro Leu Ala Glu Gin Phe Leu Asn Gin Val Asp Leu 100 105 110

Thr Glu ΊΙίγ Leu Glu Arg Tyr Gin Gin Arg Leu Asn Thr Tyr Ala Leu 115 120 125

Val Ser Lys Asp Leu Ala Ser Tyr Arg Ser Phe Ser Gin Gin Leu Lys 130 135 140

Ala Gin Asp Ser Leu Gly Gin Gin Fro Thr Thr Val Pro Pro Pro lie 145 150 155 160

Asp Leu Ser lie Pro His Val Trp Met Pro Pro Gin Thr Thr Pro His 165 170 175

Asp Trp Lys Gly Ser His Thr Thr Ser Gly Leu His Arg Pro His Phe 158864 - Sequence Listing _doc 201215618 180 185 190

Asn Gin Thr Cys 195 lie Leu Phe Asp Gly His 200

Asp Leu Leu Phe Ser Thr 205

Val Thr Pro Cys 210

Leu His Gin Gly Phe Tyr 215

Leu Met Asp Glu Leu Arg 220

Tyr Val Lys lie 225

Thr Leu Thr GJu Asp Phe 230

Phe Val Val Thr Val Ser 235 240 lie Asp Asp Asp

Thr Pro Met Leu Leu He 245 250

Phe Gly His Leu Pro Arg 255

Val Lea Phe Lys 260

Ala Pro Tyr GJn Arg Asp 265

Asn Phe lie Leu Arg Gin 270

Thr Glu Lys His 275

Glu Leu Leu Val Leu Val 2S0

Lys Lys Ala Gin Leu Asn 285

Arg His Ser Tyr 290

Leu Lys Asp Ser Asp Phe 295

Leu Asp Ala Ala Leu Asp 300

Phe Asn Tyr Leu 305

Asp Leu Ser Ala Leu Leu 310

Arg Asn Ser Phe His Arg 315 320

Tyr Ala Val Asp

Val Leu Lys Ser Gly Arg 325 330

Cys Gin Met Leu Asp Arg 335

Arg Thr Val Glu 340

Met Ala Phe Ala Tyr Ala 345

Leu Ala Leu Phe Ala Ala 350

Ala Arg Gin Glu ' 355

Glu Ala Gly Thr Glu lie 360

Ser lie Pro Arg Ala Leu 365

Asp Arg Gin Ala 370

Ala Leu Leu Gin lie Gin 375

Glu Phe Met lie Thr Cys 380

Leu Ser Gin Thr 385

Pro Pro Arg Thr Thr Leu 390

Leu Leu Tyr Pro Thr Ala 395 400

Val Asp Leu Ala

Lys Arg Ala Leu Trp Thr 405 410

Pro Asp Gin lie Thr Asp 415 lie Thr Ser Leu 420

Val Arg Leu Val Tyr lie 425

Leu Ser Lys Gin Asn Gin 430

Gin His Leu lie 435

Pro Gin Trp Ala Leu Arg 440 G】n lie A]a Asp Phe Ala 445

Leu Gin Leu His 450

Lys Thr His Leu Ala Ser 455

Phe Leu Ser Ala Phe Ala 460

Arg Gin Glu Leu 465

Tyr Leu Met Gly Ser Leu 470

Val His Ser Met Leu Val 475 480 !58864 - Sequence Listing.doc -2- s 201215618

His Thr Thr Glu Arg Arg Glu lie Phe lie Val Glu Thr Gly Leu Cys 485 490 495

Ser Leu Ala Glu Leu Ser His Phe Thr Gin Leu Leu Ala His Pro His 500 505 510

His Glu Tyr Leu Ser Asp Leu Tyr Thr Pro Cys Ser Ser Ser Gly Arg 515 520 525

Arg Asp His Ser Leu Glu Arg Leu Thr Arg Leu Phe Pro Asp Ala Thr 530 535 540

Val Pro Ala Thr Val Pro Ala Ala Leu Ser lie Leu Ser Thr Met Gin 545 550 555 560

Pro Ser Thr Leu Glu Thr Phe Pro Asp Leu Phe Cys Leu Pro Leu Gly 565 570 575

Glu Ser Phe Ser Ala Leu Thr Val Ser Glu His Val Ser Tyr Val Val 580 585 590

Thr Asn Gin Tyr Leu lie Lys Gly lie Ser Tyr Pro Val Ser rfhr Thr 595 600 605

Val Val Gly Gin Ser Leu lie lie Thr Gin Thr Asp Ser Gin Thi Lys 610 615 620

Cys Glu Leu Thr Arg Asn Met His Thr Thr His Ser lie Thr Ala Ala 625 630 635 640

Leu Asn lie Ser Leu Glu Asn Cys Ala Phe Cys Gin Ser Ala Leu Leu 645 650 655

Glu Tyr Asp Asp Thr Gin Gly Val lie Asn lie Met Tyr Met His Asp 660 665 670

Ser Asp Asp Val Leu Phe Ala Leu Asp Pro Tyr Asn Glu Val Val Val 675 680 685

Ser Ser Pro Arg Thr His Tyr Leu Met Leu Leu Lys Asn Gly Thr Val 690 695 700

Leu Glu Val ITir Asp Val Val Val Asp Ala Thr Asp Ser Arg Leu Leu 705 710 715 720

Met Met Scr Val Tyr Ala Leu Ser Ala lie lie Gly lie Tyr Leu Leu 725 730 735

Tyr Arg Met Leu Lys Thr Cys 740 <210> 2 <211> 278 <2]2> PR Ding <213> Human Cell Huge Virus <400> 2

Met Cys Arg Arg Pro Asp Cys Gly Phe Scr Phe Ser Pro Gly Pro Val 158864 - Sequence Listing.doc 201215618 15 10 15

Val Leu Leu Trp Cys Cys Leu Leu Leu Pro lie Val Ser Ser Val Ala 20 25 30

Val Ser Val Ala Pro Thx Ala Ala Glu Lys Val Pro Ala Glu Cys Pro 35 40 45

Glu Leu Thr Arg Arg Cys Leu Leu Gly Glu Val Phe Gin Giy Asp Lys 50 55 60

Tyr Glu Ser Trp Leu Arg Pro Leu Val Asn Val Thr Arg Arg Asp Gly 65 70 75 80

Pro Leu Ser Gin Leu He Arg Tyr Arg Pro Val Thr Pro Glu Ala Ala 85 90 95

Asn Ser Val Leu Leu Asp Asp Ala Phe Leu Asp Thr Leu Ala Leu Leu 100 105 110

Tyr Asn Asn Pro Asp Gin Leu Arg AJa Leu Leu Thr Leu Leu Ser Ser 115 120 125

Asp ITir Ala Pro Arg Trp Met Thr Val Met Arg Gly Tyr Ser Glu Cys 130 135 140

Gly Asp Giy Ser Pro Ala Val Tyr Thr Cys Val Asp Asp Leu Cys Arg 145 150 155 160

Gly Tyr Asp Leu Thr Arg Leu Ser Tyr Gly Arg Ser He Phe Thr Glu 165 170 175

His Val Leu Gly Phe Glu Leu Val Pro Pro Ser Leu Phe Asn Val Val 180 185 190

Val A1a lie Arg Asn Glu Ala Thr Arg Thr Asn Arg Ala Val Arg Leu 195 200 205

Pro Val Ser Thr Ala Ala Ala Pro Glu Gly lie Thr Leu Phe Tyr Gly 210 215 220

Lea Tyr Asn Ala Val Lys Glu Phe Cys Leu Arg His Gin Leu Asp Pro 225 230 235 240

Pro Leu Leu Arg His Leu Asp Lys Tyr Tyr Ala Gly Leu Pro Pro Glu 245 250 255

Leu Lys Gin Thr Arg Val Asn Leu Pro Ala His Ser Arg Tyr Gly Pro 260 265 270

Gin Ala Val Asp Ala Arg 275

<210> 3 <211> 171 <212> PRT <213> Human cell giant virus -4 - 158864 - Sequence Listing.doc 201215618 <400> 3

Met Ser Pro Lys Asn Leu Thr Pro Phe Leu Thr Ala Leu Trp Leu Leu 15 10 15

Leu Gly His Ser Arg Val Pro Arg Val Arg Ala Glu Glu Cys Cys Glu 20 25 30

Phe lie Asn Val Asn His Pro Pro Glu Arg Cys Tyr Asp Phe Lys Mei 35 40 45

Cys Asn Arg Phe Thr Val Ala Leu Arg Cys Fro Asp Gly Glu Val Cys 50 55 60

Tyr Ser Pro Glu Lys Thr Ala Glu lie Arg Gly lie Val Thr Thr Met 65 70 75 80

Thr His Ser Leu Thr Arg Gin Val Val His As Lys Leu Thr Ser Cys 85 90 95

Asn Tyr Asn Pro Leu Tyr Leu Glu Ala Asp Gly Arg lie Arg Cys Gly ]00 105 110

Lys Val Asn Asp Lys Ala Gin Tyr Leu Leu Gly Ala Ala Gly Ser Val 115 120 125

Pro Tyr Arg Trp lie Asn Leu Glu Tyr Asp Lys lie Thr Arg lie Val 130 135 140

Gly Leu Asp Gin Tyr Leu Glu Ser Val Lys Lys His Lys Arg Leu Asp 145 150 155 160

Val Cys Arg Ala Lys Met Gly Tyr Met Leu Gin 165 170

<210> 4 <21!> 214 <212> PRT <213> Human Cell Huge Virus <400> 4

Met Leu Arg Leu Leu Leu Arg His His Phe His Cys Leu Leu Leu Cys 15 10 15

Ala Val Trp Ala Thr Pro Cys Leu Ala Ser Pro Trp Ser Thr Leu Thr 20 25 30

Ala Asn Gin Asn Pro Ser Pro Pro Trp Ser Lys Leu Thr Tyr Ser Lys 35 40 45

Pro His Asp Ala Ala Thr Phe Tyr Cys Pro Phe Leu Tyr Pro Ser Pro 50 55 60

Pro Arg Ser Pro Leu Gin Phe Ser Gly Phe Gin Arg Val Ser Thr Gly 65 70 75 80

Pro Glu Cys Arg Asn Glu Thr Leu Tyr Leu Leu Tyr Asn Arg Glu Gly 85 90 95 158864 - Sequence Listing.doc 201215618

Gin Thr Leu Val Glu Lys Ser Ser Thr Trp Val Lys Lys Val lie Trp 100 105 110

Tyr Leu Ser Gly Arg Asn Gin Thr lie Leu Gin Arg Met Pro Arg TTir 115 120 125

Ala Ser Lys Pro Ser Asp Gly Asn Val Gin lie Ser Val Glu Asp Ala 130 135 140

Lys lie Phe Gly Ala His Met Val Pro Lys Gin Thr Lys Leu Leu Arg 145 150 155 160

Phe Val Val Asn Asp Gly Thr Arg Tyr Gin Met Cys Val Met Lys Leu 165 170 175

Glu Scr Trp Ala His Val Phe Arg Asp Tyr Ser Val Ser Phe Gin Val 180 1S5 190

Arg Leu Thr Phe Thr Glu Ala Asn Asn Gin Thr Tyr Thr Phe Cys Thr 195 200 205

His Pro Asn Leu lie Val 210

<210> 5 <211> 76 <212> PRT <213> Human Cell Huge Virus <400>

Met Cys Met Met Ser His Asn Lys Ala Phe Phe Leu Ser Leu Gin His 15 10 15

Ala Ala Val Ser Gly Val Ala Val Cys Leu Ser Val Arg Arg Gly Ala 20 25 30

Gly Ser Val Pro Ala Gly Asn Arg Gly Lys Lys Thr lie lie Thr Glu 35 40 45

Tyr Arg lie Thr Gly Thr Arg Ala Leu Ala Arg Cys Pro Thr Lys Pro 50 55 60

Val llir Ser Met Trp Asn Ser Ser Trp Thr Ser Arg 65 70 75 <2)0> 6 <211> 10 <212> FRT <213> Mus musculus <400>

Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn 1 5 10 <210> 7 <211> 17 <212> PRT <213> Mus musculus <400> 7 -6-

158864-Sequence List.doc s 201215618

Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys 1 5 10 15

Gly <210> 8 <211> 13 <212> PRT <213> Mus musculus <400> 8

Ser Trp Tyr Tyr Val Ser Asn Tyr Trp Tyr Phe Asp Val 1 5 10 <210> 9 <211> 12 <212> PRT <213> Mus musculus <400>

Thr Leu Ser Ser Gin His Ser Thr Tyr Thr He Glu 1 5 10

<210> 10 <211> 11 <212> PRT <213> Mus musculus <400>

Leu Lys Lys Asp Gly Ser His Ser Thr Gly Asp <210> 11 <211> 11 <2\2> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Small Synthetic Mutation Mouse HVR-L2 peptide <400> 11

Leu Lys Lys Asp Ala Ser His Ser Thr Gly Asp 1 5 10 <210> 12 <211> 11 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Mutation Mouse HVR-L2 peptide <400> 12

Leu Lys Lys Glu Gly vSer His Ser Thr Gly Asp 1 5 10 <210> 13 <211> 11 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Mutation Mouse HVR-L2 peptide 158864 - Sequence Listing. doc -7- 201215618 <400> 13

Leu Lys Lys Thr G]y Ser His Ser Thr Gly Asp 1 5 10 <210> 14 <211> 11 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic mutant mouse HVR-L2 peptide <400> 14

Leu Lys Lys Asp Gly Ser His Ser Thr Gly Asp 1 5 10 <210> 15 <211> 11 <2i2> PRT <2i3> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Mutation Mouse HVR-L2 peptide

<400> 15

Leu Lys Lys Asp Gly Ser His Ser Thr Gly Glu I 5 3〇<210> 16 <211> 11 <212> PRT <213>Artificial Sequence<220><223> Description of Artificial Sequence: Synthesis Mutant Mouse HVR-L2 Peptide <400> 16

Leu Lys Lys Asp Gly Ser His Ser Thr Gly Thr 1 5 10 <210> 17 <211> 11 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Mutation Mouse HVR-L2 peptide <400> 17

Leu Lys Lys Ser Gly Ser His Ser Thr Gly Asp 1 5 10 <210> 18 <211> 11 <212> PRT <213>Artificial Sequence ' <220><223> Description of Artificial Sequence: Synthesis Mutant mouse HVR-L2 peptide <400> 18

Leu Lys Lys Ser Gly Ser His Ser Thr Gly Ser i 5 10 158864 - Sequence Listing. doc · 8 · s 201215618 <210> 19 <211> 11 <212> PRT <213> Manual Sequence <220><223> Description of artificial sequence: synthetic mutant mouse HVR-L2 peptide <400> 19

Leu Lys Lys Thr Gly Ser His Ser Thr Gly Asp 1 5 10 <210> 20 <211> 13 <212> PRT <2丨3> Mus musculus <400> 20

Gly Val Gly Asp Thr lie Lys Glu Gin Phe Val Tyr Val

<210> 21 <211> 12 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis of Common HVR-L2 Sequence <220><221> MOD- RES <222> (4)..(4) <223> Any amino acid <220><221> MOD_RES <222> (5)..(5) <223> Any amino acid <220><221> M0DJES <222> (11)..(11) <223> Any amino acid <220><221> MOD_RES <222> (127..(12) <;223>any amino acid <400> 2]

Leu Lys Lys Xaa Xaa Ser His Ser Thr Gly Xaa Xaa 1 5 10 <210> 22 <211> 25 <212> PRT <213> Homo sapiens <400>

Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser 20 25 <210> 23 <2U> 14

158864 - Sequence Listing. doc -9- 201215618 <212> PRT <213> Homo sapiens <400> 23

Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp lie Gly 1 5 10 <210> 24 <211> 32 <212> PRT <2i3> Homo sapiens <400>

Arg Val Thr lie Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr Leu Glu 15 10 15

Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 25 <211> 11 <212> PRT <213> Homo sapiens <400>

Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 26 <211> 25 <212> PRT <21.3> Mus musculus <400>

Gin lie His Leu Val Gin Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 15 10 15

Thr Val Lys lie Ser Cys Lys Ala Ser 20 25 <210> 27 <211> 14 <212> PRT <213> Mus musculus <400> 27

Trp Val Lys Gin Ala Pro Gly Lys Gly Leu Lys Trp Met Gly 1 5 10 <2I0> 28 <211> 32 <212> PRT <213> Mus musculus <400>

Arg Fhe Aia Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu Gin 15 10 15 lie Asn Asn Leu Lys Asn Glu Asp Met Ala Thr Tyr Phe Cys Ala Arg 20 25 30 <210> 29 <231> 11 <212> PRT <213> Mus musculus-10-158864 - Sequence Listing.doc 201215618 <400> 29

Trp Gly Gin Gly llir Leu Val Thr Val Ser Ser 1 5 10 <21〇> 30 <211> 25 <212> PRT <213> Homo sapiens <4-00> 30

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Fro Gly Gly 1 5 ]〇 15

Ser Leu Arg l^u Ser Cys Ala Ala Ser 20 25 <210> 31 <211> 14 <212> PRT <213> Homo sapiens <400>

Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly

<210> 32 <211> 32 <212> PRT <213> Homo sapiens <400> 32

Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 1 5 10 15

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 33 <213> 25 <212> PRT <213> Homo sapiens <400>

Glu Val Gin Leu Val Gin Ser Gly Scr Glu Leu Lys Lys Pro Gly Ala 】 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser 20 25 <210> 34 <21]> 32 <212> PRT <2丨3> Homo sapiens <400> 34

Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr Leu Gin 15 10 15 lie Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 35 <211> 22 <212> PRT <213> Mus musculus 158864 - Sequence Listing.doc - 11 - 201215618 <400> 35

Gin Leu Val Leu Thr Gin Ser Ser Ser Ala Ser Phe Ser Leu Gly Ala 15 10 15

Ser Ala Lys Leu Thr Cys 20 <210> 36 <211> 15 <232> PRT <213> Mus musculus <400> 36

Trp Tyr Gin Gin Gin Pro Leu Lys Pro Pro Lys Tyr Val Met Glu 15 10 15 <210> 37 <2L1> 32 <212> PRT <213> Mus musculus <400> 37

Gly lie Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Ala Asp Arg Tyr 1 5 10 Ϊ5

Leu Ser lie Ser Asn lie Gin Pro Glu Asp Glu Ala He Tyr lie Cys 20 25 30 <210> 38 <211> 11 <212> PRT <213> Mus musculus <400> 38

Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 1 5 10 <210> 39 <211> 22 <212> PRT <213> Homo sapiens <400> 39

Gin Pro Val Leu Thr Gin Ser Pro Ser Ala Ser Ala Ser Leu Gly Ala 15 10 15

Ser Val Lys Leu Thr Cys 20 <210> 40 <211> 15 <212> PRT <213> Homo sapiens <400> 40

Trp His Gin Gin Gin Pro Gly Lys Gly Pro Arg Tyr Leu Met Lys 15 10 15 <210> 4L <211> 32 <212> PRT <213> Homo sapiens <400>

Gly lie Pro Asp Arg Phe Scr Gly Ser Ser Ser Gly Ala Asp Arg Tyr 12- 158864 - Sequence Listing.doc 201215618 15 10

Leu Thr lie Ser Asn Leu Gin Ser Glu Asp Glu Ala Asp Tyr Tyr Cys 20 25 30 <210> 42 <211> 11 <212> PRT <213> Homo sapiens <400>

Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 1 5 10 <210> 43 <211> 21 <212> PRT <213> Homo sapiens <400>

Ser Val Leu Thr Gin Ser Pro Ser Ala i5er Ala Ser Leu Gly Ala Ser 1 5 10 15

Val Lys Leu Thr Cys 20 <210> 44 <211> 15 <212> PRT <213> Homo sapiens <400> 44

Trp Tyr Gin Gin Gin Pro Gly Lys Gly Pro Arg Tyr Leu Met Lys 15 10 15 <210> 45 <211> 122 <212> PRT <213> Artificial Sequence <220><223> Artificial Sequence Description: Synthetic humanized 8G8 immunoglobulin heavy chain polypeptide <400> 45

Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30

Gly Met Asn Trp Val Arg Gin Ala Fro Gly Gin Gly Leu Glu Trp lie 35 40 45

Gly Trp lie Asn rrhr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60

Lys Glv Arg Val Thr lie Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80

Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 -13- 158864 - Sequence Listing.doc 201215618

Ala Arg Ser Trp Tyr Tyr Val Ser Asn Tyr Trp Tyr Phe Asp Val Trp 100 105 110

Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 46 <21i> 122 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Humanized 8G8 Immunoglobulin heavy chain polypeptide <4〇〇> 46

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30

Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Uu Glu Trp Val 35 40 45

Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60

Lys Gly Arg Phe Thr Jle Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys S5 90 95

AlaAr, Ser Trp Tyr Tyr Val Ser Asn Tyr Trp Tyr Phe Asp Val T,p

Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 47 <21I> 122 <212> PRT <2]3>Artificial Sequence<220><223> Description of Artificial Sequence: Synthetic Human 8G8 Immunoglobulin Heavy Chain Peptide <400> 47

Glu Val Gin Leu Val Gin Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30

Gly Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp He 35 40 45

Gly Trp ile Asn Tlir Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 -14- 158864 - Sequence Listing, doc 201215618

Lys G!y Arg Phe Val Phe Ser Leu Asp Thr Ser Val Scr Thr Ala Tyr 65 70 75 80

Leu Gin ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Ser Trp Tyr Tyr Val Ser Asn Tyr Trp Tyr Phe Asp Val Trp 100 1.05 110

Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 48 <211> 116 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Humanized 8G8 Immunoglobulin light chain polypeptide <400> 48

Gin Pro Val Leu Thr Gin Ser Pro Ser Ala Ser Ala Scr Leu Gly Ala 1 5 10 15

Scr Val Lys Leu Thr Cys Thr Leu Ser Ser Gin His Ser Thr Tyr Thr 20 25 30 lie Glu Trp His Gin Gin Gin Pro Gly Lys Gly Pro Arg Tyr Leu Met 35 40 45

Lys Leu Lys Lys Asp Gly Ser His Ser Thr Gly Asp Gly lie Pro Asp 50 55 60

Arg Phe Scr Gly Ser Ser Ser Gly Ala Asp Arg Tyr Leu Thr He Ser 65 70 75 80

Asn Leu Gin Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Val Gly Asp 85 90 95

Thr lie Lys Glu Gin Phe Val Tyr Val Phe Gly Gly Gly Thr Lys Leu 100 105 110

Thr Val Leu Gly 115 <210> 49 <21I> 115 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis of Humanized 8G8 Immunoglobulin Light Chain (Mutation ) Peptide <400> 49

Ser Val Leu Thr Gin Ser Pro Ser Ala Ser Ala Ser Leu Gly Ala Ser 15 10 15

Val Lys Leu Thr Cys Thr Leu Ser Ser Gin His Ser Thr Tyr Thr lie 158864 - Sequence Listing. doc -15- on* 201215618 20 25 30

Glu rp Tyr Gin Gin Gin Pro Gly Lys G】y Pro Arg Tyr Leu Met Lys 35 40 45

Leu Lys Lys Asp Gly Set His Ser Thr Gly Asp Gly He Pro Asp Arg 50 55 60

Phe Ser Gly Set Ser Ser Gly Ala Asp Arg Tyr Leu Thr lie Ser Asn 65 70 75 80

Leu Gin Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Val Gly Asp Thr 85 90 95 lie Lys Glu Gin Phe Val Tyr Val Phe Giy Gly Cty Thr Lys Leu Thr 100 105 110

Val Leu Gly 115 <210> 50 <21l> 122 <212> PRT <213> Mus musculus <400> 50

Gin lie His Leu Val Gin Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 15 10 15

Thr Va] Lys I]e Ser Cys Lys A] a Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30

Gly Met Asn Trp Val Lys Gin Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45

Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80

Leu Gin lie Asn Asn Leu Lys Asn Glu Asp Met Ala Thr Tyr Phe Cys 85 90 95

Ala Arg Ser Trp Tyr Tyr Val Ser Asn Tyr Trp Tyr Phe Asp Val Trp 100 105 110

Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 5i <211> 116 <212> PRT <213> Mus musculus <400>

Gin Leu Val Leu Tlir Gin Scr Ser Ser Ala Ser Phe Ser Leu Gly Ala 15 10 15 •16- 158864-Sequence List.doc 201215618

Ser Ala Lys Leu Thr Cys Thr Leu Ser Ser Gin His Ser Thr Tyr Thr 20 25 30 lie GIu Trp Tyr Gin Gin Gin Pro Leu Lys Pro Pro Lys Tyr Va! Met 35 40 45

Glu Leu Lys Lys Asp Gly Scr His Ser Thr Gly Asp Gly lie Pro Asp 50 55 60

Arg Phe Ser Gly Ser Ser Ser Gly Ala Asp Arg Tyr Leu Ser lie Ser 65 70 75 80

Asn lie Gin Pro Glu Asp Glu Ala lie Tyr lie Cys Gly Val Gly Asp 85 90 95

Thr He Lys Glu Gin Phe Val Tyr Val Phe Gly Gly Gly Thr Lys Val 100 105 110

Thr Val Leu Gly 115

<2i0> 52 <211> 117 <212> PRT <213> Homo sapiens <400> 52

Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30

Tyr lie His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45

Gly Trp He Asn Pro Gly Ser Gly Asn Thr Asn Tyr Ala Gin Lys Phe 50 55 60

Gin Gly Arg Val Thr lie Thr Arg Asp rFhr Ser Thr Ser Thr Ala Tyr 65 70 75 80

Leu Glu Leu Ser Ser Leu Arg vSer Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Thr Ala Ala Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110

Val Thr Val Ser Ser 115 <210> 53 <2U> 117 <212> PRT <213> Homo sapiens <400> 53

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 •17- 158864-Sequence List.doc 201215618

Ser Leu Atg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Gly Ala He Ser Scr Ser Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Thr Ala Ala Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu }〇〇 105 110

Val Thr Val Ser Ser 115

<210> 54 <211> 117 <212> PRT <213> Homo sapiens <400> 54

Glu Val Gin Leu Val Gin Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ding hr Phe Thr Ser Tyr 20 25 30

Tyr lie His Trp Va] Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp He 35 40 45

Gly Trp He Asn Pro Gly Ser Gly Asn Thr Asn Tyr Ala Gin Lys Phe 50 55 60

Gin Gly Arg Phe Vai Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr 65 70 75 80

Leu Gin He Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Thr Ala Ala Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110

Val Thr Val Ser Ser U5 <210> 55 <211> 112 <212> PRT <213> Homo sapiens <400> 55

Gin Pro Val Leu Thr Gin Ser Pro Set Ala Ser Ala Ser Leu Gly Ala 15 10 15 158864 - Sequence Listing.doc -18- s 201215618

Ser Val Lys Leu Thr Cys Thr Leu Ser Ser Gly His Ser Ser Tyr Thr 20 25 30 lie Ala Trp His Gin Gin Gin Pro Gly Lys Gly Pro Arg Tyr Leu Met 35 40 45

Lys Leu Asn Ser Asp Gly Ser His Ser Lys Gly Asp Gly lie Pro Asp 50 55 60

Arg Phe Ser Gly Ser Ser Ser Gly Ala Asp Arg Tyr Leu Thr lie Ser 65 70 75 80

Asn Leu Gin Ser Glu Asp GIu Ala Asp Tyr Tyr Cys Gly Thr Trp Gly 85 90 95

Thr Gly lie Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110

<210> 56 <211> 345 <212> DNA <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis of Humanized 8G8 Immunoglobulin Light Chain Polynucleotide <400>; 56 tctgtgctga cccagagccc aagcgccagc gccagcctgg gcgccagcgt gaaactgacc 60 tgcaccctga gcagccagca cagcacctac accatcgaat ggiatcagca gcagccaggc 120 aaaggcccac gctacctgat gaaactgaaa aaagatggca gccacagcac cggc £ atggc 180 atcccagatc gcttcagcgg cagcagcagc ggcgccgatc gctacctgac catcagcaac 240 ctgcagagcg aagatgaagc cgattactac tgcggcgtgg gcgataccat caaagaacag 300 ttcgtgtacg tgttcggcgg cggtaccaaa ctgaccgtgc tgggc 345 < 210 > 57 <211> 12 <212> PRT <2Π> Mus musculus <400> 57

Leu Lys Lys Asp Gly Ser His Ser Thr Gly Asp Gly <210> 58 <211> 12 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Mutant Mouse Sequence <400> 58

Leu Lys Lys Asp Ala Ser His Ser Thr Gly Asp Gly 1 5 10 <210> 59 <211> 12 •19· 158864 - Sequence Listing.doc 6 201215618 <212> PRT <213>Artificial Sequence<220>;<223> Description of artificial sequence: synthetic mutant mouse sequence <400> 59

Leu Lys Lys Glu Gly Ser His Ser Thr Gly Asp Gly 1 5 10 <210> 60 <211> 12 <212> PRT <213>Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis Mutant mouse sequence <400> 60

Leu Lys Lys Thr Gly Ser His Ser Thr Gly Asp Gly 1 5 10

<210> 61 <211> 12 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: synthetic mutant mouse sequence <400>

Leu Lys Lys Asp Gly Ser His Ser Thr Gly Asp Ala 1 5 10

<210> 62 <213> 12 <212> PRT artificial sequence <220><223> Description of artificial sequence: synthetic mutant mouse sequence <400>

Leu Lys Lys Asp Gly Ser His Ser Thr Gly Glu Gly 1 5 10

<210> 63 <211> 12 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: synthetic mutant mouse sequence <400> 63

Leu Lys Lys Asp Gly Ser His Ser Thr Gly Thr Gly 1 5 10 <210> 64 <211> 12 <212> PRT <213>Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis Mutant mouse sequence 158864 - Sequence Listing.doc •20·

201215618 <400> 64

Leu Lys Lys Ser Gly Ser His Ser Thr Gly Asp Gly 1 5 10 <210> 65 <211> 12 <212> PRT <213>Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis Mutant mouse sequence <400> 65

Leu Lys Lys Ser Gly Ser His Ser Thr Gly Ser Gly 1 5 10 <210> 66 <211> 12 <212> PRT <213>Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis Mutant mouse sequence

<400> 66

Leu Lys Lys Thr Gly Ser His Ser Thr Gly Asp Ala 1 5 10 <210> 67 <211> 32 <212> PRT <213>Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis Mutant mouse FR3 polypeptide <400> 67

Ala I3e Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Ala Asp Arg Tyr 15 10 15

Leu Ser He Ser Asn lie Gin Pro Glu Asp Glu Ala lie Tyr lie Cys 20 25 30 <210> 68 <21l> 32 <212> PRT <213> Artificial sequence <220><223> Description: Synthetic mutant human MFR3 polypeptide <400> 68

Ala He Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Ala Asp Arg Tyr 15 10 15

Leu Thr lie Ser Asn Leu Gin Ser Glu Asp Glu Ala Asp Tyr Tyr Cys 20 25 30 <210> 69 <211> 109 <212> PRT <213> Homo sapiens-21 · 158864 · Sequence Listing.doc 201215618 <400> 69

Ser Tyr Glu Leu Tlir Gin Pro Pro Ser Val Ser Val Ser Pro Gly Gin 15 10 15

Thr Ala Arg lie Thr Cys Gin Gly Asp Ala Leu Arg Ser Tyr Tyr Ala 20 25 30

Ser Trp Tyr Gin Gin Lys Fro Gly Gin Ala Pro Val Leu Val lie Tyr 35 40 45

Lys Asp Asn Asn Arg Pro Ser Gly lie Pro Glu Arg Phe Ser Gly Ser 50 55 60

Ser Ser Gly Asn Thr Ala Thr Leu Thr He Ser Gly Ala Gin Ala Glu 65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His 85 90 95

Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Giy 100 105

<210> 70 <211> 117 c232> PRT <213> Human Cell Huge Virus <400> 70

Val Glu Met Ala Phe Ala Tyr Ala Leu Ala Leu Phe Ala Ala Ala Arg 15 10 15

Gin Glu Glu Ala Gly Ala Gin Val Ser Val Pro Arg Ala Leu Asp Arg 20 25 30

Gin Ala Ala Leu Leu Gin lie Gin Glu Phe Met lie Thr Cys Leu Ser 35 40 45

Gin Thr Pro Pro Arg Thr Thr Leu Leu Leu Tyr Pro Thr Ala Val Asp 50 55 60

Leu Ala Lys Arg Ala Leu Trp Thr Pro Asn Gin lie Thr Asp lie Thr 65 70 75 80

Ser Leu Val Arg Leu Val Tyr ile Leu Ser Lys Gin Asn Gin Gin His 85 90 95

Leu lie Pro Gin Trp Ala Leu Arg Gin Ile Ala Asp Phe Ala Leu Lys 100 105 110

Leu His Lys Thr His 115 <210> 71 <211> 10 <212> PRT <213> Homo sapiens <400> 71

Gly Phe Thr Phe Ser Pro Tyr Ser Val Phe -22·

!58864-Sequence table.doc

201215618 <210> 72 <21!> 18 <2]2> PRT <213> Homo sapiens <400> 72

Ser Ser lie Asn Ser Asn Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 15 10 15

Lys Gly <210> 73 <211> 18 <212> PRT <213> Homo sapiens <400> 73

Ser Ser lie Asn Ser Asp Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 15 10 15

Lys Gly

<210> 74 <211> 18 <212> PRT <213> Homo sapiens <400> 74

Ser Ser lie Asn Ser Asn Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 15 !0 15

Lys Gly <210> 75 <211> 23 <212> PRT <2] 3> Homo sapiens <400> 75

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 1 5 10 15

Tyr Tyr Tyr Gly Leu Asp Val 20 <210> 76 <211> 16 <212> PRT <2]3> Homo sapiens <400> 76

Arg Ser Scr Gin Ser Leu Leu His Tlu Asn Gly Tyr Asn Tyr Leu Asp 15 10 15 <210> 77 <211> 7 <212> PRT <213> Homo sapiens <400> 77

Leu Ala Ser Asn Arg Ala Ser 158864 - Sequence Listing. doc -23- § 201215618 <210> 78 <211> 9 <212> PRT <2]3> Homo sapiens <400>

Met Gin Ala Leu Gin lie Pro Arg Thr <210> 79 <231> 25 <212> PRT <213> Homo sapiens <400> 79

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser 20 25 person rg 8013 四智80丨0>I>2>3>Kbva 1 1 *—· 1 p <2<2<2<2<4Tr. eo LI y G1 s Ly y G, o pr va rp <210> 81 <211> 30 <212> PRT <213> Homo sapiens <400>

Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser He Phe Leu Gin 1 5 10 15

Met Asn Scr Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 20 25 30 <210> 82 <2Π> Π <212> PRT <213> Homo sapiens <400>

Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 83 <211> 23 <212> PRT <213> Homo sapiens <400> 83

Asp lie Val Met rFhr Gin Ser Pro Leu Ser Leu Ser Val Thr Pro Gly 15 10 15

Glu Pro Ala Ser lie Ser Cys 20 24-158864 - Sequence Listing.doc 201215618 <210> 84 <211> 15 <212> PRT <213> Homo sapiens <400> 84

Trp Tyr Val Gin Lys Pro Gly Gin Scr Pro Gin Leu Leu He Tyr 15 10 15 <230> 85 <211> 32 <212> PRT <2]3> Homo sapiens <400> g5

Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Lys lie Scr Arg Val Glu Thr Glu Asp Val Gly Val Tyr Tyr Cys 20 25 30

<210> 86 <211> 10 <212> PRT <213> Homo sapiens <400> 86

Phe Giy Gin Gly Thr Lys Val Glu lie Lys <210> 87 <211> 130 <212> PRT <2i3> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Affinity Mature Human Ig Heavy Chain Peptide <400> 87

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe ΊΙιγ Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Lea Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Asn Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Scr Arg Asp Asn Ala Glu Asn Ser He Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Giy Ser Leu Scr Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Tlu Val 115 120 125 -25- 158864 - Sequence Listing.doc 201215618

Scr Ser 130 <210> 88 <211> 130 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis of Affinity Mature Human Ig Heavy Chain Polypeptide <400> 88 GIu Glu Gin Val Leu GIu Ser Gly Gly Gly Leu Val Lys Fro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Fro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Scr Asp Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Scr Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly ΊΉγ Leu Val Thr Val 115 120 125

Ser Ser 130 <210> S9 <211> 130 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis of Affinity Mature Human lg Heavy Chain Polypeptide <400> 89

Glu Glu Gin Val Leu GIu Scr Gly Gly Gly Leu Val Lys 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

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Scr Ser lie Asn Ser Asn Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 158864 · Sequence Listing.doc - 26 - s 201215618

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 90 <211> 112 <212> PRT <213> Homo sapiens <400> 90

Asp lie Val Met Thr Gin Ser Pro Leu Ser Leu Ser Val Thr Pro Gly

Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His Thr 20 25 30

Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Val Gin Lys Pro Gly Gin Ser 35 40 45

Pro Gin Leu Leu lie Tyr Leu Ala Ser Asn Arg Ala Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 'Fhr Leu Lys lie 65 70 75 80

Ser Arg Val Glu Thr Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95

Leu Gin lie Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 100 105 110 <210> 91 <211> 18 <212> PRT <213> Homo sapiens <400>91

Ser Ser lie Asn Ser Asp Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 15 10 15

Lys Gly <210> 92 <211> 130 <212> PRT <213> Homo sapiens • 27-158864 - Sequence Listing.doc 201215618 <400> 92

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phc Thr Phe Ser Fro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Asp Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Vai Trp Gly Gin Gly Thr Uu Val Thr Val Π5 120 125

Ser Ser 130 <210> 93 <211> 18 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis of Affinity Mature Human ig Heavy Chain Peptide <220><221> M0DJRES <222> (4)..(4) <223> Asn or Ser <220>

<221> TOJES <222> (6)..(6) <223> Any amino acid <220>

<221> M0D_RES <222> (8)..(8) <223> Any amino acid <400>

Ser Ser lie Xaa Ser Xaa Ser Xaa Tyr Lys Tyr Tyr Ala Asp Ser Val 1 5 10 . 15

Lys Gly <210> 94 <211> 130 <212> PRT <213> Artificial sequence 28-158864 - Sequence Listing.doc 201215618 <220><223> Description of artificial sequence: synthesis of affinity mature human Ig heavy chain polypeptide <220><221> M0D.RES <222> (52)..(52) <223> A_sn or Ser <220> <22]> MOD RES <222> (54)., (54) <223> Any amino acid <220><221> M0DJES <222> (56).. (56) <223> Any amino acid <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Xaa Ser Xaa Ser Xaa Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 95 <211> 22 <212> PR Ding <213> Homo sapiens <400> 95

Leu Glu Trp Val Ser Ser lie Ser Ser Ser Ser Tyr lie Tyr Tyr 15 10 15

Ala Asp Ser Val Lys Gly 20

<210> 96 <211> 130 <212> PRT • 29-158864 - Sequence Listing. doc 201215618 <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Affinity Mature Human HC Peptide <400> 96

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phc Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Ser Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val ITir Val 115 120 125

Ser Ser 130 <210> 97 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys 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

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser lie Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Tlir lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp ΊΉγ Ala Val Tyr Tyr Cys 85 90 95 -30- 158864 - Sequence Listing.doc 201215618

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Scr Ser 130 <210> 98 <211> 130 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis of Affinity Mature Human HC Polypeptide <400>

Glu Glu G! A Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Ding rp Va] 35 40 45

Ser Ser lie Asn Ser Asn Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 99 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Giu Glu Gin Vai E.eu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr • 31 158864 - Sequence Listing.doc 201215618 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Gin Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe ITir lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 100 <2il> 130 <212> PCT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Phe Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Va] Trp Gly Gin Gly Thr Leu Val Thr Vai 115 120 125

Ser Ser 130 • 32-158864 - Sequence Listing. doc 201215618 <210> 101 <211> 130 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Affinity Mature Human HC polypeptide <400> 1〇]

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Met Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu G3n Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 ]〇5 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 102 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly G!y Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Vai Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser He Asn Ser Leu Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 158864 - Sequence Listing.doc -33- 201215618 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Ar£ Scr Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp ]〇〇 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Scr Ser 130 <210> 103 <231> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Gly Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Scr Ser 130 <210> 104 <211> 130 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis of affinity matured human HC polypeptide <400> 104 158864 · Sequence Listing.doc -34-

201215618

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly ] 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Scr Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser His Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser He Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly rFhr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 105 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys 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

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser He Asn Ser Lys Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Giu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val -35- 158864 - Sequence Listing.doc 201215618 115 120 125

Ser Ser 30 <210> 106 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400> 106

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Trp Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 107 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Ding rp Val 35 40 45 -36- 158864 - Sequence Listing.doc 201215618

Ser Ser lie Asn Ser Tyr Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Tlir Val 115 320 125

Ser Ser 130 <210> 108 <213> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser He Asn Ser Val Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Scr Arg Asp Asn Ala Glu Asn Ser lie Phe 05 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp TTir Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 109 <211> 130 <212> PRT <213> Artificial Sequence -37-158864 - Sequence Listing.doc 201215618 <220><223> Description of Artificial Sequence: Synthetic Affinity Mature Human HC polypeptide <400> 109

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Va] Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Ser Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Uu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 110 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Giy Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser vSer lie Ser Ser lie Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr ile Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 -38-

158864-Sequence List.doc s 201215618

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 111 <2il> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser He Ser Ser Asn Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr Ue Scr Arg Asp Asn Ala Glu Asn Scr He Phe 65 70 75 80

Leu Gin Met Asn Ser Lea Arg Ala Glu Asp rrhr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Scr Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 112 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30 39· 158864-Sequence List.doc 201215618

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Ding rp Val 35 40 45

Ser Ser lie Ser Ser Gin Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser He Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 113 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Phe Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp ΊΤίγ Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Set 130 - 40- 158864 - Sequence Listing. doc 201215618 <210> 114 <211> 130 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Affinity Mature Human HC polypeptide <400> 114

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Met Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 115 <211> 130 <212> PRT <213> artificial sequence <220>

<223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys 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

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Leu Ser Tlir Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80 158864 - Sequence Listing.doc -41- 201215618

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Scr Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Va丨 Trp Gly Gin Gly Thr Leu Va丨 Thr Val 115 120 125

Ser Ser 130 <210> 116 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Aia Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Gly Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 117 <211> 130 <212> PRT c2]3>Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15 -42- 158864 - Sequence Listing.doc 201215618

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser His Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser He Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala G]u Asp Thr Ala Val Dyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 118 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400> Π8

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Lys Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125 -43 - 158864 - Sequence Listing.doc 201215618

Ser vSer 130 <210> 119 <211> 130 <212> PRT <2I3> artificial sequence <220><223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Trp Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 】 00 105 120

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 120 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly l 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Tyr Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 -44 - 158864 - Sequence Listing.doc 201215618

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 121 <211> 130 <212> PRT <2i3> artificial sequence <220>

<223> Description of artificial sequence: Synthesis of affinity mature human HC polypeptide <400> 121

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Tip Vai 35 40 45

Ser Ser lie Ser Ser Val Scr Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Mel Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Ding yr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Scr Gly Ser Leu Ser Asp 100 105 Π0

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 122 <211> 130 <212> PRT <213> Artificial sequence synthesis affinity matured human HC polypeptide • 45- <220><223> Description of artificial sequence 158864 - Sequence Listing .doc 201215618 <40ft> 122

Glu Glu Gin Val Leu Glu Ser Giy Gly Gly Leu Val Lys Pro Oly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Ser Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Giu Asn Ser He Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp m 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 123 <211> 130 <212> PRT <2]3>Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400> 123

Glu Glu Gin Val Leu Giu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser lie Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Giu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110 •46· 158864-Sequence List.doc 201215618

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 124 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Scr Gly Gly Gly Leu Val Lys Fro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Asn Ser Arg Dingyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Scr lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Va】Tyr Tyr Cys 85 9Q 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 125 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400> 125

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 158864 - Sequence Listing.doc -47- 201215618 35 40 45

Ser Ser He Asn Set Gin Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Giu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Va] Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 126 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys 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

Ser Val Phe Ding rp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 vSer Ser lie Asn Ser Phe Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Hir Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Oly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 127 <211> 130 -48·158864·Sequence List.doc 201215618 <212> PRT <2i3> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Affinity Mature Human HC polypeptide <400> 127

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Met Ser Arg Tyr Lys Tyr Tyr Ala Asp Scr Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Ding rp Gly Gin Giy Thr Leu Vai Thr Val 115 120 125

Ser Ser 130 <210> 128 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys 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

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser ile Asn Ser Leu Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys -49- 158864 · Sequence Listing.doc 201215618 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Uu Scr Asp 100 〗 05 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 129 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Fro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Gly Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser He Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Giu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Scr Asp 100 105 110

Tyr Dyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val IIS 120 125

Ser Ser 130 <210> 130 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15 -50- 158864 - Sequence Listing.doc 201215618

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser His Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Va! Thr Val 115 120 125

Ser Ser 130 <210> 131 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Fro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Lys Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 Π0

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Scr -51 - 158864 - Sequence Listing.doc 201215618 130 <210> 132 <211> 130 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Affinity Mature Human HC polypeptide <400> 132

Olu Glu Gin Val Leu GIu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser Tie Asn Ser Trp Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Ding rp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 230 <210> 133 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys 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

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Tyr Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 -52- 158864 - Sequence Listing, doc 201215618

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Scr Ser Gly Ser Leu Ser Asp 100 105 1]0

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 134 <211> 130 <212> PRT <213> artificial sequence <220>

<223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Ττρ Val 35 40 45

Ser Ser lie Asn Ser Val Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Aia Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <21.0> 135 <211> 130 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis of Affinity Mature Human HC Polypeptide-53-158864- Sequence Listing.doc 201215618 <400> 135

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Ser Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Scr Arg Asp Asn Ala Glu Asn Ser He Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp loo 105 no

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <230> 136 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Set Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser He Asn Ser lie Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Scr Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Scr Gly Ser Leu Ser Asp 100 105 110 -54- 158864 - Sequence Listing.doc 201215618

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 137 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ή; γ Phc Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser He Asn Ser Asn Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 SO

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 138 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 -55· 158864 - Sequence Listing.doc 201215618

Ser Ser He Asn Ser Gin Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Ixu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 320 125

Ser Ser 130 <2I0> 139 <211> 130 <212> PRT <2]3>Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400> 139

Glu Glu Gin Val Leu Glu Ser Gly Giy Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Phe Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Tlir Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp (Jly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 140 <211> 130 <212> PRT <213> Artificial Sequence -56-158864 - Sequence Listing.doc 201215618 <220><223> Description of Artificial Sequence: Synthetic Affinity Mature Human HC polypeptide <400> 140

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys 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

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Met Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Scr 130 <210> 141 <211> 130 <212> PRT <2i3> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Scr Ser lie Asn Ser Leu Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 •57- 158864 · Sequence Listing.doc 201215618

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 142 <211> 130 <212> PRT <2I3> artificial sequence <22Q><223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Gly Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Scr He Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 143 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Va] Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30 -58- 158864 - Sequence Listing.doc 201215618

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser His Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser He Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 . 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Tin Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 144 <211> 130 <212> PRT <2i3> artificial sequence <220><223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <4〇〇&gt ; 144

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Ding rp Val 35 40 45

Ser Ser lie Asn Ser Lys Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 1]5 120 125

Ser Ser 130 -59- 158864 - Sequence Listing.doc 201215618 <210> 145 <213> 130 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Affinity Mature Human HC polypeptide <400> 145

Glu Glu Gin Vai Leu Glu Ser Gly Gly Gly Leu Val Lys Fro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Scr Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Trp Ser Lys Ding yr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asa Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 146 <21l> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 Ϊ5

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser He Asn Ser Tyr Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80 -60· 158864 - Sequence Listing, doc 201215618

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Scr Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 147 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Scr Scr lie Asn Scr Val Ser Lys Tyr Lys Tyr Tyr Ala Asp Set Val 50 55 60

Lys Gly Arg Phe Thr I】e Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Dyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Scr Ser 130 <210> 148 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly -61 - 158864 - Sequence Listing.doc 201215618 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Va) Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Ser Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp !00 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val TTir Val 115 320 125

Ser Ser 130 <210> 149 <211> 130 <212> PRT <2I3> artificial sequence <220><223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser He Ser Ser lie Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125 -62- 158864 - Sequence Listing.doc 201215618

Ser Ser 130 <210> 150 <211> 330 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu GIu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Giy Leu Glu Trp Val 35 40 45

Ser Scr lie Ser Ser Asn Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Tht lie Ser Arg Asp Asn Ala Glu Asn Scr lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Scr Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 205 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 151 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 】5

Ser Leu Arg Leu Scr Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Gin Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 158864 - Sequence Listing.doc -63- 201215618 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 315 120 125

Ser Ser 130 <210> 152 <211> 230 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Giy Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Phe Ser Ar £ Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp A$n Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Aia Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 】 00 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 153 <211> 130 <212> PRT <213> Artificial Sequence <220> -64- 158S64_ Sequence Listing.doc 201215618 <223> Description of Artificial Sequence: Synthetic Affinity Mature Human HC polypeptide <400> 153

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Scr Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Ding rp Val Arg G]n Ala Pro Giy Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Met Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Scr Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly ITir Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 154 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly GJy Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Scr Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Scr Scr lie Ser Ser Leu Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 SO

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 158864 - Sequence Listing.doc -65- s· 201215618 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <2I0> 155 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Set Gly Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr AU Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 156 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30 66-

158864-Sequence List.doc s 201215618

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser His Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser He Phc 65 70 75 80

Leu Gin Met Asn Scr Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phc Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Giy llir Leu Val Thr Val 115 320 125

Ser Ser 130 <230> 157 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <4〇〇&gt ; 157

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Lys Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Scr Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Giy Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 158 -67- 158864 · Sequence Listing.doc 201215618 <211> 130 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Affinity Mature Human HC polypeptide <400> 158

Glu Glu Gin Val Leu Glu Scr Gly Gly Gly Leu Val Lys Pro Gly Gly 】 5 10 15

Ser Leu Ar£ Leu Ser Cys Ala Ala Ser Gly Phc Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Trp Ser Arg Tyr Lys Tyf Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 159 <211> 130 <2i2> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Giy Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Aia Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Scr lie vSer Ser Tyr Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Va] 50 55 60

Lys Gly Arg Phe Thr IJe Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80 -68- 158864 - Sequence Listing.doc 201215618

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <21〇> 160 <211> 130 <212> FRT <2]3> Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis of Affinity Mature Human HC Polypeptide<400> 160

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phc Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Val Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser Me Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Dyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Va] Thr Val 115 120 125

Ser Ser 130 <210> 161 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Giu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15 •69- 158864 · Sequence Listing.doc 201215618

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Fhe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Ser Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser He Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 162 <211> 130 <212> PKT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Vai Leu Glu Ser Gly Gly Gly Leu Val Lys 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

Ser Val Phe Trp Val Arg Gin Ata Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser He Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125 -70- 158864 - Sequence Listing.doc 201215618

Scr Ser 130 <210> 163 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly G!y 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Asn Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val

Lys Gly Arg Phe Thr lie Scr Arg Asp Asn Ala Glu Asn Ser He Phe 65 70 75 80

Leu Girt Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 164 <211> 130 <212> FRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Scr Pro Tyr 20 25 30

Scr Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser He Ser Ser Gin Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

158864 - Sequence Listing.doc -71 - 201215618

Lys Giy Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Ixu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Giy Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Giy Leu Asp Va] Trp Giy Gin Giy Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 165 <211> 130 <212> PRT <213> artificial sequence <220>

<223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Giy Giy Giy Leu Val Lys Pro Giy Giy 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Giy Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Giy Lys Giy Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Phe Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Giy Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Giy Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Giy Leu Asp Val Trp Giy Gin Giy Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 166 <211> 130 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis of Affinity Mature Human HC Polypeptide 158864 Sequence Listing.doc -72-

S 201215618 <400> 166

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Fro Gly Lys Gly Leu Glu Trp Val 35 40 45

Scr Ser lie Ser Ser Met Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Scr Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 30 <210> 167 <211> 130 <232> PRT <213> Artificial sequence <220><223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Scr Scr lie Ser Ser Leu Ser lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Aig Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110 -73- 158864 - Sequence Listing.doc 201215618

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 168 <2Π> 130 <232> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Giu Glu Gin Val Leu Glu Ser Gly Gly Gly I^eu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Scr Gly Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin G]y Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 169 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Ding rp Va】Arg Gin Ala Pro Gly Lys Gly Leu G】u Trp Vai 35 40 45 •74-

158864-SEQ ID NO.doc 201215618

Ser Ser lie Ser Ser His Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Scr Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Scr Ser 130

<210> 170 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Gla Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Scr Scr Lys Scr Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Scr Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp llir Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Uu Scr Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130

<210> 171 <211> 130 <212> PRT -75-158864 - Sequence Listing.doc 201215618 <213>Artificial Sequence<220><223> Description of Artificial Sequence: Synthesis of Mature Human HC Peptide <400> 171

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15

Ser Leu Ar^ Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Trp Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Ding rp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 172 <212> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys 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

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Tyr Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr Jle Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Tlir Ala Val Tyr Tyr Cys 85 90 95 -76- 158864 - Sequence Listing.doc 201215618

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val rrhr Val 115 120 125

Ser Ser 130 <230> 173 <211> 130 <212> PRT <2i3> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Fro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Ττρ Val 35 40 45

Ser Ser lie Ser Ser Val Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 174 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr -77- 158864 - Sequence Listing.doc 201215618 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Scr Ser lie Asn Ser Ala Ser Tlir Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Scr Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Scr Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 175 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Lea Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Ala Ser Ήιγ Tyr Lys Tyr Tyr Ala Asp Ser Val SO 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr teu Val Thr Val Π5 120 125

Ser Ser 130 -78- 158864 - Sequence Listing.doc 201215618 <210> Ϊ76 <21I> 130 <212> PRT <213>Artificial Sequence<220><223> Description of Artificial Sequence: Synthetic Affinity Mature Human HC polypeptide <400> 176 GIu Glu Gin Val Leu GIu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly I 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala vSer Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Scr Ser Ile'Asn Ser Ala Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr Ne Ser Arg Asp Asn A!a Glu Asn Ser He Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Dyr yr Gly Leu Asp Val Trp Gly G]n G]y Thr Leu Val Thr Val 115 320 125

Ser Ser 130 <210> 177 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu GIu Ser Gly Gly Gly Leu Val Lys 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

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Ala Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe llir lie Ser Arg Asp Asn Ala Glu Asn Scr lie Phe 158864 - Sequence Listing.doc - 79 - 201215618 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr G】y Leu Asp Val Trp Gly Gin G!y Thr Leu Val Ding hr Val 115 120 125

Ser Ser 130 <210> 178 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Scr Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Ala Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Scr Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Giy Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 179 <211> 130 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthesis of affinity matured human HC polypeptide <400> 80-158864-Sequence List.doc 201215618

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Ala Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Scr Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 180 <211> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Set Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser ile Asn Ser Asp Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val -81 - 158864 - Sequence Listing.doc 201215618 115 120 125

Ser Ser 130 <2i0> 181 <211> 130 <212> PRT <2]3>Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400> 181

Glu Glu Gin Va) Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly G!y 15 10 35

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Ser Asp Ser Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser He Phe 65 70 75 SO

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 no

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 182 <2il> 130 <212> PRT <2i3> artificial sequence <220><223> Description of artificial sequence: synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Giy 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 -82- 158864 - Sequence Listing.doc 201215618

Ser Ser lie Asn Ser Asp Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala GIu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Scr Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 115 120 125

Ser Ser 130

<210> 1S3 <21!> 130 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of affinity matured human HC polypeptide <400>

Glu Glu Gin Val Leu GIu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Ser Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser He Ser Ser Asp Ser Lys Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala GIu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Ser Leu Ser Asp 100 105 110 Dingyr Dyr Tyr Gly Leu Asp Val Trp Gly Gin G!y Thr Leu Val Thr Val 115 120 125

Ser Ser 130 <210> 184 <211) 130 <212> PRT <213> Artificial sequence -83-158864 - Sequence Listing.doc 201215618 <220><223> Description of artificial sequence: synthetic affinity mature Human HC polypeptide <400> 184

Glu Glu Gin Val Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Tyr 20 25 30

Scr Val Phe Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Asn Ser Asp Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Glu Asn Ser lie Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Ser Tyr Tyr Ala Phe Ser Ser Gly Sex Leu Ser Asp 100 105 110

Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 1.15 120 125

Ser Ser 130 <210> 185 <211> 366 <212> DNA <213>Artificial sequence <220><223> Description of artificial sequence: synthetic humanized 8G8 immunoglobulin heavy chain polypeptide <220>;<221> (DS <222> (1)..(366) <400> 185 gag gtt cag ctg gtg cag tct ggc gcc gaa gtg aaa aaa cca ggg gcc 48 G]u Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 tea gtg aaa gtg tcc tgt aaa get tct ggc tac acc tic acc aac tac 96

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 ggc atg aac Xgg gtg cgt cag gcc ccg ggt cag ggc ctg gaa tgg ate 144

Gly Met Asn Trp Val Arg Gla Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45 ggc tgg ate aac acc tac acc ggc gaa cca acc tac gcc gat gat ttc 192

Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 aaa ggc cgt gtg act ala acc cgt gac acc tcc acc age aca gcc tac 240

Lys 6Ty Arg VaT Thr lie Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 -84 158864 - Sequence Listing.doc 201215618 eta gaa ctg age age tta aga age gag gac act gee gtc tat tat tgc 288

Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 geg cgt age tgg tac tac gtg age aac tac tgg lac ttc gat gtg tgg 336

Ala Arg Ser Trp Tyr Tyr Val Ser Asn Tyr Trp Tyr Phe Asp Val Trp 100 105 110 ggt caa gga acc ctg gtc acc gtc tee teg 366

Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 320 <210> 186 <211> 345 <212> DNA <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Humanized 8G8 Immunoglobulin light chain (mutant) polypeptide

<220><221> CDS <222> (1)..(345) <400> 186 let gtg ctg acc cag age cca age gee age gee age ctg ggc gee age Ser Val Leu Thr Gin Ser Pro Ser Ala Ser Ala Ser Leu Gly Ala Ser 1 5 10 15 gtg aaa ctg acc igc acc ctg age age cag cac age acc tac acc ate Val Lys Leu Thr Cys Thr Leu Ser Ser Gin His Ser Thr Tyr Thr lie 20 25 30 gaa tgg tat Cag cag cag cca ggc aaa ggc cca ege tac ctg atg aaa Glu Trp Tyr Gin Gin Gin Pro Gly Lys Gly Pro Arg Tyr Leu Met Lys 35 40 45 ctg aaa aaa gat ggc age cac age acc ggc gat ggc ate cca gat ege Leu Lys Lys Asp Gly Ser His Ser Thr Gly Asp Gly He Pro Asp Arg 50 55 60 ttc age ggc age age ggc gee gat ege tac ctg acc ate age aac Phe Ser Gly Ser Ser Ser Gly Ala Asp Arg Tyr Leu Thr lie Ser Asn 65 70 75 80 ctg cag age gaa gat gaa gee gat tac tac tgc ggc gtg ggc gat acc Leu Gin Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Val Gly Asp Thr 85 90 95 ate aaa gaa cag ttc gtg tac gtg tic ggc ggc ggt Acc aaa ctg acc lie Lys Glu Gin Phe Val Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr 100 105 110 48 96 144 192 240 gtg ctg ggc 288 336 345

Val Leu Gly 115 <210> 187 <211> 22 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: Synthesis of IGHV3-21*01 peptide <400> 187

Leu Glu Trp Val Ser Ser lie Ser Ser Ser Ser Serr Tyr Tyr 15 10 15 '•mi 15_8864-Sequence List.doc -85- 201215618 Aa Asp Ser Val Lys Gly <210> 188 <211> 22 <212> PRT <2]3>Artificial sequence <220><223> Description of artificial sequence: Synthesis of MSL-109 peptide <220><221>MOD RES <222> (10).. (10 <223> into sp, $er, Thr, Asn, Gin, Phe, Met or Leu <220><221> MOD RES <222> (12)..(12) <223> Thr or Human rg <400> 188 Leu Glu Trp Val Ser Ser lie Asn Ser Xaa Ser Xaa Tyr Lys Tyr Tyr 1 5 10 15

Ala Asp Ser Val Lys Gly 20 <210> 189 <211> 15 <212> IM <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Oligonucleotide <400> 189 tcgcgcccga agagg 15 <210> 190 <2Π> 17 <212> DNA <213> Artificial sequence <220><223> Description of artificial sequence: synthetic oligonucleotide

<400> 190 cggccggatt gtggatt 17 <210> 191 <211> 23 <212> DNA <213> Artificial sequence <220><223> Description of artificial sequence: synthetic oligonucleotide <400> 191 caccgacgag gaticcgaca acg <210> 192 23 158864 - Sequence Listing. doc -86-s 201215618 <211> 28 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence : synthetic peptide <400> 192

Thr Ala Glu Lys Asn Asp Tyr Tyr Arg Val Pro His Tyr Trp Asp Ala 1 5 10 15

Cys Ser Arg Ala Leu Pro Asp Gin Thr Arg Tyr Lys 20 25 <210> 193 <211> 28 <2J2> PRT <2]3> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic peptide

<400> 193

Cys Pro His Val Trp Met Pro Pro Gin Thr Thr Pro His Asp Trp Lys 15 10 15

Gly Ser His Thr Thr Ser Gly Leu His Arg Pro His 20 25 <210> 194 <211> 28 <212> PRT <213> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic Peptide <400> 194

Ser Arg Ala Leu Pro Asp Gin Thr Arg Tyr Lys Tyr Val Glu Gin Leu 15 10 15

Val Asp Leu Thr Leu Asn Tyr His Tyr Asp Ala Ser 20 25 <210> 195 <211> 29 <212> PRT <213:> Artificial Sequence <220><223> Description of Artificial Sequence: Synthetic peptide <400> 195

His Pro His His Glu Tyr Leu Ser Asp Leu Tyr Thr Pro Cys Ser Ser 1 5 10 15

Ser Gly Arg Arg Asp His Ser Leu Glu Arg Leu Thr Arg 20 25 <210> 196 <211> 28 <212> PRT <213> Artificial Sequence -87-158864 · Sequence Listing.doc 201215618 <220><223> Description of the artificial sequence: <400> 196 Cys Pro His Val Trp Met

Gly Ser His Thr Thr Ser 20 Synthetic Peptide Pro Pro G!n Thr Thr Pro His Asp Trp Lys 10 15 Gly Leu His Arg Pro His 25 <210> 197 <211> 28 <212> PRT <213> Sequence <220><223> Description of the artificial sequence: <400> 197 Cys Gly Leu Pro Pro Glu

His Ser Arg Tyr Gly Pro 20 Synthetic peptide Leu Lys Gin Thr Arg Val Asn Leu Pro Ala 10 35 Gin Ala Val Asp Ala Arg 25 >>>>> 012 3 03 11 Τ* 11 ΙΑ ΟΛ <2&lt ;2<T2<2<2<2 column order 8 τ ^1928 咫人明说列序工<400> 198 Val Gly Leu Asp Gin Tyr

Asp Val Cys Arg Ala Lys 20 Synthetic peptide Leu Glu Ser Val Lys Lys His Lys Arg Leu 10 15 Met Gly Tyr Met Leu Gin 25 <210> 199 <211> 25 <212> PRT <213>Artificial sequence<;220><223> Description of the artificial sequence: <400> 199 Arg Gin Val Val His Asn 1 5

Tyr Leu Glu Ala Asp Gly 20 Synthetic peptide Lys Leu Thr Ser Cys Asn Tyr Asn Pro Leu 10 15 Arg lie Arg 25 <210> 200 <21i> 28 <212> PRT <213>Artificial sequence<220><223> Description of artificial sequence: synthetic peptide 158864 - Sequence Listing. doe -88 - 201215618 <400> 200

Phe Thr Glu Ala 15

Arg Asp Tyr Ser Val Ser Arg Gin Val Arg Leu Thr 1 5 10

Asn Asn Gin Thr Tyr Thr Phe Cys rrhr His Pro Asn 20 25 <210> 201 <211> 27 <212> PHT <213> Artificial Sequence <220> Description of Artificial Sequence: Synthetic Peptide <400> 201

Ser Pro Trp Phe Thr Leu Thr Ala Asn Gin Asn Pro Ser Pro Pro Trp 15 10 15

Ser Lys Leu Thr Tyr Pro Lys Pro His Asp Cys 20 25

<210> 202 <2il> 28 <212> PRT <213> Artificial sequence <220><223> Description of artificial sequence: synthetic peptide <400> 202

Thr Ala Glu Lys Asn Asp Tyr Tyr Arg Val Pro His Tyr Trp Asp Ala 15 10 15

Cys Ser Arg Ala Leu Pro Asp Gin Thr Arg Tyr Lys 20 25

<210> 203 <211> 129 <212> PRT <213> Human Cell Huge Virus <400> 203

Met Arg Leu Cys Arg Val Trp Leu Ser Val Cys Leu Cys Ala Va3 Val 15 10 15

Leu Gly Gin Cys Gin Arg Glu Thr Ala Glu Lys Asn Asp Tyr Tyr Arg 20 25 30

Val Pro His Tyr Trp Asp Ala Cys Ser Arg Ala Leu Pro Asp Gin Thr 35 40 45

Arg Tyr Lys Tyr Val Glu Gin Leu Val Asp Leu Thr Leu Asn Tyr His 50 55 60

Tyr Asp Ala Ser His Gly Leu Asp Asn Phe Asp Val Leu Lys Arg lie 65 70 75 80

Asn Val Tlir Glu Val Ser Leu Leu He Ser Asp Phe Arg Arg Gin Asn 85 90 95 «hr· 158864-Sequence List.doc -89- 201215618

Arg Arg Gly Gly Tlir Asn Lys Arg Thr Thr Phe Asn Ala Ala Gly Ser 100 105 110

Leu Ala Pro His Ala Arg Ser Leu GIu Phe Ser Val Arg Leu Phe Ala 115 120 125

Asn

<210> 204 <221> 214 <212> PRT <213> Human Cell Huge Virus <400> 204

Met Leu Arg Leu Leu Leu Arg His His Phe His Cys Leu Leu Leu Cys 15 10 15

Ala Val Trp Ala Thr Pro Cys Leu Ala Ser Pro Trp Phe Thr Leu Tlir 20 25 30

Ala Asn Gin Asn Pro Ser Pro Pro Trp Ser Lys Leu Thr Tyr Pro Lys 35 40 45

Pro His Asp AJa Ala Thr Phe Tyr Cys Pro Phe Leu Tyr Pro Ser Pro 50 55 60

Pro Arg Ser Pro Ser Gin Phe Ser Gly Phe Gin Arg Val Ser Thr Gly 65 70 75 80

Pro Glu Cys Arg Asn GIu Ήιγ Lcu Tyr Leu Leu Tyr Asn Arg Glu Gly 85 90 95

Gin Thr Leu Val Glu Arg Ser Ser ΊΙιγ Trp Val Lys Lys Val He Trp 100 105 110

Tyr Leu Ser Gly Arg Asn Gin Thr lie Leu Gin Arg Met Pro Arg Thr 115 320 125

Ala Ser Lys Pro Ser Asp Gly Asn Val Gin lie Ser Val Glu Asp Ala 130 135 140

Lys He Fhe Gly Ala His Met Val Pro Lys Gin Thr Lys Leu Leu Arg 145 150 155 160

Phe Val Val Asn Asp Gly Thr Arg Tyr Gin Met Cys Val Met Lys Leu 165 170 175

Glu Ser Trp Ala His Val Phe Arg Asp Tyr Ser Val Ser Phe Gin Val 180 185 190

Arg Leu Thr Phe Thr Glu Ala Asn Asn Gin Thr Tyr Thr Phe Cys Thr 195 200 205

His Pro Asn Leu lie Val 210 -90- 158864 · Sequence Listing.doc 201215618

<210> 205 <21l> 171 <212> PRT <213> Human Cell Huge Virus <400> 205

Met Ser Pro Lys Asn Leu Thr Pro Phe Leu Thr Ala Leu Trp Leu Leu 15 10 15

Leu G!y His Ser Arg Val Pro Arg Val Arg Ala Glu Glu Cys Cys Glu 20 25 30

Phe lie Asn Val Asn His Pro Pro Glu Arg Cys Tyr Asp Phe Lys Met 35 40 45

Cys Asn Arg Phe Thr Val Ala Leu Arg Cys Pro Asp Gly Glu Val Cys 50 55 60

Tyr Ser Pro Glu Lys Thr Ala Glu He Arg Gly lie Val Thr Thr Met 65 70 75 80

Thr His Ser Leu Thr Arg Gin Val Val His Asn Lys Leu Thr Ser Cys

Asn Tyr Asn Pro Leu Tyr Leu Glu Ala Asp Gly Arg lie Arg Cys Gly 100 105 110

Lys Val Asn Asp Lys Ala Gin Tyr Leu Leu Gly Ala Ala Gly Ser Val 115 120 125

Pro Tyr Arg Trp lie Asn Leu Glu Tyr Asp Lys lie Thr Arg lie Val 130 135 HO

Gly Leu Asp Gin Tyr Leu Glu Ser Val Lys Lys His Lys Arg Leu Asp 145 150 155 160

Val Cys Arg Ala Lys Met Gly Tyr Met Leu Gin 165 170

<210> 206 <21]> 743 <212> PRT <213> Human Cell Huge Virus <400> 206

Met Arg Pro Gly Leu Pro Phe Tyr Leu Thr Val Phe Ala Val Tyr Leu 15 10 15

Leu Ser His Leu Pro Ser Gin Arg Tyr Gly Ala Asp Ala Ala Ser Glu 20 25 30

Ala Leu Asp Pro His Ala Fhe His Leu leu Leu Asn Thr Tyr Gly Arg 35 40 45

Pro lie Arg Phe Leu Arg Glu Asn Thr Thr Gin Cys Thr Tyr Asn Ser 50 55 60

Ser Leu Arg Asn Ser Thr Val Val Arg Glu Asn Ala He Ser Phe Asn 65 70 75 80 •91 - 158864 - Sequence Listing.doc 201215618

Phe Phe Gin Ser Tyr Asn Gin Tyr Tyr Val Phe His Met Pro Arg Cys 85 90 95

Leu Phe Ala Gly Pro Leu Ala Glu Gin Phe Leu Asn Gin Val Asp Leu 100 105 110

Thr Glu Thr Leu Glu Arg Tyr Gin Gin Arg Leu Asn Thr Tyr Ala Leu 115 120 125

Val Ser Lys Asp Leu Ala Ser Tyr Arg Ser Phe Pro Gin Gin Leu Lys 130 135 140

Ala Gin Asp Ser Leu Gly Gin Gin Pro Thr Thr Val Pro Pro Pro lie 145 150 155 160

Asp Leu Ser lie Pro His Val Trp Met Pro Pro Gin Thr Tlir Pro His 165 170 175

Asp Trp Lys Gly Ser His Thr Thr Ser Gly Leu His Arg Pro His Phe 180 185 190

Asn Gin Thr Cys lie Leu Phe Asp Gly His Asp Leu Leu Phe Ser Thr 195 200 205

Val Thr Pro Cys Leu His Gin Gly Phe Tyr Leu Met Asp Glu Leu Arg 210 215 220

Tyr Val Lys lie Thr Leu Thr Glu Asp Phe Phe Val Val Thr Val Ser 225 230 235 240

He Asp Asp Asp Thr Pro Met Leu Leu lie Phe Gly His Leu Pro Arg 245 250 255

Val Leu Phe Lys Ala Pro Tyr Gin Arg Asp Asn Phe lie Leu Arg Gin 260 265 270

Thr Glu Lys His Glu Leu Leu Val Leu Val Lys Lys Thr Gin Leu Asn 275 280 285

Arg His Ser Tyr Leu Lys Asp Ser Asp Phe Leu Asp Ala Ala Leu Asp 290 295 300

Phe Asn Tyr Leu Asp Leu Ser Ala Leu Leu Arg Asn Ser Phe His Arg 305 310 315 320

Tyr Ala Val Asp Val Leu Lys Ser Gly Arg Cys Gin Met Leu Asp Arg 325 330 335

Arg Thr Val Glu Met Ala Phe Ala Tyr Ala Leu Ala Leu Phe Ala A]a 340 345 350

Ala Arg Gin Glu Glu Ala Gly Thr Glu lie Ser lie Pro Arg Ala Leu 355 360 365

Asp Arg Gin Ala Ala Leu Uu Gin He Gin Glu Phe Met lie Thr Cys -92- 158864 - Sequence Listing.doc 201215618 370 375 380

Leu Ser G3n Thr Pro Pro Arg Thr Thr Leu Leu Leu Tyr Pro Thr Ala 385 390 395 400

Val Asp Leu Ala Lys Arg AU Leu Ding rp Thr Pro Asp Gin lie Thr Asp 405 410 415

He Thr Ser Leu Val Arg Leu Val Tyr lie Leu Ser Lys Gin Asn Gin 420 425 430

Gin His Leu lie Pro Gin Trp Ala Leu Arg Gin He Ala Asp Phe Ala 435 440 445

Leu Gin Leu His Lys Thr His Leu Ala Ser Phe Leu Ser Ala Phe Ala 450 455 460

Arg Gin Glu Leu Tyr Leu Met Gly Ser Leu Val His Ser Met Leu Val 465 470 475 480

His Thr Thr Glu Arg Arg Glu lie Phe He Val Glu Tiir Gly Leu Cys 485 490 495

Ser Leu Ala Glu Leu Ser His Phe Thr Gin Leu Leu Ala His Pro His 500 505 510

His Glu Tyr Leu Ser Asp Leu Dingyr Thr Pro Cys Ser Ser Ser Gly Ar£ 515 520 525

Arg Asp His Ser Leu Glu Arg Leu Thr Arg Leu Fhe Pro Asp Ala Thr 530 535 540

Val Pro Ala Thr Val Pro Ala Ala Leu Ser lie Leu Ser Thr Met Gin 545 550 555 560

Pro Ser Thr Leu Glu Thr Phe Pro Asp Leu Phe Cys Leu Pro Leu Gly 565 570 575

Glu Ser Phe Ser Ala Leu Thr Val Ser Glu His Val Ser Tyr Val Val 580 585 590

Thr Asn Gin Tyr Leu lie Lys Gly He Ser Tyr Pro Val Ser Tlir Thr 595 600 605

Val Val Gly Gin Scr Leu lie He Thr G!n Thr Asp Ser Gin Ser Lys 610 615 620

Cys Glu Leu Thr Arg Asn Met His Thr Thr His Ser lie Thr Ala Ala 625 630 635 640

Leu Asn [le Ser Leu Glu Asn Cys Ala Phe Cys Gin Ser Ala Leu Leu 645 650 655

Glu Tyr Asp Asp Thr Gin Gly Val lie Asn lie Met Tyr Met His Asp 660 665 670 -93- 158864 - Sequence Listing.doc 201215618

Ser Asp Asp Val Leu Phe Ala Leu Asp Pro Tyr Asn Glu Val Val Val 675 6S0 685

Ser Ser Pro Arg Thr His Tyr Leu Met Leu Leu Lys Asn Gly ITir Val 690 695 700

Leu Glu Val Thr Asp Val Val Val Asp Ala Thr Asp Ser Arg Leu Leu 705 710 715 720

Met Met Ser Val Tyr Ala Leu Ser Ala lie lie Gly lie Tyr Leu Leu 725 730 735

Tyr Arg Met Leu Lys Thr Cys 740

<210> 207 <211> 464 <212> PRT <213> Human Cell Huge Virus <400>

Met Gly Arg Lys Glu Asp Met Arg Ser lie Ser Lys Leu Phe Phe lie 15 10 15 lie Ser Leu Thr Val Leu Leu Phe Ser lie lie Asn Cys Lys Val Val 20 25 30

Arg Pro Pro Gly Arg Tyr Trp Leu Gly Thr Val Leu Ser Thr He Gly 35 40 45

Lys Gin Lys Leu Asp Lys Phe Lys Leu Glu lie Leu Lys Gin Leu Glu 50 55 60

Arg Glu Pro Tyr Hu Lys Tyr Phe Asn Met Thr Arg Gin His Val Lys 65 70 75 SO

Asn Leu Tlir Met Asn Met Thr Gin Phe Pro Gin Tyr Tyr lie Leu Ala 85 90 95

Gly Pro lie Arg Asn Asp Ser He Thr Tyr Leu Trp Phe Asp Phe Tyr 100 105 110

Ser Thr Gin Leu Arg Lys Pro Ala Lys Tyr Val Tyr Ser Gin Tyr Asn 115 120 125

His Thr Ala Lys Thr lie Thr Phe Arg Fro Pro Ser Cys Gly Tlir Val 130 135 140

Pro Ser Met Thr Cys Leu Ser Glu Met Leu Asn Val Ser Lys Arg Asa 145 150 155 160

Asp llir Gly Glu Gin Gly Cys Gly Asn Phe Thr Thr Phe Asn Pro Met 165 170 175

Phe Phe Asn Val Pro Arg Trp Asn Thr Lys Leu Tyr Val Gly Pro Thr 180 185 190

Lys Val Asn Val Asp Ser Gin Thr lie Tyr Phe Leu Gly Leu Thr Ala -94- 158864 - Sequence Listing.doc 201215618 195 200 205

Leu Leu Leu Arg Tyr Ala Gin Arg Asn Cys Thr His Ser Phe Tyr Leu 210 215 220

Val Asn Ala Met Ser Arg Asn Leu Phe Arg Val Pro Lys Tyr lie Asn 225 230 235 240

Gly Tlir Lys Leu Lys Asn Thr Met Arg Lys Leu Lys Arg Lys Gin Ala 245 250 25S

Pro Val Lys Glu Gin Leu Glu Lys Lys Thr Lys Lys Ser Gin Ser Thr 260 265 270

Thr frhr Pro Tyr Phe Ser Tyr Thr Thr Ser Thr Ala Leu Asn Val Thr 275 280 285

Thr Asn Ala Thr Tyr Arg Val Thr Thr Scr Ala Lys Arg lie Pro Thr 290 295 300

Ser Thr lie Ala Tyr Arg Pro Asp Ser Ser Phe Met Lys Ser He Met 305 310 315 320

Ala Thr Gin Leu Arg Asp Leu Ala Thr Trp Val Tyr Thr Thr Leu Arg 325 330 335

Tyr Arg Asn Glu Pro Phe Cys Lys Pro Asp Arg Asn Arg Thr Ala Val 340 345 350

Ser Glu Phe Met Lys Asn Thr His Val Leu He Arg Asn Glu Thr Pro 355 360 365

Tyr Thr lie Tyr Gly Thr Uu Asp Met Ser Ser Leu Tyr Tyr Asn Glu 370 375 380

Thr Met Ser Val Glu Asn Glu Thr Ala Ser Asp Asn Asn Gn Thr Thr 385 390 395 400

Pro Thr Ser Pro Ser Thr Arg Phe Gin Lys Thr Phe lie Asp Pro Leu 405 410 415

Trp Asp Tyr Leu Asp Ser Leu Leu Phe Leu Asp Lys lie Arg Asn Phe 420 425 430

Ser Leu Gin Leu Pro Ala Tyr Gly Asn Leu Thr Pro Pro Glu His Arg 435 440 445

Arg Ala Val Asn Leu Ser Thr Leu Asn Ser Leu Trp Trp Trp Leu Gin 450 455 460

<210> 208 <211> 278 <212> PRT <213> Human Cell Huge Virus <400> 208

Mel Cys Arg Arg Pro Asp Cys Gly Phe Ser Phe Ser Pro Gly Pro Val 15 10 15 -95- 158864 - Sequence Listing.doc 201215618

Val Leu Leu Trp Cys Cys Leu Leu Leu Pro lie Val Ser Ser Val Ala 20 25 30

Val Ser Val Ala Pro Thr Ala Ala Glu Lys Val Pro Ala Glu Cys Pro 35 40 45

Glu Leu Thr Arg Arg Cys Leu Leu Gly Glu Val Phe Gin Gly Asp Lys 50 55 60

Tyr Glu Ser Trp Leu Arg Pro Leu Val Asn Val Thr Gly Arg Asn Gly 65 70 75 80

Pro Leu Ser Gin Leu I】e Arg Tyr Arg Pro Val Thr Pro Glu /Ua Ala 85 90 95

Asn Ser Val Leu Leu Asp Asp Ala Phe Lea Asp Thr Lea Ala Leu Leu 100 105 110

Tyr Asn Asn Pro Asp Gin Leu Arg Ala Leu Leu Thr Leu Leu Ser Ser 115 120 125

Asp Thr Ala Pro Arg Trp Met Thr Val Met Arg Gly Tyr Ser Glu Cys 130 135 140

Gly Asp Gly Ser Pro Ala Val Tyr Thr Cys Val Asp Asp Leu Cys Arg 145 350 155 160

Gly Tyr Asp Leu Thr Arg Leu Ser Tyr Gly Arg Ser lie Phe Thr Glu 165 170 175

His Val Leu Gly Phe Glu Leu Val Pro Pro Ser Leu Fhe Asn Val Val ISO 185 190

Val Ala He Arg Asn Glu Ala Thr Arg Thr Asn Arg Ala Val Arg Leu 195 200 205

Pro Val Ser Thr Ala Ala Ala Fro GJu Gly lie Thr Leu Phe Tyr Gly 210 215 220

Leu Tyr Asn Ala Val Lys Glu Phe Cys Leu Arg His Gin Leu Asp Pro 225 230 235 240

Pro Leu Leu Arg His Leu Asp Lys Tyr Tyr Ala Gly Leu Pro Pro Glu 245 250 255

Leu Lys Gin Thr Arg Val Asn Leu Pro Ala His Ser Arg Tyr Gly Pro 260 265 270

Gin Ala Val Asp Ala Arg 275

<210> 209 <211> 472 <212> PRT <213> Human cell giant virus -96-

158864-Sequence Listing.doc s 201215618 <400> 209

Met Gly Lys Lys GIu Met lie Met Val Lys Gly lie Pro Lys lie Met 15 10 15

Leu Leu lie Ser lie Thr Phe Leu Leu Leu Ser Leu He Asn Cys Asn 20 25 30

Val Leu Val Asn Ser Arg Gly Thr Arg Arg Ser Trp Pro Tyr Thr Val 35 40 45

Leu Ser Tyr Arg Gly Lys Glu lie Leu Lys Lys Gin Lys Glu Asp lie 50 55 60

Leu Lys Arg Leu Met Ser Thr Ser Ser Asp G]y Ding yr Arg Phe Leu Met 65 70 75 80

Tyr Pro Ser Gin Gin Lys Fhe His Ala lie Val lie Ser Met Asp Lys 85 90 95

Phe Pro Gin Asp Tyr lie Leu Ala Gly Pro He Arg Asn Asp Ser He 100 105 110

Thr His Met Trp Phe Asp Phe Tyr Ser Thr Gin Leu Arg Lys Pro Ala 115 120 125

Lys Tyr Va] Tyr Ser Glu Tyr Asn His Thr Ala His Lys He Thr Leu 130 135 140

Arg Pro Pro Pro Cys Gly Thr Val Pro Ser Met Asn Cys Leu Ser Glu 145 150 155 160

Met Leu Asn Val Ser Lys Arg Asn Asp Thr Gly Glu Lys Gly Cys Gly 165 170 175

Asn Phe Thr Thr Phe Asn Pro Met Phe Phe Asn Val Pro Arg Trp Asn 180 185 190

Thr Lys Leu Tyr lie Gly Ser Asn Lys Val Asn Val Asp Ser Gin Thr 195 200 205 lie Tyr Phe Leu Gly Leu Thr AU Leu Leu Leu Arg Tyr Ala Gin Arg 210 215 220

Asn Cys Thr Arg Ser Phe Tyr Leu Val Asn Ala Met Ser Arg Asn Leu 225 230 235 240

Phe Arg Val Pro Lys Tyr lie Asn Gly Thr Lys Leu Lys Asn Thr Met 245 250 255

Arg Lys Leu Lys Arg Lys Gin Ala Leu Val Lys Glu Gin Pro Gin Lys 260 265 270

Lys Asn Lys Lys Ser Gin Ser Thr Thr Thr Pro Tyr Leu Ser Tyr Thr 275 280 285

Thr Ser Thr Ala Phe Asn Val Thr Thr Asn Val Thr Tyr Ser Ala Thr 290 295 300 -97- 158864 - Sequence Listing.doc 201215618

Ala Ala Val Thr Arg Val Ala Thr Ser Thr Thr Gly Tyr Arg Pro Asp 305 310 315 320

Ser Asn Phc Met Lys Ser lie Met Ala Thr Gin Leu Arg Asp Leu Ala 325 330 335

Thr Trp Val Tyr Thr Thr Leu Arg Tyr Arg Asn Glu Pro Phe Cys Lys 340 345 350

Pro Asp Arg Asn Arg Thr Ala Val Scr Glu Phe Met Lys Asn Thr His 355 360 365

Val Leu lie Arg Asn Glu Thr Pro Tyr Thr lie Tyr Gly Thr Leu Asp 370 375 380

Met Ser Ser Leu Tyr Tyr Asn Glu Thr Met Ser Val Glu Asn Glu llir 385 390 395 400

Ala Ser Asp Asn Asn Glu Thr Thr Pro Thr Ser Pro Ser ITir Arg Phe 405 410 415

Gin Arg ΊΤιγ Phe He Asp Pro Leu Trp Asp Tyr Leu Asp Ser Leu Leu 420 425 430

Phe Leu Asp Lys lie Arg Asn Phe Ser Leu Gin Leu Pro Ala Tyr Giy 435 440 445.

Asn Leu Thr Pro Pro Glu His Arg Arg Ala Ala Asn Leu Ser Thr Leu 450 455 460

Asn Ser Leu Trp Trp Trp Ser Gin 465 470 -98·

158864_ Sequence Listing.doc s

Claims (1)

201215618 VII. Patent application scope: 1. An isolated antibody that binds to HCMV complex I, which comprises three heavy chain hypervariable regions (HVR-H1, HVR-H2 and HVR-H3) and three light chain hypervariable regions. (HVR-L1, HVR-L2 and HVR-L3), wherein: (a) HVR-H1 comprises the amino acid sequence SEQ ID NO: 6; (b) HVR-H2 comprises the amino acid sequence SEQ ID NO: 7; (c) HVR-H3 comprises the amino acid sequence SEQ ID NO: 8; (d) HVR-L1 comprises the amino acid sequence SEQ ID NO: 9; φ (e) HVR-L2 comprises a selected from the group consisting of SEQ ID NO: 10- 19 amino acid sequence; and (f) HVR-L3 comprises the amino acid sequence SEQ ID NO: 20. 2. An isolated antibody that binds to HCMV complex I, comprising three heavy chain hypervariable regions (HVR-H1, HVR-H2, and HVR-H3) and three light chain hypervariable regions (HVR-L1, HVR- L2 and HVR-L3), wherein: (a) HVR-H1 comprises the amino acid sequence SEQ ID NO: 6; (b) HVR-H2 comprises the amino acid sequence SEQ ID NO: 7; (c) HVR-H3 comprises Amino acid sequence SEQ ID NO: 8; 0 (d) HVR-L1 comprises the amino acid sequence SEQ ID NO: 9; (f) HVR-L3 comprises the amino acid sequence SEQ ID NO: 20; and (e) HVR The first amino acid of the -L2 and light chain variable domain framework FR3 comprises the amino acid sequence SEQ ID NO:21. 3. The antibody of claim 1, wherein the antibody that binds to HCMV complex I comprises: a light chain variable domain framework FR1 comprising SEQ ID NO: 35, 8 卩 10 1^0: 3 9 and 8 £(5 10 1^0:43 amino acid sequence; and light chain variable domain framework FR2 comprising an amine group selected from the group consisting of SEQ ID NO: 36, SEQ ID 158864. doc 201215618 NO: 40 and SEQ ID NO: 44 4. The antibody of claim 1, wherein the antibody that binds to HCMV complex I comprises: a light chain variable domain framework FR3 comprising an amino acid selected from the group consisting of SEQ ID NO: 37 and SEQ ID NO: 41 And a light chain variable domain framework FR4 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 38 and SEQ ID NO: 42. 5. The antibody of claim 1, wherein the antibody that binds to HCMV complex I A VH sequence comprising at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46 and SEQ ID NO: 47, and an amino acid sequence SEQ ID NO: 48 or SEQ ID NO: 49 is a V1 sequence having at least 95% sequence identity. 6. The antibody of claim 5, wherein the VH sequence comprises an amine selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46, and SEQ ID NO: 47 Base acid sequence. The antibody of claim 5, wherein the VL sequence comprises the amino acid sequence of SEQ ID NO: 48 or SEQ ID NO: 49. 8. The antibody of claim 5, wherein the antibody that binds to HCMV complex I comprises an antibody selected from the group consisting of ID NO: 45, VH of the amino acid sequence of SEQ ID NO: 46 or SEQ ID NO: 47; and VL containing the amino acid sequence of SEQ ID NO: 48 or SEQ ID NO: 49. The antibody, wherein the antibody that binds to the HCMV complex I comprises the VH sequence of SEQ ID NO: 45 or SEQ ID NO: 46 and the VL sequence of SEQ ID NO: 49. 10. The antibody of any one of claims 1 to 9, Wherein the antibody that binds to HCMV complex I neutralizes HCMV of 50%/〇 at an antibody concentration of 0.05 pg/ml to 0.0007 pg/ml or 0.0007 pg/ml 158864.doc 201215618. 11. A combination of HCMV gH The isolated antibody comprises three heavy chain hypervariable regions (HVR-H1, HVR-H2 and HVR-H3) and three light chain hypervariable regions (HVR-L1, HVR-L2 and HVR-L3), wherein: (a) HVR-H1 comprises the amino acid sequence SEQ ID NO: 71; (b) HVR-H2 comprises an amino acid selected from the group consisting of SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74 and SEQ ID NO: Sequence; (c) HVR-H3 contains an amine Acid sequence SEQ ID NO: 75; φ (d) HVR-L1 comprises the amino acid sequence SEQ ID NO: 76; (e) HVR-L2 comprises the amino acid sequence SEQ ID NO: 77; and (f) HVR-L3 The amino acid sequence SEQ ID NO: 78 is included. 12. The antibody of claim 11, wherein the antibody that binds to HCMV gH comprises HVR-H2 comprising the amino acid sequence SEQ ID NO: 93, wherein the amino acid at position 6 of SEQ ID NO: 93 is selected from the group consisting of A group consisting of Ser, Thr, Asn, Gin, Phe, Met and Leu, and the amino acid at position 8 of SEQ ID NO: 93 is selected from the group consisting of Thr and Arg. The antibody of claim 12, wherein the antibody that binds to HCMV gH comprises HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 72, SEQ ID NO: 73, and SEQ ID NO: 74. 14. The antibody of claim 13, wherein HVR-H2 comprises the amino acid sequence SEQ ID NO:74. 15. The antibody of claim 12, wherein the antibody that binds to HCMV gH comprises a VH sequence having at least 95°/❶ sequence identity to amino acid sequence SEQ ID NO: 94, wherein position 54 of SEQ ID NO: 94 The amino acid is selected from the group consisting of Ser, Thr, Asn, Gin, Phe, Met and Leu and the amino acid at position 56 of SEQ ID NO: 94 is selected from Thr or Arg. . 16. The antibody of claim 15, wherein the VH comprises an amino acid sequence selected from the group consisting of: 8 卩 1 〇] ^ 0: 87, 8 £ (5 10 1^0: 8 8 and 8 £ 17. The antibody of claim 15, wherein the antibody that binds to HCMV gH comprises a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 90. The antibody of 17, wherein the antibody that binds to HCMV gH comprises the VL sequence of SEQ ID NO: 90. 19. The antibody of claim 18, wherein the antibody that binds to HCMV gH comprises the VH sequence of SEQ ID NO: 89. The antibody according to any one of items 11 to 19, wherein the antibody which binds to HCMV gH neutralizes HCMV with an EC90 of from 0.001 pg/ml to 0.01 pg/ml ° 2 1. As claimed in claims 1 to 9 and 11 to 19 An antibody, wherein the antibody is a monoclonal antibody. The antibody according to any one of claims 1 to 9 and 11 to 19, which is a human antibody, a humanized antibody or a chimeric antibody. The antibody of any one of claims 1 to 9 wherein the antibody is an antibody fragment, wherein the antibody of any one of claims 1 to 9 wherein the antibody that binds to HCMV complex I is The antibody of any one of claims 11 to 19, wherein the antibody that binds to HCMV gH 158864.doc 201215618 is a full-length IgG1 antibody. 26. A composition comprising the requirements 1 to 25 The antibody of any one of claims 2 to 6, further comprising another therapeutic agent. 28. The composition of claim 26 or 27, further comprising a pharmaceutically acceptable carrier 29. An isolated nucleic acid encoding the antibody of any one of claims 1 to 25. 3 0. A host cell comprising the nucleic acid of claim 29. 3 3. A method comprising culturing a host cell as claimed in claim 30 for producing an antibody. 32. A composition comprising an isolated antibody that binds to HCMV complex I and an isolated antibody that binds to HCMV gH. The composition of claim 32, wherein the composition is neutralized by HCMV. 34. The composition of claim 33, wherein the composition neutralizes at least 50% of HCMV. 35. The combination of any one of claims 32 to 34. And the antibody that binds to HCMV ® complex I and The antibody that binds to HCMV gH is present in the composition at a ratio of 1:1. The composition of any one of claims 32 to 34, wherein the concentration of the antibody that binds to HCMV complex I is at least 0.0007 pg/ The composition of any one of claims 32 to 34, wherein the combination of HCMV is at a concentration of at least 0.001 pg/ml to 0. 01 pg/ml. The antibody of complex I contains three heavy chain hypervariable regions (HVR-H1 'HVR-H2 and 158864.doc 201215618 HVR-H3) and three light chain hypervariable regions (HVR-Ll, HVR-L2 and HVR-L3). Wherein: (a) HVR-H1 comprises the amino acid sequence SEQ ID NO: 6; (b) HVR-H2 comprises the amino acid sequence SEQ ID NO: 7; (c) HVR-H3 comprises the amino acid sequence SEQ ID NO: 8; (d) HVR-L1 comprises the amino acid sequence SEQ ID NO: 9; (e) HVR-L2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-19; and (f) HVR-L3 comprises Amino acid sequence SEQ ID NO:20. The composition of any one of claims 32 to 34, wherein the antibody that binds to HCMV gH comprises three heavy chain hypervariable regions (HVR-H1, HVR-H2 and HVR-H3) and three light chains Hypervariable regions (HVR-L1, HVR-L2, and HVR-L3), wherein: (a) HVR-H1 comprises the amino acid sequence SEQ ID NO: 71; (b) HVR-H2 comprises a mutation selected from SEQ ID NO: 72 SEQ ID NO: 73, SEQ ID NO: 74 and SEQ ID NO: 93 amino acid sequence 歹ιJ; (c) HVR-H3 comprises the amino acid sequence SEQ ID NO: 75; (d) HVR-L1 comprises an amino acid sequence SEQ ID NO:76; (e) HVR-L2 comprises the amino acid sequence SEQ ID NO:77; and (f) HVR-L3 comprises the amino acid sequence SEQ ID NO:78. The composition of any one of claims 32 to 37, wherein the antibody that binds to HCMV complex I comprises: a light chain variable domain framework FR1 comprising SEQ ID NO: 35, SEQ ID NO: 39 And an amino acid sequence of SEQ ID NO: 43; and a light chain variable domain framework FR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 36, SEQ ID NO: 40, and SEQ ID NO: 44. The composition of any one of claims 32 to 37, wherein the antibody that binds to HCMV complex I comprises: a light chain variable domain framework FR3 comprising from 8 ug (^10> 0:3 7 and 8 £ (5 10 1^0:41 amino acid sequence; and light chain variable domain framework FR4 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 38 and SEQ ID NO: 42 The composition of any one of claims 32 to 34, wherein the antibody that binds to HCMV complex I comprises an amine group selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46, and SEQ ID NO: 47. The acid sequence has a VH sequence of at least 95% sequence identity and a V1 sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 48 or SEQ ID NO: 49. 42. The composition of claim 41, Wherein the VH sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46 and SEQ ID NO: 47. The composition of claim 41, wherein the VL sequence comprises the amino acid sequence SEQ ID NO: 48 or SEQ ID NO: 49. The composition of claim 41, wherein the antibody that binds to HCMV complex I comprises (a) comprises a mutation selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46 or SEQ. ID NO: 47 amino group VH of the acid sequence; and (b) a VL comprising the amino acid sequence of SEQ ID NO: 48 or SEQ ID NO: 49. The composition of claim 44, wherein the antibody that binds to HCMV complex I comprises a VH sequence SEQ ID NO: 45 or SEQ ID NO: 46 and VL sequence SEQ ID NO: 49. The composition of any one of claims 32 to 38, wherein the antibody that binds to HCMV gH comprises an amino acid sequence comprising SEQ ID NO: 93 HVR-H2, wherein the amino acid at position 6 of SEQ ID NO: 93 is selected from the group consisting of S 158864.doc -7- 201215618 Ser, Thr, Asn, Gin, Phe, Met and Leu The group, and the amino acid at position 8 of SEQ ID NO: 93 is selected from the group consisting of Thr and Arg. The composition of any one of claims 32 to 38, wherein the antibody that binds to HCMV gH HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 72, SEQ ID NO: 73 and SEQ ID NO: 74. 48. The composition of claim 47, wherein HVR-H2 comprises an amino acid sequence SEQ ID NO:74. The composition of any one of claims 32 to 34, wherein the antibody that binds to HCMV gH comprises a VH sequence having at least 95% sequence identity to amino acid sequence SEQ ID ΝΟ, ·94, wherein SEQ ID The amino acid at position 54 of 94 is selected from the group consisting of Ser, Thr, Asn, Gin, Phe, Met and Leu and the amino acid at position 56 of SEQ ID NO: 94 is selected from Thr or Arg. 50. The composition of claim 49, wherein the VH comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 87, SEQ ID NO: 88 & SEQ ID NO: 89. 51. The composition of claim 50, wherein the antibody that binds to HCMV gH comprises a VL sequence having at least 95% sequence identity to the amino acid sequence SEQ ID NO:90. 52. The composition of claim 51, wherein the antibody that binds to HCMV gH comprises the VL sequence SEQ ID NO:90. 53. The composition of claim 52, wherein the antibody that binds to HCMV gH comprises the VH sequence SEQ ID NO:89. The composition of any one of claims 32 to 53, wherein the antibody that binds to HCMV complex I and the antibody that binds to HCMV gH are monoclonal antibodies. The composition of any one of claims 32 to 54, wherein the antibody that binds to HCMV complex I and the antibody that binds to HCMV gH are human antibodies, humanized antibodies or chimeric antibodies. The composition of any one of claims 32 to 55, wherein the antibody that binds to HCMV complex I is an antibody fragment. The composition of any one of claims 32 to 55, wherein the antibody that binds to HCMV_gH is an antibody fragment. The composition of any one of claims 32 to 55, wherein the antibody that binds to HCMV complex I is a full-length IgG1 antibody. The composition of any one of claims 32 to 55, wherein the antibody that binds to HCMV gH is a full-length IgG1 antibody. The composition of any one of claims 32 to 59, which further comprises a pharmaceutically acceptable carrier. 61. The composition of claim 60, further comprising another therapeutic agent. 62. The composition of claim 61, wherein the additional therapeutic agent is selected from the group consisting of ganciclovir, foscarnet, valganciclovir, and citrine Wei (cidofovir). 63. The composition of any of claims 26 to 28 and 32 to 62 for use as a medicament. The composition of any one of claims 26 to 28 and 32 to 62 for use in inhibiting, treating or preventing HCMV infection. The composition of any one of claims 26 to 28 and 32 to 62 for use in 158864.doc 201215618 to inhibit, treat or prevent congenital HCMV infection or HCMV infection in a transplant recipient. The composition of any one of claims 63 to 65, wherein the anti-system that binds to HCMV gH is in the form of a composition separate from the antibody that binds to HCMV complex I. 67. Use of a composition according to any one of claims 26 to 28 and 32 to 62 for the manufacture of a medicament. 68. The use of claim 67, wherein the agent is for treating, inhibiting or preventing HCMV infection. 69. The use of claim 68, wherein the agent is for use in inhibiting, preventing or treating a congenital HCMV infection or a HCMV infection in a transplant recipient. 70. The use of claim 69, wherein the transplant recipient is HCMV serum negative. 71. The use of claim 70, wherein the transplant recipient is receiving or has received an organ or tissue from a HCMV seropositive donor. The use of any one of claims 67 to 71, wherein the medicament further comprises another therapeutic agent. The use of any one of claims 67 to 71, wherein the agent comprises the antibody that binds to HCMV complex I in the form of a composition separate from the antibody that binds to HCMV gH. The use according to any one of claims 67 to 71, wherein the composition comprising the antibody that binds to HCMV complex I is administered separately from the composition comprising the antibody that binds to HCMV gH. 75. The use of claim 74, comprising the antibody that binds HCMV gH 158864.doc -10- 201215618 The composition is administered concurrently with the composition comprising the antibody that binds HCMV complex I. 76. The use of claim 74, wherein the composition comprising the antibody that binds to HCMV gH is administered before or after the composition comprising the antibody that binds to HCMV complex I. 77. Use of a combination of antibodies or antibodies according to any one of claims 1 to 25 for the manufacture of a medicament. 78. The use of claim 77, wherein the agent is for use in inhibiting, preventing or treating an HCMV infection. 79. The use of claim 78, wherein the agent is for use in inhibiting, preventing or treating a congenital HCMV infection or a HCMV infection in a transplant recipient. 80. The use of claim 79, wherein the transplant recipient is HCMV serum negative. 8. The use of claim 80, wherein the transplant recipient is receiving or has received an organ or tissue from a HCMV seropositive donor. 82. The use of claim 18, wherein the medicament further comprises another therapeutic agent. The use according to any one of claims 77 to 82, wherein the antibody that binds to HCMV complex I is administered separately from the antibody that binds to HCMV gH. 84. The use of claim 83, wherein the antibody that binds to HCMV gH is administered concurrently with the antibody that binds to HCMV complex I. 85. The use of claim 83, wherein the antibody that binds to HCMV gH is administered before or after the antibody that binds to HCMV complex I. 86. An isolated antibody which binds to the same epitope as antibody 158864.doc 201215618 of any one of claims 1 to 25. 87. An isolated antibody that binds to an epitope of HCMV gH, the epitope comprising an amino acid corresponding to an amino acid selected from the group consisting of: (i) at position 168 of SEQ ID NO: 1. a tryptophan acid; (ii) aspartic acid at position 446 of SEQ ID NO: 1, (iii) proline at position 171 of SEQ ID NO: 1, and (iv) a combination thereof. 88. The antibody of claim 87, which binds to an epitope of HCMV gH, the epitope comprising an amino acid selected from the group consisting of: (i) a color at position 168 of SEQ ID NO: Amino acid; (ii) aspartic acid at position 446 of SEQ ID NO: 1; (iii) proline at position 171 of SEQ ID NO: 1; and (iv) combinations thereof. 89. An isolated antibody that binds to an epitope of HCMV complex I, the epitope comprising an amino acid corresponding to an amino acid selected from the group consisting of: (1) at position 47 of SEQ ID NO: 203 The glutamic acid; (ii) the lyophilic acid at position 51 of SEQ ID NO: 203; (iii) the aspartic acid at position 46 of SEQ ID NO: 203; and (iv) the combination thereof. 90. The antibody of claim 89, which comprises an amino acid selected from the group consisting of: (1) branic acid at position 47 of SEQ ID NO: 203; 158864.doc • 12· 201215618 (ii) in SEQ ID NO: (10) aspartic acid at position 46 of SEQ ID NO: 203; and (iv) a combination thereof. 9. An isolated antibody that binds to a polypeptide of HCMV complex I, which comprises the amino acid sequence SRALPDQTRYKYVEQLVDLT LNYHYDAS (SEQ ID NO: 194). 158864.doc -13-