JPWO2021262840A5 - - Google Patents

Description

である、項目１６６または１６７に記載の方法。
（項目１６９）
前記ｓｉＲＮＡが、次の構造：

で示される通り、前記リガンドにコンジュゲートされ、式中、ＸがＯまたはＳである、項目１６８に記載の方法。
（項目１７０）
前記ｓｉＲＮＡの少なくとも１つのヌクレオチドが、デオキシ－ヌクレオチドを含む改変ヌクレオチド、３’末端デオキシ－チミン（ｄＴ）ヌクレオチド、２’－Ｏ－メチル改変ヌクレオチド、２’－フルオロ改変ヌクレオチド、２’－デオキシ－改変ヌクレオチド、ロックドヌクレオチド、アンロックドヌクレオチド、立体構造的に制限されたヌクレオチド、拘束されたエチルヌクレオチド、無塩基ヌクレオチド、２’－アミノ－改変ヌクレオチド、２’－Ｏ－アリル－改変ヌクレオチド、２’－Ｃ－アルキル－改変ヌクレオチド、２’－ヒドロキシル－改変ヌクレオチド、２’－メトキシエチル改変ヌクレオチド、２’－Ｏ－アルキル－改変ヌクレオチド、モルホリノヌクレオチド、ホスホロアミダート、非天然塩基を含むヌクレオチド、テトラヒドロピラン改変ヌクレオチド、１，５－アンヒドロヘキシトール改変ヌクレオチド、シクロヘキセニル改変ヌクレオチド、ホスホロチオエート基を含むヌクレオチド、メチルホスホネート基を含むヌクレオチド、５’－リン酸を含むヌクレオチド、アデノシン－グリコール核酸、または５’－リン酸模倣物を含むヌクレオチドである、項目１５１～１６９のいずれか一項に記載の方法。
（項目１７１）
前記ｓｉＲＮＡが、リン酸骨格改変、２’リボース改変、５’三リン酸改変、またはＧａｌＮＡｃコンジュゲーション改変を含む、項目１５１～１６９のいずれか一項に記載の方法。
（項目１７２）
前記リン酸骨格改変が、ホスホロチオエート結合を含む、項目１７１に記載の方法。
（項目１７３）
前記２’リボース改変が、フルオロまたは－Ｏ－メチル置換を含む、項目１７１または項目１７２に記載の方法。
（項目１７４）
前記ｓｉＲＮＡが、５’－ｇｓｕｓｇｕＧｆｃＡｆＣｆＵｆｕｃｇｃｕｕｃａｃａＬ９６－３’（配列番号１２２）を含むセンス鎖および５’－ｕｓＧｆｓｕｇａＡｆｇＣｆＧｆａａｇｕＧｆｃＡｆｃａｃｓｕｓｕ－３’（配列番号１２３）を含むアンチセンス鎖を有し、
式中、ａ、ｃ、ｇ、およびｕが、それぞれ２’－Ｏ－メチルアデノシン－３’－リン酸、２’－Ｏ－メチルシチジン－３’－リン酸、２’－Ｏ－メチルグアノシン－３’－リン酸、および２’－Ｏ－メチルウリジン－３’－リン酸であり；
Ａｆ、Ｃｆ、Ｇｆ、およびＵｆが、それぞれ２’－フルオロアデノシン－３’－リン酸、２’－フルオロシチジン－３’－リン酸、２’－フルオログアノシン－３’－リン酸、および２’－フルオロウリジン－３’－リン酸であり；
ｓが、ホスホロチオエート連結であり；
Ｌ９６が、Ｎ－［トリス（ＧａｌＮＡｃ－アルキル）－アミドデカノイル）］－４－ヒドロキシプロリノールである
項目１５１～１５９および１６６～１７３のいずれか一項に記載の方法。
（項目１７５）
前記ｓｉＲＮＡが、５’－ｇｓｕｓｇｕＧｆｃＡｆＣｆＵｆｕｃｇｃｕｕｃａｃａＬ９６－３’（配列番号１２４）を含むセンス鎖および５’－ｕｓＧｆｓｕｇａ（Ａｇｎ）ｇＣｆＧｆａａｇｕＧｆｃＡｆｃａｃｓｕｓｕ－３’（配列番号１２５）を含むアンチセンス鎖を有し、
式中、ａ、ｃ、ｇ、およびｕが、それぞれ２’－Ｏ－メチルアデノシン－３’－リン酸、２’－Ｏ－メチルシチジン－３’－リン酸、２’－Ｏ－メチルグアノシン－３’－リン酸、および２’－Ｏ－メチルウリジン－３’－リン酸であり；
Ａｆ、Ｃｆ、Ｇｆ、およびＵｆが、それぞれ２’－フルオロアデノシン－３’－リン酸、２’－フルオロシチジン－３’－リン酸、２’－フルオログアノシン－３’－リン酸、および２’－フルオロウリジン－３’－リン酸であり；
（Ａｇｎ）が、アデノシン－グリコール核酸（ＧＮＡ）であり；
ｓが、ホスホロチオエート連結であり；
Ｌ９６が、Ｎ－［トリス（ＧａｌＮＡｃ－アルキル）－アミドデカノイル）］－４－ヒドロキシプロリノールである、
項目１５１～１５９および１６６～１７３のいずれか一項に記載の方法。
（項目１７６）
前記ｓｉＲＮＡが、５’－ｇｓｇｓｕｇｇａＣｆｕＵｆＣｆＵｆｃｕｃａＡｆＵｆｕｕｕａＬ９６－３’（配列番号１２６）を含むセンス鎖および５’－ｕｓＡｆｓａａａＵｆｕＧｆＡｆｇａｇａＡｆｇＵｆｃｃａｃｃｓａｓｃ－３’（配列番号１２７）を含むアンチセンス鎖を有し、
式中、ａ、ｃ、ｇ、およびｕが、それぞれ２’－Ｏ－メチルアデノシン－３’－リン酸、２’－Ｏ－メチルシチジン－３’－リン酸、２’－Ｏ－メチルグアノシン－３’－リン酸、および２’－Ｏ－メチルウリジン－３’－リン酸であり；
Ａｆ、Ｃｆ、Ｇｆ、およびＵｆが、それぞれ２’－フルオロアデノシン－３’－リン酸、２’－フルオロシチジン－３’－リン酸、２’－フルオログアノシン－３’－リン酸、および２’－フルオロウリジン－３’－リン酸であり；
ｓが、ホスホロチオエート連結であり；
Ｌ９６が、Ｎ－［トリス（ＧａｌＮＡｃ－アルキル）－アミドデカノイル）］－４－ヒドロキシプロリノールである、
項目１５１～１５３および１６０～１７３のいずれか一項に記載の方法、使用のための組成物、または使用。
（項目１７７）
前記被験体がヒトであり、ＲＮＡｉ剤またはｓｉＲＮＡの治療有効量が前記被験体に投与され；前記ＲＮＡｉ剤またはｓｉＲＮＡの前記有効量が、約１ｍｇ／ｋｇ～約８ｍｇ／ｋｇである、項目１３７～１７６のいずれか一項に記載の方法。
（項目１７８）
前記ＲＮＡｉ剤またはｓｉＲＮＡが、１日２回、１日１回、２日毎、３日毎、１週間に２回、１週間に１回、１週間おき、４週間毎、または１か月に１回、前記被験体に投与される、項目１３７～１７７のいずれか一項に記載の方法。
（項目１７９）
前記ＲＮＡｉ剤またはｓｉＲＮＡが、４週間毎に前記被験体に投与される、項目１３７～１７７のいずれか一項に記載の方法。
（項目１８０）
各々がＨＢＶ遺伝子に指向される２つのｓｉＲＮＡが投与され、第１のｓｉＲＮＡが、配列番号１１９、配列番号１２０、または配列番号１２６を含むアンチセンス鎖を有し；第２のｓｉＲＮＡが、配列番号１１６のヌクレオチド２８５０～３１８２の少なくとも１５連続するヌクレオチドを含むセンス鎖を有するｓｉＲＮＡを含む、項目１５１～１７９のいずれか一項に記載の方法。
（項目１８１）
ＨＢＶ遺伝子に指向される２つのｓｉＲＮＡが投与され、前記２つのｓｉＲＮＡが、ＨＢＶ Ｘ遺伝子に指向されるｓｉＲＮＡおよびＨＢＶ Ｓ遺伝子に指向されるｓｉＲＮＡを含む、項目１５１～１７９のいずれか一項に記載の方法。
（項目１８２）
各々がＨＢＶ遺伝子に指向される２つのｓｉＲＮＡが投与され、第１のｓｉＲＮＡが、配列番号１１９、配列番号１２３、または配列番号１２５を含むアンチセンス鎖を有し；第２のｓｉＲＮＡが、配列番号１２１または配列番号１２７を含むアンチセンス鎖を有する、項目１５１～１７９のいずれか一項に記載の方法。
（項目１８３）
第１のｓｉＲＮＡが、配列番号１１８、配列番号１２２、または配列番号１２４を含むセンス鎖を有し；第２のｓｉＲＮＡが、配列番号１２０または配列番号１２６を含むセンス鎖を有する、項目１８１に記載の方法。
（項目１８４）
前記２つのｓｉＲＮＡが同時に投与される、項目１７９～１８３のいずれか一項に記載の方法。
（項目１８５）
ヌクレオチ（シ）ドアナログを前記被験体に投与することをさらに含むか、または前記被験体がヌクレオチ（シ）ドアナログもまた投与される、項目１３７～１８４のいずれか一項に記載の方法。
（項目１８６）
前記ヌクレオチ（シ）ドアナログが、テノホビルジソプロキシルフマル酸塩（ＴＤＦ）、テノホビルアラフェナミド（ＴＡＦ）、ラミブジン、アデホビルジピボキシル、エンテカビル（ＥＴＶ）、テルビブジン、ＡＧＸ－１００９、エムトリシタビン（ＦＴＣ）、クレブジン、リトナビル、ジピボキシル、ロブカビル、ファムビル、Ｎ－アセチル－システイン（ＮＡＣ）、ＰＣ１３２３、ｔｈｅｒａｄｉｇｍ－ＨＢＶ、サイモシン－アルファ、およびガンシクロビル、ベシホビル（ｂｅｓｉｆｏｖｉｒ）（ＡＮＡ－３８０／ＬＢ－８０３８０）、またはテノホビル－エクサリアデス（ｔｅｎｏｆｖｉｒ－ｅｘａｌｉａｄｅｓ）（ＴＬＸ／ＣＭＸ１５７）である、項目１８５に記載の方法、使用のための組成物、または使用。 These and other changes can be made to the embodiments in light of the above detailed description. In general, the terms used in the following claims should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but rather to include all possible embodiments along with the full scope of equivalents to which the claims are entitled. Accordingly, the claims are not limited by this disclosure.
In certain embodiments, for example, the following are provided:
(Item 1)
(i) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34, the amino acid sequence of SEQ ID NO: 35 or SEQ ID NO: 36, and the amino acid sequence of SEQ ID NO: 37; and
(ii) a light chain variable region (VL) comprising any one of the amino acid sequences of SEQ ID NOs: 41, 40, 42, and 43, any one of the amino acid sequences of SEQ ID NOs: 49, 44-48, and 50-53, and the amino acid sequence of SEQ ID NO: 55 or 56.
1. An antibody, or antigen-binding fragment thereof, comprising:
Optionally, said VL comprises a R60N substitution mutation, a R60A substitution mutation, a R60K substitution mutation, a S64A substitution mutation, a I74A substitution mutation, or any combination thereof, compared to SEQ ID NO:58, wherein the amino acid numbering of said substitution mutations is according to SEQ ID NO:58; and still further optionally, said VL does not comprise any further mutations compared to SEQ ID NO:58;
the antibody or antigen-binding fragment thereof is capable of binding to an antigenic loop region of HBsAg and, optionally, neutralizing infection by Hepatitis B virus (HBV) of genotypes D, A, B, C, E, F, G, H, I, or J, or any combination thereof;
An antibody, or an antigen-binding fragment thereof.
(Item 2)
(i) in said VH the amino acid sequences set forth in SEQ ID NOs: 34, 35, and 37, respectively, and in said VL the amino acid sequences set forth in SEQ ID NOs: 41, 49, and 55, respectively;
(ii) in said VH, the amino acid sequences set forth in SEQ ID NOs: 34, 35, and 37, and in said VL, the amino acid sequences set forth in SEQ ID NOs: 41, 46, and 55, respectively;
(iii) in said VH, the amino acid sequences set forth in SEQ ID NOs: 34, 35, and 37, respectively, and in said VL, the amino acid sequences set forth in SEQ ID NOs: 41, 47, and 55, respectively;
(iv) in said VH the amino acid sequences set forth in SEQ ID NOs: 34, 35, and 37, respectively, and in said VL the amino acid sequences set forth in SEQ ID NOs: 41, 48, and 55, respectively;
(v) in said VH the amino acid sequences set forth in SEQ ID NOs: 34, 35, and 37, respectively, and in said VL the amino acid sequences set forth in SEQ ID NOs: 41, 45, and 55, respectively;
(vi) in said VH the amino acid sequences set forth in SEQ ID NOs: 34, 35, and 37, respectively, and in said VL the amino acid sequences set forth in SEQ ID NOs: 41, 50, and 55, respectively;
(vii) in said VH the amino acid sequences set forth in SEQ ID NOs: 34, 35, and 37, respectively, and in said VL the amino acid sequences set forth in SEQ ID NOs: 41, 51, and 55, respectively;
(viii) in said VH, the amino acid sequences set forth in SEQ ID NOs: 34, 35, and 37, respectively, and in said VL, the amino acid sequences set forth in SEQ ID NOs: 41, 52, and 55, respectively; or
(ix) the amino acid sequences set forth in SEQ ID NOs: 34, 35, and 37, respectively, in the VH, and the amino acid sequences set forth in SEQ ID NOs: 41, 53, and 55, respectively, in the VL;
2. The antibody or antigen-binding fragment of claim 1, comprising:
(Item 3)
(i) a heavy chain variable region (VH) comprising a CDRH1 amino acid sequence set forth in SEQ ID NO: 34, a CDRH2 amino acid sequence set forth in SEQ ID NO: 35 or 36, and a CDRH3 amino acid sequence set forth in SEQ ID NO: 37; and
(ii) a light chain variable region (VL) comprising a CDRL1 amino acid sequence set forth in any one of SEQ ID NOs: 40-43, a CDRL2 amino acid sequence set forth in any one of SEQ ID NOs: 49, 44-48, and 50-53, and a CDRL3 amino acid sequence set forth in SEQ ID NO: 55 or 56.
1. An antibody, or antigen-binding fragment thereof, comprising:
The CDRs are defined according to the CCG numbering system,
The antibody or antigen-binding fragment thereof is capable of binding to an antigenic loop region of HBsAg and, optionally, neutralizing infection by Hepatitis B virus (HBV) of genotypes D, A, B, C, E, F, G, H, I, or J, or any combination thereof, with the proviso that the antibody or antigen-binding fragment does not comprise the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in SEQ ID NOs: 34, 35, 37, 41, 44, and 45, respectively.
An antibody, or an antigen-binding fragment thereof.
(Item 4)
the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences being
(i) SEQ ID NOs: 34, 35, 37, 41, 49, and 55, respectively;
(ii) SEQ ID NOs: 34, 35, 37, 41, 46, and 55, respectively;
(iii) SEQ ID NOs: 34, 35, 37, 41, 47, and 55, respectively;
(iv) SEQ ID NOs: 34, 35, 37, 41, 48, and 55, respectively;
(v) SEQ ID NOs: 34, 35, 37, 41, 45, and 55, respectively;
(vi) SEQ ID NOs: 34, 35, 37, 41, 50, and 55, respectively;
(vii) SEQ ID NOs: 34, 35, 37, 41, 51, and 55, respectively;
(viii) SEQ ID NOs: 34, 35, 37, 41, 52, and 55, respectively;
(ix) SEQ ID NOs: 34, 35, 37, 41, 53, and 55, respectively; or
(x) SEQ ID NOs: 34, 35, 37, 41, 44, and 55, respectively.
4. The antibody or antigen-binding fragment according to claim 3,
(Item 5)
an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and the VL comprise CDRH1, CDRH2, CDRH3 and CDRL1, CDRL2, CDRL3 as set forth in HBC34-v40; HBC34-v36; HBC34-v37; HBC34-v38; HBC34-v39; HBC34-v41; HBC34-v42; HBC34-v43; HBC34-v44; HBC34-v45; HBC34-v46; HBC34-v47; HBC34-v48; HBC34-v49; or HBC34-v50, respectively;
the CDRs are defined according to IMGT numbering, and optionally the VL further comprises a R60N substitution mutation, a R60A substitution mutation, a R60K substitution mutation, a S64A substitution mutation, a I74A substitution mutation, or any combination thereof, compared to SEQ ID NO:58, and the amino acid numbering of the substitution mutations is according to SEQ ID NO:58, and optionally further the VL does not comprise any further mutations compared to SEQ ID NO:58.
An antibody, or an antigen-binding fragment thereof.
(Item 6)
an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and the VL comprise CDRH1, CDRH2, CDRH3 and CDRL1, CDRL2, CDRL3 as set forth in HBC34-v40; HBC34-v36; HBC34-v37; HBC34-v38; HBC34-v39; HBC34-v41; HBC34-v42; HBC34-v43; HBC34-v44; HBC34-v45; HBC34-v46; HBC34-v47; HBC34-v48; HBC34-v49; or HBC34-v50, respectively;
the CDRs are defined according to CCG numbering, and optionally the VL further comprises a R60N substitution mutation, a R60A substitution mutation, a R60K substitution mutation, a S64A substitution mutation, a I74A substitution mutation, or any combination thereof, compared to SEQ ID NO:58, wherein the amino acid numbering of the substitution mutations is according to SEQ ID NO:58, and optionally further wherein the VL does not comprise any other mutations compared to SEQ ID NO:58.
An antibody, or an antigen-binding fragment thereof.
(Item 7)
(i) the VH comprises or consists of an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 38 or 39; and/or
(ii) the VL comprises or consists of an amino acid sequence having at least 90% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 62, 58-61, 63-66, 69, 71, and 72;
7. The antibody or antigen-binding fragment of any one of items 1 to 6.
(Item 8)
(i) the VH comprises or consists of an amino acid sequence having at least 90% identity (i.e., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or any non-integer value therebetween) to the amino acid sequence set forth in SEQ ID NO: 38 or 39; and/or
(ii) the VL comprises or consists of an amino acid sequence having at least 90% identity (i.e., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or any non-integer value therebetween) to the amino acid sequence set forth in any one of SEQ ID NOs: 62, 58-61, 63-66, 69, 71, and 72;
8. The antibody or antigen-binding fragment of any one of items 1 to 7.
(Item 9)
9. The antibody or antigen-binding fragment of any one of items 1 to 8, wherein the VH and the VL comprise or consist of an amino acid sequence having at least 90% identity (i.e., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or any non-integer value therebetween) to the amino acid sequences set forth in: (i) SEQ ID NOs: 38 and 62, respectively; (ii) SEQ ID NOs: 38 and 59, respectively; (iii) SEQ ID NOs: 38 and 60, respectively; (iv) SEQ ID NOs: 38 and 61, respectively; (v) SEQ ID NOs: 38 and 58, respectively; (vi) SEQ ID NOs: 38 and 63, respectively; (vii) SEQ ID NOs: 38 and 64, respectively; (viii) SEQ ID NOs: 38 and 65, respectively; (ix) SEQ ID NOs: 38 and 66, respectively; (x) SEQ ID NOs: 38 and 71, respectively; or (xi) SEQ ID NOs: 38 and 72, respectively.
(Item 10)
1. An antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region (VH) comprising or consisting of the amino acid sequence of SEQ ID NO: 38 or 39, and a light chain variable region (VL) comprising a variant of any one of SEQ ID NOs: 62, 57-61, and 63-72, wherein said variant comprises any one or more of the following mutations: R60A; R60N; R60K; S64A; and I74A, optionally wherein said VL variant does not comprise any further mutations compared to SEQ ID NOs: 62, 57-61, and 63-72, respectively.
(Item 11)
An antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region (VH) comprising or consisting of the amino acid sequence of SEQ ID NO: 38 or 39, and a light chain variable region (VL) comprising a variant of any one of SEQ ID NOs: 62, 57-61, and 63-72, wherein said variant comprises a substitution mutation (such as a conservative amino acid substitution, or a mutation to a germline encoded amino acid) at Q78, D81, or both, and optionally said VL variant does not comprise any further mutations compared to SEQ ID NOs: 62, 57-61, and 63-72, respectively.
(Item 12)
10. The antibody or antigen-binding fragment of any one of claims 1 to 9, wherein the VH comprises or consists of the amino acid sequence set forth in SEQ ID NO: 38 or 39; and/or the VL comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs: 62, 58-61, 63-66, 69, 71, or 72.
(Item 13)
The VH and the VL are
(i) SEQ ID NOs: 38 and 62, respectively;
(ii) SEQ ID NOs: 38 and 59, respectively;
(iii) SEQ ID NOs: 38 and 60, respectively;
(iv) SEQ ID NOs: 38 and 61, respectively;
(v) SEQ ID NOs: 38 and 58, respectively;
(vi) SEQ ID NOs: 38 and 63, respectively;
(vii) SEQ ID NOs: 38 and 64, respectively;
(viii) SEQ ID NOs: 38 and 65, respectively;
(ix) SEQ ID NOs: 38 and 66, respectively;
(x) SEQ ID NOs: 38 and 71, respectively; or
(xi) SEQ ID NOs: 38 and 72, respectively
13. The antibody or antigen-binding fragment according to any one of items 1 to 9 and 12, comprising or consisting of an amino acid sequence as set forth in
(Item 14)
1. An antibody or antigen-binding fragment comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and the VL are
(i) SEQ ID NOs: 38 and 62, respectively;
(ii) SEQ ID NOs: 38 and 66, respectively;
(iii) SEQ ID NOs: 38 and 67, respectively;
(iv) SEQ ID NOs: 38 and 68, respectively; or
(v) SEQ ID NOs: 38 and 72, respectively
comprising or consisting of the amino acid sequence set forth in
The antibody or antigen-binding fragment thereof is capable of binding to an antigenic loop region of HBsAg and is capable of neutralizing infection by Hepatitis B virus (HBV) of genotypes D, A, B, C, E, F, G, H, I, or J, or any combination thereof.
(Item 15)
15. The antibody or antigen-binding fragment of any one of items 1 to 14, which is capable of neutralizing infection by Hepatitis D virus (HDV).
(Item 16)
16. The antibody or antigen-binding fragment of any one of items 1 to 15, wherein when a sample comprising a plurality of said antibodies or antigen-binding fragments is incubated at about 40° C. for about 120 to about 168 hours, the sample contains less than 12%, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, or 2% or less of said plurality as dimers, optionally wherein the presence of dimers is determined by absolute size exclusion chromatography.
(Item 17)
incubation of a plurality of said antibodies or antigen-binding fragments results in a reduction in dimer formation compared to incubation of a plurality of reference antibodies or antigen-binding fragments;
the reference antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in the amino acid sequences set forth in SEQ ID NOs: 34, 35, 37, 41, 44, and 55, respectively, and optionally comprises the VH amino acid sequence set forth in SEQ ID NO: 38 and the VL amino acid sequence set forth in SEQ ID NO: 57;
Optionally, the presence of antibody dimers is determined by absolute size exclusion chromatography.
17. The antibody or antigen-binding fragment of any one of items 1 to 16.
(Item 18)
(i) at 4° C. for 5 days, 15 days, and/or 32 days of incubation;
(ii) at 25° C. for 5 days, 15 days, and/or 32 days of incubation; and/or
(iii) upon incubation at 40° C. for 5 days, 15 days, and/or 32 days,
forms a lower amount of dimers and/or forms dimers at a reduced frequency and/or as a lower percentage of the total antibody or antigen-binding fragment molecules in the sample or composition compared to a reference antibody;
the reference antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in the amino acid sequences set forth in SEQ ID NOs: 34, 35, 37, 41, 44, and 55, respectively, and optionally comprises the VH amino acid sequence set forth in SEQ ID NO: 38 and the VL amino acid sequence set forth in SEQ ID NO: 57;
18. The antibody or antigen-binding fragment of any one of items 1 to 17.
(Item 19)
19. The antibody or antigen-binding fragment of any one of items 1 to 18, wherein the percentage of antibody or antigen-binding fragment molecules in the composition that are comprised as dimers is less than 4/5, less than 3/4, less than 1/2, less than 1/3, less than 1/4, less than 1/5, less than 1/6, less than 1/7, less than 1/8, less than 1/9, or less than 1/10, respectively, of the percentage of reference antibody molecules in the composition that are present as dimers.
(Item 20)
20. The antibody or antigen-binding fragment of any one of items 1 to 19, wherein a host cell transfected with a polynucleotide encoding the antibody or antigen-binding fragment provides 1.5-fold or more, 2-fold or more, 3-fold or more, or 4-fold or more of the antibody or antigen-binding fragment, respectively, than a reference host cell transfected with a polynucleotide encoding a reference antibody or antigen-binding fragment, wherein the reference antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in the amino acid sequences set forth in SEQ ID NOs: 34, 35, 37, 41, 44, and 55, respectively, and optionally comprises the VH amino acid sequence set forth in SEQ ID NO: 38 and the VL amino acid sequence set forth in SEQ ID NO: 57.
(Item 21)
21. The antibody or antigen-binding fragment of any one of items 1 to 20, wherein the antibody or antigen-binding fragment is produced in a transfected cell with a higher titer compared to a reference antibody or antigen-binding fragment produced in a transfected reference cell, wherein the reference antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in the amino acid sequences set forth in SEQ ID NOs: 34, 35, 37, 41, 44, and 55, respectively, and optionally comprises the VH amino acid sequence set forth in SEQ ID NO: 38 and the VL amino acid sequence set forth in SEQ ID NO: 57.
(Item 22)
22. The antibody or antigen-binding fragment of any one of items 1 to 21, wherein the antibody or antigen-binding fragment is produced in transfected cells at a titer that is at least 1.5-fold, at least 2-fold, at least 3-fold, or at least 4-fold higher than the titer at which a reference antibody or antigen-binding fragment is produced, and the reference antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in the amino acid sequences set forth in SEQ ID NOs: 34, 35, 37, 41, 44, and 55, respectively, and optionally comprises the VH amino acid sequence set forth in SEQ ID NO: 38 and the VL amino acid sequence set forth in SEQ ID NO: 57.
(Item 23)
23. The antibody or antigen-binding fragment of any one of items 1 to 22, wherein the antibody or antigen-binding fragment is capable of binding to HBsAg(adw) with an EC50 (ng/ml) of about 3.2 or less, less than 3.0, less than 2.5, less than 2.0, less than 1.5, or less than 1.0.
(Item 24)
24. The antibody or antigen-binding fragment of any one of items 1 to 23, wherein the antibody or antigen-binding fragment is capable of binding to HBsAg (e.g. of subtype adw) with an EC50 (ng/ml) of less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, less than 1.2, less than 1.1, or less than 1.0.
(Item 25)
25. The antibody or antigen-binding fragment of any one of items 1 to 24, wherein the antibody or antigen-binding fragment is capable of binding to HBsAg (e.g. of subtype adw) with an EC50 (ng/ml) of between 0.9 and 2.0, or between 0.9 and 1.9, or between 0.9 and 1.8, or between 0.9 and 1.7, or between 0.9 and 1.6, or between 0.9 and 1.5, or between 0.9 and 1.4, or between 0.9 and 1.3, or between 0.9 and 1.2, or between 0.9 and 1.1, or between 0.9 and 1.0, or between 1.0 and 2.0.
(Item 26)
26. The antibody or antigen-binding fragment of any one of items 1 to 25, wherein the antibody or antigen-binding fragment is capable of binding to HBsAg(adw) with an EC50 (ng/ml) of 2.0 or less.
(Item 27)
27. The antibody or antigen-binding fragment of any one of items 1 to 26, having an EC50 for neutralizing Hepatitis B virus infection of less than 20 ng/ml, preferably 15 ng/ml or less, more preferably 10 ng/mL or less.
(Item 28)
28. The antibody or antigen-binding fragment of any one of items 1 to 27, wherein the antibody or antigen-binding fragment is capable of neutralizing Hepatitis B virus infection with an infection-neutralizing EC50 of 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, or 7 ng/mL.
(Item 29)
29. The antibody or antigen-binding fragment of any one of items 1 to 28, wherein the antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in the amino acid sequences set forth in SEQ ID NOs: 34, 35, 37, 41, 44, and 55, respectively, and is capable of neutralizing Hepatitis B virus infection with an infection neutralization EC50 lower than the infection neutralization EC50 of a reference antibody or antigen-binding fragment comprising the VH amino acid sequence set forth in SEQ ID NO: 38 and the VL amino acid sequence set forth in SEQ ID NO: 57.
(Item 30)
30. The antibody or antigen-binding fragment of any one of items 1 to 29, wherein the antibody or antigen-binding fragment comprises a human antibody, a monoclonal antibody, a purified antibody, a single chain antibody, a Fab, a Fab', a F(ab')2, an Fv, or a scFv.
(Item 31)
31. The antibody or antigen-binding fragment of any one of items 1 to 30, wherein the antibody or antigen-binding fragment is a multispecific antibody or antigen-binding fragment.
(Item 32)
32. The antibody or antigen-binding fragment of any one of the preceding claims, wherein the antibody or antigen-binding fragment is a bispecific antibody or antigen-binding fragment.
(Item 33)
33. The antibody or antigen-binding fragment thereof of any one of items 1 to 32, wherein the antibody or antigen-binding fragment comprises an Fc portion.
(Item 34)
34. The antibody or antigen-binding fragment of claim 33, wherein the Fc portion comprises a mutation that enhances binding to FcRn compared to a reference Fc portion that does not contain the mutation.
(Item 35)
35. The antibody or antigen-binding fragment of claim 33 or 34, wherein the Fc portion comprises a mutation that enhances binding to an FcγR, preferably FcγRIIA and/or FcγRIIIA, compared to a reference Fc portion, and the reference Fc portion does not comprise the mutation.
(Item 36)
36. The antibody or antigen-binding fragment of any one of claims 33 to 35, wherein the Fc portion is of an IgG isotype, e.g., IgG1, or is derived from an IgG isotype, e.g., IgG1.
(Item 37)
IgG1m17,1 (IgHG1 ^* 01).
(Item 38)
The mutation that enhances binding to FcRn is
(i) M428L/N434S;
(ii) M252Y/S254T/T256E;
(iii) T250Q/M428L;
(iv) P257I/Q311I;
(v) P257I/N434H;
(vi) D376V/N434H;
(vii) T307A/E380A/N434A; or
(viii) any combination of (i) to (vii)
Including,
the amino acid numbering of the Fc portion is according to the EU numbering system;
38. The antibody or antigen-binding fragment of any one of items 34 to 37.
(Item 39)
39. The antibody or antigen-binding fragment of claim 38, wherein the mutation that enhances binding to FcRn comprises M428L/N434S.
(Item 40)
40. The antibody or antigen-binding fragment of any one of claims 35 to 39, wherein the mutations that enhance binding to FcγR include S239D; I332E; A330L; G236A; or any combination thereof, and the amino acid numbering of the Fc portion is according to the EU numbering system.
(Item 41)
The mutation that enhances binding to FcγR is
(i) S239D/I332E;
(ii) S239D/A330L/I332E;
(iii) G236A/S239D/I332E; or
(iv) G236A/A330L/I332E
41. The antibody or antigen-binding fragment of claim 40, comprising:
(Item 42)
42. The antibody or antigen-binding fragment of claim 40 or 41, wherein the mutations that enhance binding to FcγR comprise or consist of G236A/A330L/I332E, and optionally the antibody or antigen-binding fragment does not comprise S239D, and optionally the antibody or antigen-binding fragment further comprises a native S at position 239.
(Item 43)
43. The antibody or antigen-binding fragment of any one of claims 33 to 42, wherein the Fc portion comprises the amino acid substitution mutations: M428L; N434S; G236A; A330L; and I332E, and optionally does not include S239D.
(Item 44)
44. The antibody or antigen-binding fragment of any one of items 1 to 43, comprising a light chain constant region (CL) comprising or consisting of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO:79.
(Item 45)
45. The antibody or antigen-binding fragment of any one of items 1 to 44, comprising a CH1-CH2-CH3 that comprises or consists of an amino acid sequence having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 73, or a variant thereof that comprises one or more of the following amino acid substitutions (EU numbering): G236A; A330L; I332E; M428L; N434S.
(Item 46)
46. The antibody or antigen-binding fragment of claim 45, wherein the C-terminal lysine has been removed from the CH1-CH2-CH3.
(Item 47)
An antibody comprising a heavy chain (HC) comprising, or consisting of, the amino acid sequence set forth in SEQ ID NO:75, optionally with the C-terminal lysine removed, and a light chain (LC) comprising, or consisting of, (i) a VL amino acid sequence set forth in any one of SEQ ID NOs:62, 58-61, and 63-72, and (ii) a CL amino acid sequence set forth in SEQ ID NO:79.
(Item 48)
48. The antibody of claim 47, wherein the LC comprises a VL amino acid sequence set forth in any one of SEQ ID NOs: 62, 66, 67, and 72.
(Item 49)
An antibody comprising a heavy chain (HC) comprising, or consisting of, the amino acid sequence set forth in SEQ ID NO:76, optionally with the C-terminal lysine removed, and a light chain (LC) comprising, or consisting of, (i) a VL amino acid sequence set forth in any one of SEQ ID NOs:62, 58-61, and 63-72, and (ii) a CL amino acid sequence set forth in SEQ ID NO:79.
(Item 50)
50. The antibody of claim 49, wherein the LC comprises a VL amino acid sequence set forth in any one of SEQ ID NOs: 62, 66, 67, and 72.
(Item 51)
An antibody comprising a heavy chain (HC) comprising, or consisting of, the amino acid sequence set forth in SEQ ID NO:77, optionally with the C-terminal lysine removed, and a light chain (LC) comprising, or consisting of, (i) a VL amino acid sequence set forth in any one of SEQ ID NOs:62, 58-61, and 63-72, and (ii) a CL amino acid sequence set forth in SEQ ID NO:79.
(Item 52)
52. The antibody of claim 51, wherein the LC comprises a VL amino acid sequence set forth in any one of SEQ ID NOs: 62, 66, 67, and 72.
(Item 53)
An antibody comprising a heavy chain (HC) comprising, or consisting of, the amino acid sequence set forth in SEQ ID NO:78, optionally with the C-terminal lysine removed, and a light chain (LC) comprising, or consisting of, (i) a VL amino acid sequence set forth in any one of SEQ ID NOs:62, 58-61, and 63-72, and (ii) a CL amino acid sequence set forth in SEQ ID NO:79.
(Item 54)
54. The antibody of claim 53, wherein the LC comprises a VL amino acid sequence set forth in any one of SEQ ID NOs: 62, 66, 67, and 72.
(Item 55)
55. The antibody or antigen-binding fragment of any one of items 1 to 54, wherein the antibody or antigen-binding fragment is capable of binding to HBsAg of a genotype selected from HBsAg genotypes A, B, C, D, E, F, G, H, I, and J, or any combination thereof.
(Item 56)
56. The antibody or antigen-binding fragment of any one of claims 1 to 55, wherein the antibody or antigen-binding fragment is capable of reducing the serum concentration of HBV DNA in a mammal having an HBV infection.
(Item 57)
57. The antibody or antigen-binding fragment of any one of items 1 to 56, wherein the antibody or antigen-binding fragment is capable of reducing the serum concentration of HBsAg in a mammal having an HBV infection.
(Item 58)
58. The antibody or antigen-binding fragment of any one of items 1 to 57, wherein the antibody or antigen-binding fragment is capable of reducing the serum concentration of HBeAg in a mammal having an HBV infection.
(Item 59)
59. The antibody or antigen-binding fragment of any one of items 1 to 58, wherein the antibody or antigen-binding fragment is capable of reducing the serum concentration of HBcrAg in a mammal having an HBV infection.
(Item 60)
60. A polynucleotide comprising a nucleotide sequence encoding the antibody or antigen-binding fragment of any one of items 1 to 59.
(Item 61)
60. A polynucleotide encoding the light chain variable region (VL) and optionally the light chain constant domain (CL) of the antibody or antigen-binding fragment of any one of items 1 to 59.
(Item 62)
62. The polynucleotide of claim 60 or 61, wherein the nucleotide sequence encoding the antibody or antigen-binding fragment is codon-optimized for expression in a host cell.
(Item 63)
63. The polynucleotide according to item 62, comprising a nucleotide sequence having at least 50% identity to any one of the nucleotide sequences set forth in SEQ ID NOs: 89, 85-88, and 90-99.
(Item 64)
64. The polynucleotide according to any one of items 60 to 63, comprising: (i) the polynucleotide sequence set forth in SEQ ID NO: 81 or SEQ ID NO: 82; and (ii) the polynucleotide sequence set forth in any one or more of SEQ ID NOs: 89, 85 to 88, and 90 to 99.
(Item 65)
64. The polynucleotide according to any one of items 60 to 63, comprising: (i) the polynucleotide sequence set forth in SEQ ID NO: 83; and (ii) the polynucleotide sequence set forth in any one or more of SEQ ID NOs: 89, 85 to 88, and 90 to 99.
(Item 66)
64. The polynucleotide according to any one of items 60 to 63, comprising: (i) the polynucleotide sequence set forth in SEQ ID NO: 84; and (ii) the polynucleotide sequence set forth in any one or more of SEQ ID NOs: 89, 85-88, and 90-99.
(Item 67)
67. A vector comprising the polynucleotide according to any one of items 60 to 66.
(Item 68)
68. The vector of item 67, comprising a lentiviral vector or a retroviral vector.
(Item 69)
A host cell comprising the polynucleotide according to any one of items 60 to 66 and/or the vector according to item 67 or 68.
(Item 70)
(i) the antibody or antigen-binding fragment according to any one of items 1 to 59;
(ii) the polynucleotide according to any one of items 60 to 66;
(iii) a vector according to item 67 or 68;
(iv) a host cell according to item 69; or
(v) any combination of (i) to (iv), and
Pharmaceutically acceptable excipients, diluents or carriers
13. A pharmaceutical composition comprising:
(Item 71)
(a)
(i) the antibody or antigen-binding fragment according to any one of items 1 to 59;
(ii) the polynucleotide according to any one of items 60 to 66;
(iii) a vector according to item 67 or 68;
(iv) a host cell according to item 69;
(v) the pharmaceutical composition according to item 70; or
(vi) Any combination of (i) to (vi).
A component selected from:
(b)
(1) instructions for using said components to prevent, treat, attenuate, and/or diagnose Hepatitis B and/or Hepatitis D infections; and/or
(2) A means for administering the component to a subject, e.g., a syringe.
Kit including:
(Item 72)
(i) a polymerase inhibitor, optionally including lamivudine, adefovir, entecavir, telbivudine, tenofovir, or any combination thereof;
(ii) interferons, optionally including IFN beta and/or IFN alpha;
(iii) a checkpoint inhibitor, optionally comprising an anti-PD-1 antibody or antigen-binding fragment thereof, an anti-PD-L1 antibody or antigen-binding fragment thereof, and/or an anti-CTLA4 antibody or antigen-binding fragment thereof;
(iv) an agonist of a stimulatory immune checkpoint molecule; or
(v) any combination of (i) to (iv)
72. The composition of claim 70 or the kit of claim 71, further comprising:
(Item 73)
73. The composition or kit of claim 72, wherein the polymerase inhibitor comprises lamivudine.
(Item 74)
69. A method of producing the antibody or antigen-binding fragment of any one of claims 1 to 59, comprising culturing the host cell of claim 69 under conditions and for a time sufficient to produce the antibody or antigen-binding fragment.
(Item 75)
67. Use of (i) the antibody or antigen-binding fragment of any one of items 1 to 59; (ii) the polynucleotide of any one of items 60 to 66; (iii) the vector of item 67 or 68; (iv) the host cell of item 69; and/or (v) the pharmaceutical composition of item 70, 72, or 73 in the manufacture of a medicament for preventing, treating, attenuating and/or diagnosing a hepatitis B infection and/or a hepatitis D infection in a subject.
(Item 76)
11. A method of treating, preventing and/or attenuating a Hepatitis B and/or Hepatitis D infection in a subject, comprising administering to the subject an effective amount of: (i) the antibody or antigen-binding fragment of any one of items 1 to 59; (ii) the polynucleotide of any one of items 60 to 66; (iii) the vector of item 67 or 68; (iv) the host cell of item 69; and/or (v) the pharmaceutical composition of item 70, 72, or 73.
(Item 77)
77. The method of claim 76, further comprising administering to the subject one or more of: (vi) a polymerase inhibitor, optionally including lamivudine, adefovir, entecavir, telbivudine, tenofovir, or any combination thereof; (vii) an interferon, optionally including IFN beta and/or IFN alpha; (viii) a checkpoint inhibitor, optionally including an anti-PD-1 antibody or antigen-binding fragment thereof, an anti-PD-L1 antibody or antigen-binding fragment thereof, and/or an anti-CTLA4 antibody or antigen-binding fragment thereof; (ix) an agonist of a stimulatory immune checkpoint molecule; or (x) any combination of (vi)-(ix).
(Item 78)
78. The method of claim 76 or 77, wherein the hepatitis B infection is a chronic hepatitis B infection.
(Item 79)
79. The method of any one of items 76 to 78, wherein the subject has undergone a liver transplant.
(Item 80)
80. The method of any one of items 76-79, wherein the subject is not immunized against Hepatitis B.
(Item 81)
81. The method of any one of items 76 to 80, wherein the subject is a newborn.
(Item 82)
82. The method of any one of items 76-81, wherein the subject is undergoing or has undergone hemodialysis.
(Item 83)
83. The method of any one of items 76 to 82, wherein the method comprises administering to the subject a single dose of a pharmaceutical composition comprising the antibody or antigen-binding fragment.
(Item 84)
84. The method of claim 83, wherein the single dose of the pharmaceutical composition comprises the antibody in the range of 2-18 mg/kg of subject body weight.
(Item 85)
wherein the single dose of the pharmaceutical composition comprises up to 6 mg, up to 10 mg, up to 15 mg, up to 18 mg, up to 25 mg, up to 30 mg, up to 35 mg, up to 40 mg, up to 45 mg, up to 50 mg, up to 55 mg, up to 60 mg, up to 75 mg, up to 90 mg, up to 300 mg, up to 900 mg, or up to 3000 mg of the antibody; or
or wherein said single dose of said pharmaceutical composition comprises said antibody in an amount within the range of 1 mg to 3000 mg, or within the range of 5 mg to 3000 mg, or within the range of 10 mg to 3000 mg, or within the range of 25 mg to 3000 mg, or within the range of 30 mg to 3000 mg, or within the range of 50 mg to 3000 mg, or within the range of 60 mg to 3000 mg, or within the range of 75 mg to 3000 mg, or within the range of 90 mg to 3000 mg, or within the range of 100 mg to 3000 mg, or within the range of 150 mg to 3000 mg, or within the range of 200 mg to 3000 mg, or within the range of 300 mg to 3000 mg, or within the range of 500 mg to 3000 mg, or within the range of 750 mg to 3000 mg, or within the range of 900 mg to 3000 mg, or within the range of 1500 mg to 3000 mg, or within the range of 2000 mg to 3000 mg;
or wherein said single dose of said pharmaceutical composition comprises said antibody in an amount within the range of 1 mg to 900 mg, or within the range of 5 mg to 900 mg, or within the range of 10 mg to 900 mg, or within the range of 25 mg to 900 mg, or within the range of 30 mg to 900 mg, or within the range of 50 mg to 900 mg, or within the range of 60 mg to 900 mg, or within the range of 75 mg to 900 mg, or within the range of 90 mg to 900 mg, or within the range of 100 mg to 900 mg, or within the range of 150 mg to 900 mg, or within the range of 200 mg to 900 mg, or within the range of 300 mg to 900 mg, or within the range of 500 mg to 900 mg, or within the range of 750 mg to 900 mg;
or wherein the single dose of the pharmaceutical composition comprises the antibody in an amount such that the single dose of the pharmaceutical composition comprises the antibody in an amount within the range of 1 mg to 500 mg, or within the range of 5 mg to 500 mg, or within the range of 10 mg to 500 mg, or within the range of 25 mg to 500 mg, or within the range of 30 mg to 500 mg, or within the range of 50 mg to 500 mg, or within the range of 60 mg to 500 mg, or within the range of 75 mg to 500 mg, or within the range of 90 mg to 500 mg, or within the range of 100 mg to 500 mg, or within the range of 150 mg to 500 mg, or within the range of 200 mg to 500 mg, or within the range of 300 mg to 500 mg, or within the range of 400 mg to 500 mg;
wherein said single dose of said pharmaceutical composition comprises said antibody in an amount within the range of 1 mg to 300 mg, or within the range of 5 mg to 300 mg, or within the range of 10 mg to 300 mg, or within the range of 25 mg to 300 mg, or within the range of 30 mg to 300 mg, or within the range of 50 mg to 300 mg, or within the range of 60 mg to 300 mg, or within the range of 75 mg to 300 mg, or within the range of 90 mg to 300 mg, or within the range of 100 mg to 300 mg, or within the range of 150 mg to 300 mg, or within the range of 200 mg to 300 mg;
wherein said single dose of said pharmaceutical composition comprises said antibody in an amount within the range of 1 mg to 200 mg, or within the range of 5 mg to 200 mg, or within the range of 10 mg to 200 mg, or within the range of 25 mg to 200 mg, or within the range of 30 mg to 200 mg, or within the range of 50 mg to 200 mg, or within the range of 60 mg to 200 mg, or within the range of 75 mg to 200 mg, or within the range of 90 mg to 200 mg, or within the range of 100 mg to 200 mg, or within the range of 150 mg to 200 mg;
wherein said single dose of said pharmaceutical composition comprises said antibody in an amount within the range of 1 mg to 100 mg, or within the range of 5 mg to 100 mg, or within the range of 10 mg to 100 mg, or within the range of 25 mg to 100 mg, or within the range of 30 mg to 100 mg, or within the range of 50 mg to 100 mg, or within the range of 60 mg to 100 mg, or within the range of 75 mg to 100 mg, or within the range of 75 mg to 100 mg, or within the range of 90 mg to 100 mg; or
wherein the single dose of the pharmaceutical composition comprises the antibody in an amount in the range of 1 mg to 25 mg, or in the range of 5 mg to 25 mg, or in the range of 10 mg to 25 mg, or in the range of 15 mg to 25 mg, or in the range of 20 mg to 25 mg; or
wherein the single dose of the pharmaceutical composition comprises the antibody in an amount within the range of 1 mg to 50 mg, or within the range of 1 mg to 25 mg, or within the range of 5 mg to 50 mg, or within the range of 5 mg to 25 mg, or within the range of 10 mg to 50 mg, or within the range of 10 mg to 25 mg, or within the range of 1 mg to 15 mg, or within the range of 5 mg to 15 mg, or within the range of 10 mg to 15 mg;
wherein the single dose of the pharmaceutical composition is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, or 1000 mg or more of said antibody; or
the single dose of the pharmaceutical composition contains the antibody in an amount less than 3000 mg, less than 2500 mg, less than 2000 mg, less than 1500 mg, less than 1000 mg, less than 900 mg, less than 500 mg, less than 300 mg, less than 200 mg, less than 100 mg, less than 90 mg, less than 75 mg, less than 50 mg, less than 25 mg, or less than 10 mg, but greater than 1 mg, greater than 2 mg, greater than 3 mg, greater than 4 mg, or greater than 5 mg;
85. The method according to item 83 or 84.
(Item 86)
86. The method of any one of items 83 to 85, wherein the single dose of the pharmaceutical composition comprises the antibody at a concentration in the range of 100 mg/mL to 200 mg/mL, such as 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, 190 mg/mL, or 200 mg/mL, preferably 150 mg/mL.
(Item 87)
87. The method of any one of claims 83 to 86, wherein the single dose of the pharmaceutical composition comprises about 75 mg of the antibody.
(Item 88)
88. The method of any one of items 83-87, wherein the single dose of the pharmaceutical composition comprises about 90 mg of the antibody.
(Item 89)
89. The method of any one of items 83 to 88, wherein the single dose of the pharmaceutical composition comprises up to 300 mg of the antibody.
(Item 90)
90. The method of any one of items 83 to 89, wherein the single dose of the pharmaceutical composition contains up to 900 mg of the antibody.
(Item 91)
91. The method of any one of items 83 to 90, wherein the single dose of the pharmaceutical composition contains up to 3,000 mg of the antibody.
(Item 92)
92. The method of any one of items 83-91, wherein the method comprises administering the single dose by subcutaneous injection, and optionally the single dose comprises or consists of 6 mg of the antibody or 18 mg of the antibody.
(Item 93)
93. The method of any one of claims 83 to 92, wherein the method comprises administering the single dose by intravenous injection.
(Item 94)
94. The method of any one of items 83 to 93, wherein the pharmaceutical composition further comprises water, optionally USP water.
(Item 95)
95. The method according to any one of items 83 to 94, wherein the pharmaceutical composition further comprises histidine, optionally at a concentration in the range of 10 mM to 40 mM, for example 20 mM, in the pharmaceutical composition.
(Item 96)
96. The method according to any one of items 83 to 95, wherein the pharmaceutical composition further comprises a disaccharide, such as sucrose, optionally at 5%, 6%, 7%, 8%, or 9%, preferably about 7% (w/v).
(Item 97)
97. The method according to any one of items 83 to 96, wherein said pharmaceutical composition further comprises a surfactant or triblock copolymer, optionally polysorbate or poloxamer-188, preferably polysorbate 80 (PS80), optionally said polysorbate or poloxamer-188 being present in the range of 0.01% to 0.05% (w/v), preferably 0.02% (w/v).
(Item 98)
98. The method of any one of items 83 to 97, wherein the pharmaceutical composition has a pH in the range of 5.8 to 6.2, in the range of 5.9 to 6.1, or of 5.8, 5.9, 6.0, 6.1, or 6.2.
(Item 99)
The pharmaceutical composition comprises:
(i) 150 mg/mL of the antibody;
(ii) USP Water;
(iii) 20 mM histidine;
(iv) 7% sucrose; and
(v) 0.02%PS80
99. The method of claim 98, wherein the pharmaceutical composition comprises a pH of 6.
(Item 100)
99. The method of any one of items 83 to 99, wherein the subject is an adult.
(Item 101)
101. The method of claim 100, wherein the subject is within the age range of 18 to 65 years old.
(Item 102)
The subject weighs between 40 kg and 125 kg, and/or the subject weighs between 18 and 35 kg/m ² 102. The method according to any one of items 83 to 101, wherein the patient has a body mass index (BMI) of 0.01 to 0.05.
(Item 103)
103. The method of any one of items 83-102, wherein the subject has chronic HBV infection, e.g., as defined by positive serum HBsAg, HBV DNA, and/or HBeAg on two occasions, the two occasions being at least 6 months apart.
(Item 104)
104. The method of any one of items 83 to 103, wherein the subject does not have cirrhosis.
(Item 105)
Absence of cirrhosis
Fibroscan assessment (e.g., within 6 months prior to administration of said single dose of said pharmaceutical composition); or
A liver biopsy (e.g., within 12 months prior to administration of said single dose of said pharmaceutical composition)
is determined by
Preferably, the absence of cirrhosis is determined by the absence of Metavir F3 fibrosis or the absence of F4 cirrhosis.
The method according to item 104.
(Item 106)
106. The method of any one of items 83-105, wherein the subject optionally received a nucleoside reverse transcriptase inhibitor (NRTI) within 120 days, and optionally within 60 days, prior to administration of the single dose.
(Item 107)
The NRTI is selected from the group consisting of tenofovir, tenofovir disoproxil (e.g., tenofovir disproxil fumarate), tenofovir alafenamide, entecavir, laminidine, ramucirumab, and ramucirumab.
107. The method of claim 106, comprising one or more of: vudine; adefovir; and adefovir dipivoxil.
(Item 108)
108. The method of any one of items 83-107, wherein the subject has a serum HBV DNA concentration of less than 100 IU/mL 28 days or less prior to administration of the single dose.
(Item 109)
109. The method of any one of items 83-108, wherein the subject has a serum HBsAg concentration of less than 3,000 IU/mL before the single dose is administered, and optionally has a serum HBsAg concentration of less than 1,000 IU/mL before the single dose is administered.
(Item 110)
109. The method of any one of items 83 to 109, wherein the subject has a serum HBsAg concentration greater than or equal to 3,000 IU/mL 28 days or less prior to administration of the single dose, and optionally has a serum HBsAg concentration greater than or equal to 1,000 IU/mL 28 days or less prior to administration of the single dose.
(Item 111)
111. The method of any one of paragraphs 83-110, wherein the subject was HBe-antigen (HBeAg) negative 28 days or less prior to administration of the single dose.
(Item 112)
112. The method of any one of claims 83-111, wherein the subject tested negative for anti-HBs antibodies 28 days or less prior to administration of the single dose.
(Item 113)
The subject, prior to administration of the single dose,
(i) does not have fibrosis and/or does not have cirrhosis; and/or
(ii) having alanine aminotransferase (ALT) < 2 x upper limit of normal (ULN);
Item 83. The method according to any one of items 83 to 112.
(Item 114)
114. The method of any one of items 83-113, wherein 56 days after administration of the single dose, the subject has a less than two-fold reduction in serum HBsAg (e.g., concentration of HBsAg in serum, e.g., as determined using an Abbott ARCHITECT assay) compared to the subject's serum HBsAg 0-28 days prior to administration of the single dose.
(Item 115)
After administration of the single dose (e.g., 56 days after administration of the single dose), the subject:
(i) has reduced or less severe intrahepatic spread of HBV compared to a reference subject; and/or
(ii) comprising an adaptive immune response to HBV;
Item 83. The method according to any one of items 83 to 114.
(Item 116)
116. The method of any one of items 83 to 115, wherein the subject is male.
(Item 117)
116. The method of any one of items 83 to 115, wherein the subject is female.
(Item 118)
60. The antibody or antigen-binding fragment according to any one of items 1 to 59, at a concentration ranging from 100 mg/mL to 200 mg/mL, for example 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, 190 mg/mL, or 200 mg/mL, preferably 150 mg/mL; and
Pharmaceutically acceptable carriers, excipients, or diluents
23. A pharmaceutical composition comprising:
(Item 119)
19. The pharmaceutical composition of claim 118, wherein the pharmaceutical composition comprises up to 6 mg, up to 18 mg, up to 75 mg, up to 90 mg, up to 300 mg, up to 900 mg, or up to 3000 mg of the antibody.
(Item 120)
120. The pharmaceutical composition of claim 118 or 119, wherein the pharmaceutical composition comprises about 75 mg of the antibody.
(Item 121)
120. The pharmaceutical composition of claim 118 or 119, wherein the pharmaceutical composition comprises about 90 mg of the antibody.
(Item 122)
120. The pharmaceutical composition of claim 118 or 119, wherein the pharmaceutical composition comprises about 300 mg of the antibody.
(Item 123)
120. The pharmaceutical composition of claim 118 or 119, wherein the pharmaceutical composition comprises about 900 mg of the antibody.
(Item 124)
120. The pharmaceutical composition of claim 118 or 119, wherein the pharmaceutical composition comprises about 3,000 mg of the antibody.
(Item 125)
125. The pharmaceutical composition according to any one of claims 118 to 124, wherein the pharmaceutical composition comprises water, optionally USP water.
(Item 126)
126. The pharmaceutical composition according to any one of items 118 to 125, wherein the pharmaceutical composition optionally comprises histidine in a concentration of 10 mM to 40 mM, for example 20 mM.
(Item 127)
127. The pharmaceutical composition according to any one of items 118 to 126, wherein the pharmaceutical composition comprises a disaccharide, such as sucrose, optionally at 5%, 6%, 7%, 8%, or 9%, preferably about 7% (w/v).
(Item 128)
128. The pharmaceutical composition according to any one of items 118 to 127, wherein the pharmaceutical composition comprises a surfactant, optionally a polysorbate, preferably polysorbate 80 (PS80), optionally wherein said polysorbate is present in the range of 0.01% to 0.05% (w/v), preferably 0.02% (w/v).
(Item 129)
129. The pharmaceutical composition according to any one of items 118 to 128, wherein the pharmaceutical composition has a pH in the range of 5.8 to 6.2, in the range of 5.9 to 6.1, or of 5.8, 5.9, 6.0, 6.1, or 6.2.
(Item 130)
The pharmaceutical composition comprises:
(i) 150 mg/mL of the antibody;
(ii) USP Water;
(iii) 20 mM histidine;
(iv) 7% sucrose; and
(v) 0.02%PS80
130. The pharmaceutical composition according to any one of items 118 to 129, wherein said pharmaceutical composition comprises a pH of 6.
(Item 131)
After administration of the single dose, the subject's serum HBsAg increases by 1.0 log compared to baseline. ¹⁰ IU/mL, 1.5log ¹⁰ 118. The method of any one of items 83-117, wherein the blood glucose level is reduced by 100 mg/mL or more, and optionally said reduction lasts for 1, 2, 3, 4, 5, 6, 7, 8 days or longer after administration of said single dose.
(Item 132)
132. The method of any one of items 83-117 and 131, wherein after administration of the single dose, the subject's serum HBsAg is reduced for at least 8, at least 15, at least 22, or at least 29 days compared to baseline.
(Item 133)
A method for the in vitro diagnosis of hepatitis B and/or hepatitis D infection comprising:
(i) contacting a sample from a subject with the antibody or antigen-binding fragment according to any one of items 1 to 59; and
(ii) detecting a complex comprising an antigen and the antibody, or a complex comprising an antigen and the antigen-binding fragment;
A method comprising:
(Item 134)
134. The method of claim 133, wherein the sample comprises blood isolated from the subject.
(Item 135)
1. A method for detecting the presence or absence of a precise conformational epitope in an anti-hepatitis B and/or anti-hepatitis D vaccine, comprising:
(i) contacting the vaccine with the antibody or antigen-binding fragment according to any one of claims 1 to 59; and
(ii) determining whether a complex comprising an antigen and the antibody, or a complex comprising an antigen and the antigen-binding fragment, is formed;
A method comprising:
(Item 136)
The pharmaceutical composition comprises:
(i) has enhanced binding to human FcγRIIA, human FcγRIIIA, or both, compared to a reference polypeptide comprising an Fc portion that does not contain G236A/A330L/I332E, wherein the human FcγRIIA is optionally H131 or R131, and/or the human FcγRIIIA is optionally F158 or V158;
(ii) has reduced binding to human FcγRIIB relative to a reference polypeptide comprising an Fc portion that does not contain G236A/A330L/I332E;
(iii) does not bind to human FcγRIIB;
(iv) has reduced binding to human C1q compared to a reference polypeptide comprising an Fc portion that does not contain G236A/A330L/I332E;
(v) does not bind to human C1q;
(vi) activates FcγRIIA, human FcγRIIIA, or both to a greater extent than a reference polypeptide comprising an Fc portion that does not contain G236A/A330L/I332E, wherein said human FcγRIIA is optionally H131 or R131, and/or said human FcγRIIIA is optionally F158 or V158;
(vii) does not activate human FcγRIIB;
(viii) activates human natural killer (NK) cells in the presence of HBsAg to a greater extent than a reference polypeptide comprising an Fc portion that does not contain G236A/A330L/I332E, wherein the reference polypeptide is optionally HB Ag, optionally an antibody that binds HBsAg;
(ix) HBsAg-Y100C/P120T, HBsAg-P120T, HBsAg-P120S/S143L, HBsAg-C121S, HBsAg- R122D, HBsAg-R122I, HBsAg-T123N, HBsAg-Q129H, HBsAg-Q129L, HBsAg-M133H, HBsA HBsAg-M133L, HBsAg-M133T, HBsAg-K141E, HBsAg-P142S, HBsAg-S143K, HBsAg-D144A, HBsAg-G145R, HBsAg-N146A, or any combination thereof. and/or
(x) HBsAg-Y100C/P120T, HBsAg-P120T, HBsAg-P120S/S143L, HBsAg-C121S, HBsAg-R122D, HBsAg-R122I, HBsAg-T123N, HBsAg-Q, or a combination thereof, as compared to a reference antibody or antigen-binding fragment comprising an Fc portion that binds HBsAg and does not contain G236A/A330L/I332E. HBsAg-Q129H, HBsAg-Q129L, HBsAg-M133H, HBsAg-M133L, HBsAg-M133T, HBsAg-K141E, HBsAg-P142S, HBsAg-S143K, HBsAg-D144A, HBsAg-G145R, HBsAg-N146A, or any combination thereof;
60. The antibody or antigen-binding fragment of any one of items 1 to 59.
(Item 137)
1. A method of treating a chronic HBV infection in a subject in need thereof, comprising:
administering to the subject an agent that reduces HBV antigenic load; and
60. Administering to the subject an anti-HBV antibody according to any one of items 1 to 59.
A method comprising:
(Item 138)
1. A method of treating a chronic HBV infection in a subject in need thereof, comprising:
administering to the subject an inhibitor of HBV gene expression; and
60. Administering to the subject an anti-HBV antibody according to any one of items 1 to 59.
A method comprising:
(Item 139)
139. The method of claim 137 or 138, wherein the RNAi agent comprises a sense strand and an antisense strand that form a double-stranded region, and wherein the sense strand comprises at least 15 contiguous nucleotides that differ by no more than 3 nucleotides from nucleotides 1579-1597 of SEQ ID NO: 116.
(Item 140)
140. The method of any one of items 137-139, wherein the RNAi agent comprises a sense strand and an antisense strand, and the sense strand comprises nucleotides 1579-1597 of SEQ ID NO:116.
(Item 141)
141. The method of any one of items 137-140, wherein at least one strand of the RNAi agent comprises a 3' overhang of at least one nucleotide.
(Item 142)
141. The method of any one of items 137-140, wherein at least one strand of the RNAi agent comprises a 3' overhang of at least 2 nucleotides.
(Item 143)
143. The method of any one of items 137-142, wherein the double-stranded region of the RNAi agent is 15-30 nucleotide pairs in length.
(Item 144)
143. The method of any one of items 137-142, wherein the double-stranded region of the RNAi agent is 17-23 nucleotide pairs in length.
(Item 145)
143. The method of any one of items 137-142, wherein the double-stranded region of the RNAi agent is 17-25 nucleotide pairs in length.
(Item 146)
143. The method of any one of claims 137-142, wherein the double-stranded region of the RNAi agent is 23-27 nucleotide pairs in length.
(Item 147)
143. The method of any one of items 137-142, wherein the double-stranded region of the RNAi agent is 19-21 nucleotide pairs in length.
(Item 148)
143. The method of any one of items 137-142, wherein the double-stranded region of the RNAi agent is 21-23 nucleotide pairs in length.
(Item 149)
143. The method of any one of items 137-142, wherein each strand of the RNAi agent has 15-30 nucleotides.
(Item 150)
143. The method of any one of items 137-142, wherein each strand of the RNAi agent has 19-30 nucleotides.
(Item 151)
151. The method of any one of items 137 to 150, wherein the RNAi agent is an siRNA.
(Item 152)
152. The method of claim 151, wherein the siRNA inhibits expression of HBV transcripts encoding HBsAg, HBcAg, and HBx proteins, or HBV DNA polymerase protein.
(Item 153)
153. The method of claim 151 or 152, wherein the siRNA binds to at least 15 consecutive nucleotides of a target encoded by the P gene, nucleotides 2309-3182 and 1-1625 of NC_003977.2; the S gene (encoding the L, M, and S proteins), nucleotides 2850-3182 and 1-837 of NC_003977.2; HBx, nucleotides 1376-1840 of NC_003977.2; or the C gene, nucleotides 1816-2454 of NC_003977.2.
(Item 154)
153. The method of claim 151 or 152, wherein the antisense strand of the siRNA comprises at least 15 contiguous nucleotides of the nucleotide sequence 5'-UGUGAAGCGAAGUGCACACUU-3' (SEQ ID NO: 119).
(Item 155)
153. The method of claim 151 or 152, wherein the antisense strand of the siRNA comprises at least 19 contiguous nucleotides of the nucleotide sequence 5'-UGUGAAGCGAAGUGCACACUU-3' (SEQ ID NO: 119).
(Item 156)
153. The method of claim 151 or 152, wherein the antisense strand of the siRNA comprises the nucleotide sequence of 5'-UGUGAAGCGAAGUGCACACUU-3' (SEQ ID NO: 119).
(Item 157)
153. The method of claim 151 or 152, wherein the antisense strand of the siRNA consists of the nucleotide sequence of 5'-UGUGAAGCGAAGUGCACACUU-3' (SEQ ID NO: 119).
(Item 158)
158. The method of any one of items 154 to 157, wherein the sense strand of the siRNA comprises the nucleotide sequence of 5'-GUGUGCACUUCGCUUCACA-3' (SEQ ID NO: 118).
(Item 159)
158. The method of any one of items 154 to 157, wherein the sense strand of the siRNA consists of the nucleotide sequence 5'-GUGUGCACUUCGCUUCACA-3' (SEQ ID NO: 118).
(Item 160)
153. The method of claim 151 or 152, wherein the antisense strand of the siRNA comprises at least 15 contiguous nucleotides of the nucleotide sequence 5'-UAAAAUUGAGAGAAGUCCACCAC-3' (SEQ ID NO: 121).
(Item 161)
153. The method of claim 151 or 152, wherein the antisense strand of the siRNA comprises at least 19 contiguous nucleotides of the nucleotide sequence 5'-UAAAAUUGAGAGAAGUCCACCAC-3' (SEQ ID NO: 121).
(Item 162)
153. The method of claim 151 or 152, wherein the antisense strand of the siRNA comprises the nucleotide sequence of 5'-UAAAAUUGAGAGAAGUCCACCAC-3' (SEQ ID NO: 121).
(Item 163)
153. The method of claim 151 or 152, wherein the antisense strand of the siRNA consists of the nucleotide sequence of 5'-UAAAAUUGAGAGAAGUCCACCAC-3' (SEQ ID NO: 121).
(Item 164)
158. The method of any one of items 154 to 157, wherein the sense strand of the siRNA comprises the nucleotide sequence of 5'-GGUGGACUUCUCUCAAUUUUA-3' (SEQ ID NO: 120).
(Item 165)
158. The method, composition for use, or use according to any one of items 154 to 157, wherein the sense strand of the siRNA consists of the nucleotide sequence 5'-GGUGGACUUCUCUCAAUUUUA-3' (SEQ ID NO: 120).
(Item 166)
substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides;
The sense strand is conjugated to a ligand attached at the 3' end.
Item 166. The method according to any one of items 151 to 165.
(Item 167)
167. The method of claim 166, wherein the ligand is one or more GalNAc derivatives attached via a monovalent linker, a divalent branched linker, or a trivalent branched linker.
(Item 168)
The ligand is

168. The method according to claim 166 or 167,
(Item 169)
The siRNA has the following structure:

wherein X is O or S.
(Item 170)
170. The method of any one of items 151 to 169, wherein at least one nucleotide of the siRNA is a modified nucleotide comprising a deoxy-nucleotide, a 3'-terminal deoxy-thymine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2'-amino-modified nucleotide, a 2'-O-allyl-modified nucleotide, a 2'-C-alkyl-modified nucleotide, a 2'-hydroxyl-modified nucleotide, a 2'-methoxyethyl-modified nucleotide, a 2'-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a nucleotide comprising a non-natural base, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5'-phosphate, an adenosine-glycol nucleic acid, or a nucleotide comprising a 5'-phosphate mimetic.
(Item 171)
170. The method of any one of items 151 to 169, wherein the siRNA comprises a phosphate backbone modification, a 2' ribose modification, a 5' triphosphate modification, or a GalNAc conjugation modification.
(Item 172)
172. The method of claim 171, wherein the phosphate backbone modification comprises a phosphorothioate linkage.
(Item 173)
173. The method of claim 171 or 172, wherein the 2' ribose modification comprises a fluoro or -O-methyl substitution.
(Item 174)
The siRNA has a sense strand comprising 5'-gsusguGfcAfCfUfucgcuucacaL96-3' (SEQ ID NO: 122) and an antisense strand comprising 5'-usGfsugaAfgCfGfaaguGfcAfcacsusu-3' (SEQ ID NO: 123);
wherein a, c, g, and u are 2'-O-methyl adenosine-3'-phosphate, 2'-O-methyl cytidine-3'-phosphate, 2'-O-methyl guanosine-3'-phosphate, and 2'-O-methyl uridine-3'-phosphate, respectively;
Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;
s is a phosphorothioate linkage;
L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl]-4-hydroxyprolinol
The method according to any one of items 151 to 159 and 166 to 173.
(Item 175)
The siRNA has a sense strand comprising 5'-gsusguGfcAfCfUfucgcuucacaL96-3' (SEQ ID NO: 124) and an antisense strand comprising 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' (SEQ ID NO: 125);
wherein a, c, g, and u are 2'-O-methyl adenosine-3'-phosphate, 2'-O-methyl cytidine-3'-phosphate, 2'-O-methyl guanosine-3'-phosphate, and 2'-O-methyl uridine-3'-phosphate, respectively;
Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;
(Agn) is adenosine glycol nucleic acid (GNA);
s is a phosphorothioate linkage;
L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl]-4-hydroxyprolinol;
The method according to any one of items 151 to 159 and 166 to 173.
(Item 176)
the siRNA has a sense strand comprising 5'-gsgsuggaCfuUfCfUfcucaAfUfuuuaL96-3' (SEQ ID NO: 126) and an antisense strand comprising 5'-usAfsaaaUfuGfAfgagaAfgUfccaccsasc-3' (SEQ ID NO: 127);
wherein a, c, g, and u are 2'-O-methyl adenosine-3'-phosphate, 2'-O-methyl cytidine-3'-phosphate, 2'-O-methyl guanosine-3'-phosphate, and 2'-O-methyl uridine-3'-phosphate, respectively;
Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;
s is a phosphorothioate linkage;
L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl]-4-hydroxyprolinol;
174. The method, composition for use, or use according to any one of items 151 to 153 and 160 to 173.
(Item 177)
177. The method of any one of claims 137-176, wherein the subject is a human and a therapeutically effective amount of an RNAi agent or siRNA is administered to the subject; and the effective amount of the RNAi agent or siRNA is from about 1 mg/kg to about 8 mg/kg.
(Item 178)
178. The method of any one of paragraphs 137-177, wherein the RNAi agent or siRNA is administered to the subject twice a day, once a day, every second day, every third day, twice a week, once a week, every other week, every four weeks, or once a month.
(Item 179)
178. The method of any one of claims 137-177, wherein the RNAi agent or siRNA is administered to the subject every four weeks.
(Item 180)
179. The method of any one of items 151-179, wherein two siRNAs, each directed to an HBV gene, are administered, wherein a first siRNA has an antisense strand comprising SEQ ID NO:119, SEQ ID NO:120, or SEQ ID NO:126; and a second siRNA comprises an siRNA having a sense strand comprising at least 15 contiguous nucleotides of nucleotides 2850-3182 of SEQ ID NO:116.
(Item 181)
180. The method of any one of items 151 to 179, wherein two siRNAs directed to HBV genes are administered, said two siRNAs comprising an siRNA directed to the HBV X gene and an siRNA directed to the HBV S gene.
(Item 182)
179. The method of any one of items 151 to 179, wherein two siRNAs, each directed to an HBV gene, are administered, a first siRNA having an antisense strand comprising SEQ ID NO: 119, SEQ ID NO: 123, or SEQ ID NO: 125; and a second siRNA having an antisense strand comprising SEQ ID NO: 121 or SEQ ID NO: 127.
(Item 183)
182. The method of claim 181, wherein the first siRNA has a sense strand comprising SEQ ID NO:118, SEQ ID NO:122, or SEQ ID NO:124; and the second siRNA has a sense strand comprising SEQ ID NO:120 or SEQ ID NO:126.
(Item 184)
184. The method of any one of items 179 to 183, wherein the two siRNAs are administered simultaneously.
(Item 185)
185. The method of any one of claims 137 to 184, further comprising administering a nucleotide analog to the subject, or wherein the subject is also administered a nucleotide analog.
(Item 186)
186. The method, composition for use, or use according to item 185, wherein said nucleotide analog is tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), lamivudine, adefovir dipivoxil, entecavir (ETV), telbivudine, AGX-1009, emtricitabine (FTC), clevudine, ritonavir, dipivoxil, lobucavir, famvir, N-acetyl-cysteine (NAC), PC1323, theradigm-HBV, thymosin-alpha, and ganciclovir, besifovir (ANA-380/LB-80380), or tenofvir-exaliades (TLX/CMX157).

Claims (30)

(i) a heavy chain variable region (VH) comprising a CDRH1 amino acid sequence set forth in SEQ ID NO: 34, a CDRH2 amino acid sequence set forth in SEQ ID NO: 35 or 36, and a CDRH3 amino acid sequence set forth in SEQ ID NO: 37; and (ii) a light chain variable region (VL) comprising a CDRL1 amino acid sequence set forth in any one of SEQ ID NOs: 40-43, a CDRL2 amino acid sequence set forth in any one of SEQ ID NOs: 49, 44-48, and 50-53, and a CDRL3 amino acid sequence set forth in SEQ ID NO: 55 or 56.
1. An antibody, or antigen-binding fragment thereof, comprising:
The CDRs are defined according to the CCG numbering system,
The antibody or antigen-binding fragment thereof is capable of binding to an antigenic loop region of HBsAg and, optionally, neutralizing infection by Hepatitis B virus (HBV) of genotypes D, A, B, C, E, F, G, H, I, or J, or any combination thereof, with the proviso that the antibody or antigen-binding fragment does not comprise the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in SEQ ID NOs: 34, 35, 37, 41, 44, and 45, respectively. the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences being
(i) SEQ ID NOs: 34, 35, 37, 41, 49, and 55, respectively;
(ii) SEQ ID NOs: 34, 35, 37, 41, 46, and 55, respectively;
(iii) SEQ ID NOs: 34, 35, 37, 41, 47, and 55, respectively;
(iv) SEQ ID NOs: 34, 35, 37, 41, 48, and 55, respectively;
(v) SEQ ID NOs: 34, 35, 37, 41, 45, and 55, respectively;
(vi) SEQ ID NOs: 34, 35, 37, 41, 50, and 55, respectively;
(vii) SEQ ID NOs: 34, 35, 37, 41, 51, and 55, respectively;
(viii) SEQ ID NOs: 34, 35, 37, 41, 52, and 55, respectively;
(ix) SEQ ID NOs: 34, 35, 37, 41, 53, and 55, respectively; or (x) SEQ ID NOs: 34, 35, 37, 41, 44, and 55, respectively.
The antibody or antigen-binding fragment of claim 1 , (v) SEQ ID NOs: 38 and 63, respectively; (vii) SEQ ID NOs: 38 and 64, respectively; (viii) SEQ ID NOs: 38 and 65, respectively; (ix) SEQ ID NOs: 38 and 66, respectively; (x) SEQ ID NOs: 38 and 71, respectively; or (xi) SEQ ID NOs: 38 and 72, respectively ; and/or
The VH and the VL are
(i) SEQ ID NOs: 38 and 62, respectively;
(ii) SEQ ID NOs: 38 and 59, respectively;
(iii) SEQ ID NOs: 38 and 60, respectively;
(iv) SEQ ID NOs: 38 and 61, respectively;
(v) SEQ ID NOs: 38 and 58, respectively;
(vi) SEQ ID NOs: 38 and 63, respectively;
(vii) SEQ ID NOs: 38 and 64, respectively;
(viii) SEQ ID NOs: 38 and 65, respectively;
(ix) SEQ ID NOs: 38 and 66, respectively;
(x) SEQ ID NOs: 38 and 71, respectively; or
(xi) SEQ ID NOs: 38 and 72, respectively
and/or
Preferably, the VH and the VL are
(i) SEQ ID NOs: 38 and 62, respectively;
(ii) SEQ ID NOs: 38 and 66, respectively;
(iii) SEQ ID NOs: 38 and 67, respectively;
(iv) SEQ ID NOs: 38 and 68, respectively; or
(v) SEQ ID NOs: 38 and 72, respectively
comprising or consisting of the amino acid sequence set forth in
Optionally, the antibody or antigen-binding fragment is capable of neutralizing infection by Hepatitis D virus (HDV). 1. An antibody or antigen-binding fragment comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and the VL are
(i) SEQ ID NOs: 38 and 62, respectively;
(ii) SEQ ID NOs: 38 and 66, respectively;
(iii) SEQ ID NOs: 38 and 67, respectively;
(iv) SEQ ID NOs: 38 and 68, respectively; or (v) SEQ ID NOs: 38 and 72, respectively.
comprising or consisting of the amino acid sequence set forth in
The antibody or antigen-binding fragment thereof is capable of binding to an antigenic loop region of HBsAg and is capable of neutralizing infection by Hepatitis B virus (HBV) of genotypes D, A, B, C, E, F, G, H, I, or J, or any combination thereof. and/or wherein when a sample comprising a plurality of said antibodies or antigen-binding fragments is incubated at about 40° C. for about 120 to about 168 hours, said sample comprises less than 12%, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, or 2% or less of said plurality as dimers, optionally wherein the presence of dimers is determined by absolute size exclusion chromatography ; and/or
incubation of a plurality of said antibodies or antigen-binding fragments results in a reduction in dimer formation compared to incubation of a plurality of reference antibodies or antigen-binding fragments;
the reference antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in the amino acid sequences set forth in SEQ ID NOs: 34, 35, 37, 41, 44, and 55, respectively, and optionally comprises the VH amino acid sequence set forth in SEQ ID NO: 38 and the VL amino acid sequence set forth in SEQ ID NO: 57;
Optionally, the presence of antibody dimers is determined by absolute size exclusion chromatography; and/or
the reference antibody or antigen-binding fragment is
(i) at 4° C. for 5 days, 15 days, and/or 32 days of incubation;
(ii) at 25° C. for 5 days, 15 days, and/or 32 days of incubation; and/or
(iii) upon incubation at 40° C. for 5 days, 15 days, and/or 32 days,
forms a lower amount of dimers and/or forms dimers at a reduced frequency and/or as a lower percentage of the total antibody or antigen-binding fragment molecules in the sample or composition compared to a reference antibody;
the reference antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in the amino acid sequences set forth in SEQ ID NOs: 34, 35, 37, 41, 44, and 55, respectively, and optionally comprises the VH amino acid sequence set forth in SEQ ID NO: 38 and the VL amino acid sequence set forth in SEQ ID NO: 57;
An antibody or antigen-binding fragment according to any one of claims 1 to 4 . the antibody or antigen-binding fragment thereof comprises a human antibody, a monoclonal antibody, a purified antibody, a single chain antibody, a Fab, a Fab', a F(ab')2, an Fv, or a scFv ; and/or
The antibody or antigen-binding fragment of any one of claims 1 to 5 , wherein the antibody or antigen-binding fragment is a multispecific antibody, a bispecific antibody, or an antigen-binding fragment . the antibody or antigen-binding fragment comprises an Fc portion ; and/or
the Fc portion comprises a mutation that enhances binding to FcRn compared to a reference Fc portion, and the reference Fc portion does not comprise the mutation;
the Fc portion comprises a mutation that enhances binding to an FcγR, preferably FcγRIIA and/or FcγRIIIA, compared to a reference Fc portion, and the reference Fc portion does not comprise said mutation; and/or
7. The antibody or antigen-binding fragment of claim 1 , wherein the Fc portion is of an IgG isotype, such as IgG1, or is derived from an IgG isotype, such as IgG1, optionally comprising or derived from IgG1m17,1 (IgHG1 ^* 01 ) . The mutation that enhances binding to FcRn is
(i) M428L/N434S;
(ii) M252Y/S254T/T256E;
(iii) T250Q/M428L;
(iv) P257I/Q311I;
(v) P257I/N434H;
(vi) D376V/N434H;
(vii) T307A/E380A/N434A; or (viii) any combination of (i)-(vii),
the amino acid numbering of the Fc portion is according to the EU numbering system ; and/or
The mutations that enhance binding to FcRn include M428L/N434S; and/or
the mutations that enhance binding to FcγR include S239D; I332E; A330L; G236A; or any combination thereof, and the amino acid numbering of the Fc portion is according to the EU numbering system; and/or
The mutation that enhances binding to FcγR is
(i) S239D/I332E;
(ii) S239D/A330L/I332E;
(iii) G236A/S239D/I332E; or
(iv) G236A/A330L/I332E
and/or
the mutations that enhance binding to an FcγR comprise or consist of G236A/A330L/I332E, optionally wherein the antibody or antigen-binding fragment does not comprise S239D, and optionally wherein the antibody or antigen-binding fragment further comprises a native S at position 239; and/or
8. The antibody or antigen-binding fragment of claim 7 , wherein the Fc portion comprises the amino acid substitution mutations: M428L; N434S; G236A; A330L; and I332E, and optionally does not include S239D. a light chain constant region (CL) comprising or consisting of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO:79 ; and/or
9. The antibody or antigen-binding fragment of any one of claims 1 to 8, comprising a CH1-CH2-CH3 that comprises or consists of an amino acid sequence having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 73, or a variant thereof comprising one or more of the following amino acid substitutions (EU numbering): G236A; A330L; I332E; M428L; N434S, optionally with the C-terminal lysine removed from said CH1-CH2-CH3 . 1. An antibody comprising a heavy chain (HC) comprising or consisting of the amino acid sequence set forth in SEQ ID NO:75, optionally with the C-terminal lysine removed, and a light chain (LC) comprising or consisting of (i) a VL amino acid sequence set forth in any one of SEQ ID NOs:62, 58-61, and 63-72, and (ii) a CL amino acid sequence set forth in SEQ ID NO :79, wherein preferably said LC comprises a VL amino acid sequence set forth in any one of SEQ ID NOs:62, 66, 67, and 72 . A polynucleotide comprising a nucleotide sequence encoding the antibody or antigen-binding fragment of any one of claims 1 to 10 , wherein, optionally, the nucleotide sequence encoding the antibody or antigen-binding fragment is codon-optimized for expression in a host cell . A polynucleotide encoding the light chain variable region (VL) and optionally the light chain constant domain (CL) of the antibody or antigen-binding fragment according to any one of claims 1 to 10 . comprises a nucleotide sequence having at least 50% identity to the nucleotide sequence set forth in any one of SEQ ID NOs: 89, 85-88, and 90-99 ; and/or
(i) a polynucleotide sequence set forth in SEQ ID NO:81 or SEQ ID NO:82, and (ii) a polynucleotide sequence set forth in any one or more of SEQ ID NOs:89, 85-88, and 90-99; and/or
(i) the polynucleotide sequence set forth in SEQ ID NO: 83, and (ii) the polynucleotide sequence set forth in any one or more of SEQ ID NOs: 89, 85-88, and 90-99; and/or
13. The polynucleotide of claim 11 or claim 12, comprising: (i) the polynucleotide sequence set forth in SEQ ID NO: 84; and (ii) the polynucleotide sequence set forth in any one or more of SEQ ID NOs: 89, 85-88, and 90-99. A vector comprising a polynucleotide according to any one of claims 11 to 13 , optionally comprising a lentiviral or retroviral vector . A host cell comprising a polynucleotide according to any one of claims 11 to 13 and/or a vector according to claim 14 . (i) an antibody or antigen-binding fragment according to any one of claims 1 to 10 ;
(ii) a polynucleotide according to any one of claims 11 to 13 ;
(iii) the vector according to claim 14 ;
(iv) a host cell according to claim 15 ; or (v) any combination of (i)-(iv), and a pharma- ceutically acceptable excipient, diluent or carrier. (a)
(i) an antibody or antigen-binding fragment according to any one of claims 1 to 10 ;
(ii) a polynucleotide according to any one of claims 11 to 13 ;
(iii) the vector according to claim 14 ;
(iv) a host cell according to claim 15 ;
(v) a pharmaceutical composition according to claim 16 ; or (vi) a member selected from any combination of (i) to (vi); and (b)
(1) instructions for using the components to prevent, treat, attenuate, and/or diagnose Hepatitis B and/or Hepatitis D infection; and/or (2) a means for administering the components to a subject, e.g., a syringe. A method for producing an antibody or antigen-binding fragment of any one of claims 1 to 10 , comprising culturing a host cell of claim 15 under conditions and for a time sufficient to produce the antibody or antigen-binding fragment. A composition for treating, preventing, and/or attenuating Hepatitis B and/or Hepatitis D infection in a subject, comprising an effective amount of: (i) an antibody or antigen-binding fragment of any one of claims 1 to 10 ; (ii) a polynucleotide of any one of claims 11 to 13 ; (iii) a vector of claim 14 ; (iv) a host cell of claim 15 ; and/or (v) a pharmaceutical composition of claim 16 . (1) the composition is for administration to the subject with one or more of: (vi) a polymerase inhibitor, optionally including lamivudine, adefovir, entecavir, telbivudine, tenofovir, or any combination thereof; (vii) an interferon, optionally including IFN beta and/or IFN alpha; (viii) a checkpoint inhibitor, optionally including an anti-PD-1 antibody or antigen-binding fragment thereof, an anti-PD-L1 antibody or antigen-binding fragment thereof, and/ or an anti-CTLA4 antibody or antigen-binding fragment thereof; (ix) an agonist of a stimulatory immune checkpoint molecule; or (x) any combination of (vi)-(ix) ; and/or
(2) the hepatitis B virus infection is a chronic hepatitis B virus infection; and/or
(3) the subject has undergone a liver transplant; and/or
(4) the subject has not been immunized against Hepatitis B virus; and/or
(5) the subject is a newborn; and/or
(6) The composition for use according to claim 19 , wherein the subject is undergoing or has undergone hemodialysis . the composition is for administration to the subject as a single dose of a pharmaceutical composition comprising the antibody or antigen-binding fragment; and/or
the single dose of the pharmaceutical composition comprises the antibody in the range of 2-18 mg/kg (subject body weight); and/or
wherein the single dose of the pharmaceutical composition comprises up to 6 mg, up to 10 mg, up to 15 mg, up to 18 mg, up to 25 mg, up to 30 mg, up to 35 mg, up to 40 mg, up to 45 mg, up to 50 mg, up to 55 mg, up to 60 mg, up to 75 mg, up to 90 mg, up to 300 mg, up to 900 mg, or up to 3000 mg of the antibody; or
or wherein said single dose of said pharmaceutical composition comprises said antibody in an amount within the range of 1 mg to 3000 mg, or within the range of 5 mg to 3000 mg, or within the range of 10 mg to 3000 mg, or within the range of 25 mg to 3000 mg, or within the range of 30 mg to 3000 mg, or within the range of 50 mg to 3000 mg, or within the range of 60 mg to 3000 mg, or within the range of 75 mg to 3000 mg, or within the range of 90 mg to 3000 mg, or within the range of 100 mg to 3000 mg, or within the range of 150 mg to 3000 mg, or within the range of 200 mg to 3000 mg, or within the range of 300 mg to 3000 mg, or within the range of 500 mg to 3000 mg, or within the range of 750 mg to 3000 mg, or within the range of 900 mg to 3000 mg, or within the range of 1500 mg to 3000 mg, or within the range of 2000 mg to 3000 mg;
or wherein said single dose of said pharmaceutical composition comprises said antibody in an amount within the range of 1 mg to 900 mg, or within the range of 5 mg to 900 mg, or within the range of 10 mg to 900 mg, or within the range of 25 mg to 900 mg, or within the range of 30 mg to 900 mg, or within the range of 50 mg to 900 mg, or within the range of 60 mg to 900 mg, or within the range of 75 mg to 900 mg, or within the range of 90 mg to 900 mg, or within the range of 100 mg to 900 mg, or within the range of 150 mg to 900 mg, or within the range of 200 mg to 900 mg, or within the range of 300 mg to 900 mg, or within the range of 500 mg to 900 mg, or within the range of 750 mg to 900 mg;
or wherein the single dose of the pharmaceutical composition comprises the antibody in an amount such that the single dose of the pharmaceutical composition comprises the antibody in an amount within the range of 1 mg to 500 mg, or within the range of 5 mg to 500 mg, or within the range of 10 mg to 500 mg, or within the range of 25 mg to 500 mg, or within the range of 30 mg to 500 mg, or within the range of 50 mg to 500 mg, or within the range of 60 mg to 500 mg, or within the range of 75 mg to 500 mg, or within the range of 90 mg to 500 mg, or within the range of 100 mg to 500 mg, or within the range of 150 mg to 500 mg, or within the range of 200 mg to 500 mg, or within the range of 300 mg to 500 mg, or within the range of 400 mg to 500 mg;
wherein said single dose of said pharmaceutical composition comprises said antibody in an amount within the range of 1 mg to 300 mg, or within the range of 5 mg to 300 mg, or within the range of 10 mg to 300 mg, or within the range of 25 mg to 300 mg, or within the range of 30 mg to 300 mg, or within the range of 50 mg to 300 mg, or within the range of 60 mg to 300 mg, or within the range of 75 mg to 300 mg, or within the range of 90 mg to 300 mg, or within the range of 100 mg to 300 mg, or within the range of 150 mg to 300 mg, or within the range of 200 mg to 300 mg;
wherein said single dose of said pharmaceutical composition comprises said antibody in an amount within the range of 1 mg to 200 mg, or within the range of 5 mg to 200 mg, or within the range of 10 mg to 200 mg, or within the range of 25 mg to 200 mg, or within the range of 30 mg to 200 mg, or within the range of 50 mg to 200 mg, or within the range of 60 mg to 200 mg, or within the range of 75 mg to 200 mg, or within the range of 90 mg to 200 mg, or within the range of 100 mg to 200 mg, or within the range of 150 mg to 200 mg;
wherein said single dose of said pharmaceutical composition comprises said antibody in an amount within the range of 1 mg to 100 mg, or within the range of 5 mg to 100 mg, or within the range of 10 mg to 100 mg, or within the range of 25 mg to 100 mg, or within the range of 30 mg to 100 mg, or within the range of 50 mg to 100 mg, or within the range of 60 mg to 100 mg, or within the range of 75 mg to 100 mg, or within the range of 75 mg to 100 mg, or within the range of 90 mg to 100 mg; or
wherein the single dose of the pharmaceutical composition comprises the antibody in an amount in the range of 1 mg to 25 mg, or in the range of 5 mg to 25 mg, or in the range of 10 mg to 25 mg, or in the range of 15 mg to 25 mg, or in the range of 20 mg to 25 mg; or
wherein the single dose of the pharmaceutical composition comprises the antibody in an amount within the range of 1 mg to 50 mg, or within the range of 1 mg to 25 mg, or within the range of 5 mg to 50 mg, or within the range of 5 mg to 25 mg, or within the range of 10 mg to 50 mg, or within the range of 10 mg to 25 mg, or within the range of 1 mg to 15 mg, or within the range of 5 mg to 15 mg, or within the range of 10 mg to 15 mg;
wherein the single dose of the pharmaceutical composition is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, or 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1000 mg or more of said antibody;
the single dose of the pharmaceutical composition contains the antibody in an amount of less than 3000 mg, less than 2500 mg, less than 2000 mg, less than 1500 mg, less than 1000 mg, less than 900 mg, less than 500 mg, less than 300 mg, less than 200 mg, less than 100 mg, less than 90 mg, less than 75 mg, less than 50 mg, less than 25 mg, or less than 10 mg, but greater than 1 mg, greater than 2 mg, greater than 3 mg, greater than 4 mg, or greater than 5 mg; and/or
21. The composition for use according to claim 19 or claim 20, wherein the single dose of the pharmaceutical composition comprises the antibody at a concentration in the range of 100 mg/mL to 200 mg/mL, for example 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, 190 mg/mL, or 200 mg/mL, preferably 150 mg/ mL . 11. A pharmaceutical composition comprising the antibody or antigen-binding fragment of any one of claims 1 to 10 at a concentration in the range of 100 mg/mL to 200 mg/mL, e.g., 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, 190 mg/mL, or 200 mg/mL, preferably 150 mg/mL , and a pharma- ceutically acceptable carrier, excipient, or diluent. the pharmaceutical composition comprises water, optionally USP water ; and/or
the pharmaceutical composition optionally comprises histidine in the pharmaceutical composition at a concentration of 10 mM to 40 mM, e.g., 20 mM; and/or
the pharmaceutical composition optionally comprises a disaccharide, e.g., sucrose, at 5%, 6%, 7%, 8%, or 9%, preferably about 7% (w/v); and/or
the pharmaceutical composition comprises a surfactant, optionally a polysorbate, preferably polysorbate 80 (PS80), optionally wherein the polysorbate is present in the range of 0.01% to 0.05% (w/v), preferably 0.02% (w/v); and/or
The pharmaceutical composition has a pH in the range of 5.8 to 6.2, in the range of 5.9 to 6.1, or of 5.8, 5.9, 6.0, 6.1, or 6.2; preferably, the pharmaceutical composition has
(i) 150 mg/mL of the antibody;
(ii) USP Water;
(iii) 20 mM histidine;
(iv) 7% sucrose; and
(v) 0.02%PS80
23. The pharmaceutical composition of claim 22 , wherein the pharmaceutical composition comprises a pH of 6 . 24. The pharmaceutical composition of claim 22 or claim 23, wherein the pharmaceutical composition is a liquid solution; and/or the pharmaceutical composition is formulated for injection via a prefilled syringe. 1. A method for providing a detected result for use in the in vitro diagnosis of Hepatitis B infection , comprising:
(i) contacting a sample from a subject with the antibody or antigen-binding fragment of any one of claims 1 to 10 ; and (ii) detecting a complex comprising an antigen and the antibody, or a complex comprising an antigen and the antigen-binding fragment. 1. A method for detecting the presence or absence of an epitope in a precise conformation in an anti-Hepatitis B vaccine , comprising:
(i) contacting the vaccine with an antibody or antigen-binding fragment of any one of claims 1 to 10 ; and (ii) determining whether a complex comprising an antigen and the antibody, or a complex comprising an antigen and the antigen-binding fragment, is formed. 11. A composition for treating chronic HBV and/or HDV infection in a subject in need thereof, said composition comprising an antibody or antigen-binding fragment of any one of claims 1 to 10,
The subject is also to be administered an agent that reduces HBV antigen load and/or inhibits HBV gene expression ;
the agent that reduces HBV antigen load and/or inhibits HBV gene expression is an RNAi agent;
the RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region, the sense strand comprising at least 15 contiguous nucleotides that differ by no more than 3 nucleotides from nucleotides 1579-1597 of SEQ ID NO: 116; and/or
A composition wherein the agent that reduces HBV antigen load and/or inhibits HBV gene expression is an RNAi agent, the RNAi agent comprising a sense strand and an antisense strand, the sense strand comprising nucleotides 1579-1597 of SEQ ID NO:116 . An antibody or antigen-binding fragment comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and the VL comprise or consist of the amino acid sequences set forth in SEQ ID NOs: 38 and 62, respectively;
The antibody or antigen-binding fragment thereof is capable of binding to an antigenic loop region of hBsAg and is capable of neutralizing infection by Hepatitis B virus (HBV) of genotypes D, A, B, C, E, F, G, H, I, or J, or any combination thereof, and/or is capable of neutralizing infection by Hepatitis D virus (HDV). A composition for treating chronic HBV and/or HDV infection in a subject in need thereof, comprising an anti-HBV antibody described in claim 28. 29. A composition for treating chronic HBV and/or HDV infection in a subject in need thereof, the composition comprising the anti-HBV antibody of claim 28 and for use in a combination therapy in which the subject is administered an siRNA,
The siRNA has a sense strand comprising 5'-gsusguGfcAfCfUfucgcuucacaL96-3' (SEQ ID NO: 124) and an antisense strand comprising 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' (SEQ ID NO: 125);
wherein a, c, g, and u are 2'-O-methyl adenosine-3'-phosphate, 2'-O-methyl cytidine-3'-phosphate, 2'-O-methyl guanosine-3'-phosphate, and 2'-O-methyl uridine-3'-phosphate, respectively;
Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;
s is a phosphorothioate linkage;
L96,

That is,
Composition.