Reshaped human to human interleukin-6 receptor

• US 5,795,965 A
• Filed: 12/20/1993
• Issued: 08/18/1998
• Est. Priority Date: 04/25/1991
• Status: Expired due to Term

• Current Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Original Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Inventors: Tsuchiya, Masayuki, Saldanha, Jose William, Sato, Koh, Bendig, Mary Margaret, Jones, Steven Tarran
• Primary Examiner(s): Feisee, Lila
• Assistant Examiner(s): Bansal, Geetha P.
• Application Number:
  US08/137,117
• Time in Patent Office: 1,702 Days
• Field of Search: 530/387.3, 530/388.22, 530/388.73
• US Class Current: 530/387.3
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

A reshaped human antibody to the human IL-6R, comprising:

(A) an L chain comprising,

(1) a human L chain C region, and

(2) an L chain V region comprising human L chain framework regions (FRs), and mouse L chain complementary determination regions (CDRS) of a momoclonal antibody to the IL-6 receptor (IL-6R); and

(B) an H chain comprising,

(1) a human H chain C region, and

(2) an H chain V region comprising human H chain FRs, and mouse H chain CDRs of a monoclonal antibody to the IL-6R.

Since major portion of the reshaped human antibody is derived from a human antibody and the mouse CDRs which are less immunogenic, the present reshaped human antibody is less immunogenic to human, and therefor is promised for therapeutic uses.

Claims

1. A variable (V) region of a heavy (H) chain of an antibody to the human IL-6 receptor having the following structure:

FR1² -CDR1² -FR2² -CDR2² -FR3² -CDR3² -FR4²

wherein CDR1², CDR2² and CDR3² represent a set of three complementarity determining regions comprising a set of the following amino acid sequences shown by;

space="preserve" listing-type="tabular">__________________________________________________________________________SEQ ID No. 125 CDR1.sup.2 Ser Asp His Ala Trp Ser SEQ ID No. 126 CDR2.sup.2 Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser SEQ ID No. 127 CDR3.sup.2 Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr;

__________________________________________________________________________

and

FR1², FR2², FR3² and FR4² comprise a set of the following amino acid sequences;

space="preserve" listing-type="tabular">__________________________________________________________________________SEQ ID No. 135 FR1.sup.2 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr SEQ ID No. 129 FR2.sup.2 Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly SEQ ID No. 132 FR3.sup.2 Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg SEQ ID No. 131 FR4.sup.2 Trp Gly Gln Gly Ser Leu Val Thr Val Ser Ser. __________________________________________________________________________

2. An H chain of an antibody to the human IL- 6 receptor, comprising:

(1) a V region of a heavy chain of an antibody to the human IL-6 receptor having the following structure;

FR1² -CDR1² -FR2² -CDR2² -FR3² -CDR3² -FR4²

wherein CDR1², CDR2² and CDR3² represent a set of three complementarity determining regions comprising a set of the following amino acid sequences;

space="preserve" listing-type="tabular">__________________________________________________________________________SEQ ID No. 125 CDR1.sup.2 Ser Asp His Ala Trp Ser SEQ ID No. 126 CDR2.sup.2 Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser SEQ ID No. 127 CDR3.sup.2 Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr;

__________________________________________________________________________

and FR1², FR2², FR3² and FR4² comprise a set of the following amino acid sequences;

space="preserve" listing-type="tabular">__________________________________________________________________________SEQ ID No. 135 FR1.sup.2 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr SEQ ID No. 129 FR2.sup.2 Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly SEQ ID No. 132 FR3.sup.2 Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg SEQ ID No. 131 FR4.sup.2 Trp Gly Gln Gly Ser Leu Val Thr Val Ser Ser;

__________________________________________________________________________

and

(2) a C region of an H chain of a human antibody Cγ

.

3. A reshaped human antibody to the human IL-6 receptor, comprising

(A) L chains of an antibody to said human IL-6 receptor, each comprising:

(1) a variable (V) region of a light (L) chain of an antibody to the human IL-6 receptor having the following structure;

FR1¹ -CDR1¹ -FR2¹ -CDR2¹ -FR3¹ -CDR3¹ -FR4¹

wherein CDR1₁, CDR2¹ and CDR3¹ represent a set of three complementarity determining regions comprising a set of the following amino acid sequences;

##STR21## and the FR1¹, FR2¹, FR3¹ and FR4¹ comprise a set of the following amino acid sequences;

##STR22## and (2) a C region of an L chain of a human antibody Cκ

; and

N

(B) H chains of an antibody to the human IL-6 receptor, each comprising;

(1) a V region of a heavy (H) chain of an antibody to the human IL-6 receptor having the following structure;

FR1² -CDR1² -FR2² CDR2² -FR3² -CDR3² -FR4²

wherein CDR1₂ CDR2² and CDR3² represent a set of three complementarity determining regions comprising a set of the amino acid sequences shown by;

##STR23## and the FR1², FR2², FR3² and FR4² comprise a set of the following amino acid sequences;

##STR24## and (2) a C region of an H chain of a human antibody Cγ

.

4. A V region of a heavy (H) chain of an antibody to the human IL-6 receptor having the following structure:

FR1⁴ -CDR1⁴ -FR2⁴ -CDR2⁴ -FR3⁴ -CDR3⁴ -FR4⁴

wherein CDR1⁴, CDR2⁴ and CDR3⁴, represent a set of three complementarity determining regions comprising a set of the following amino acid sequences;

space="preserve" listing-type="tabular">__________________________________________________________________________SEQ ID No. 143 CDR1.sup.4 Ser Tyr Tyr Ile His SEQ ID No. 144 CDR2.sup.4 Tyr Ile Asp Pro Phe Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys Gly SEQ ID No. 145 CDR3.sup.4 Gly Gly Asn Arg Phe Ala Tyr;

__________________________________________________________________________

and

the FR1⁴, FR2 4, FR3⁴ and FR4⁴ comprise a set of the following amino acid sequences;

space="preserve" listing-type="tabular">__________________________________________________________________________SEQ ID No. 146 FR1.sup.4 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr SEQ ID No. 147 FR2.sup.4 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val Gly SEQ ID No. 150 FR3.sup.4 Lys Val Thr Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Gly Asp Thr Ala Val Tyr Tyr Cys Ala Arg SEQ ID No. 149 FR4.sup.4 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser;

SEQ ID No. 146 FR1.sup.4 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr SEQ ID No. 151 FR2.sup.4 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly SEQ ID No. 150 FR3.sup.4 Lys Val Thr Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg SEQ ID No. 149 FR4.sup.4 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser;

SEQ ID No. 152 FR1.sup.4 Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Gly SEQ ID No. 155 FR2.sup.4 Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Gly SEQ ID No. 154 FR3.sup.4 Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg SEQ ID No. 149 FR4.sup.4 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser;

SEQ ID No. 152 FR1.sup.4 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr SEQ ID No. 153 FR2.sup.4 Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met Gly SEQ ID No. 156 FR3.sup.4 Lys Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg SEQ ID No. 149 FR4.sup.4 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser;

or SEQ ID No. 152 FR1.sup.4 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr SEQ ID No. 155 FR2.sup.4 Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Gly SEQ ID No. 156 FR3.sup.4 Lys Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg SEQ ID No. 149 FR4.sup.4 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser. __________________________________________________________________________

5. An H chain of an antibody to the human IL- 6 receptor, comprising:

(1) a V region of heavy (H) chain of an antibody to the human IL-6 receptor having the following structure;

FR1⁴ -CDR1⁴ -FR2⁴ -CDR2⁴ -FR3⁴ -CDR3⁴ -FR4⁴

where CDR1⁴, CDR2⁴, and CDR3⁴ represent a set of three complementarity determining regions comprising a set of the following sequences shown by;

space="preserve" listing-type="tabular">__________________________________________________________________________SEQ ID No. 143 CDR1.sup.4 Ser Tyr Tyr Ile His SEQ ID No. 144 CDR2.sup.4 Tyr Ile Asp Pro Phe Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys Gly SEQ ID No. 145 CDR3.sup.4 Gly Gly Asn Arg Phe Ala Tyr;

__________________________________________________________________________

and

the FR1⁴, FR2⁴, FR3⁴, and FR4⁴ comprise a set of the following amino acid sequences;

space="preserve" listing-type="tabular">__________________________________________________________________________SEQ ID No. 146 FR1.sup.4 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr SEQ ID No. 147 FR2.sup.4 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val Gly SEQ ID No. 150 FR3.sup.4 Lys Val Thr Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg SEQ ID No. 149 FR4.sup.4 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser;

SEQ ID No. 146 FR1.sup.4 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr SEQ ID No. 151 FR2.sup.4 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly SEQ ID No. 150 FR3.sup.4 Lys Val Thr Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg SEQ ID No. 149 FR4.sup.4 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser;

SEQ ID No. 157 FR1.sup.4 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr SEQ ID No. 158 FR2.sup.4 Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Gly SEQ ID No. 154 FR3.sup.4 Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg SEQ ID No. 149 FR4.sup.4 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser;

SEQ ID No. 152 FR1.sup.4 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr SEQ ID No. 153 FR2.sup.4 Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met Gly SEQ ID No. 156 FR3.sup.4 Lys Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg SEQ ID No. 149 FR4.sup.4 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser;

or SEQ ID No. 152 FR1.sup.4 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr SEQ ID No. 155 FR2.sup.4 Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Gly SEQ ID No. 156 FR3.sup.4 Lys Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg SEQ ID No. 149 FR4.sup.4 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser;

__________________________________________________________________________

and

(2) a C region of an H chain of a human antibody Cγ

.

6. A reshaped human antibody to the human IL-6 receptor, comprising:

(A) L chains of an antibody to the human IL-6 receptor, each comprising;

(1) a variable (V) region of a light (L) chain of an antibody to the human IL-6 receptor having the following structure;

FR1³ -CDR1³ -FR2³ -CDR2³ -FR3³ -CDR3³ -FR4³

wherein CDR1³, CDR2³ and CDR3³ represent a set of three complementarity determining regions comprising a set of the following amino acid sequences;

##STR25## and FR1³, FR2³, FR3³ and FR4³ comprise a set of the following amino acid sequences;

##STR26## and (2) a C region of an L chain of a human antibody Cκ

; and

(B) H chains of an antibody to the human IL-6 receptor, each comprising;

(1) a V region of a heavy (H) chain of an antibody to the human IL-6 receptor having the following structure;

FR1⁴ -CDR1⁴ -FR2⁴ -CDR2⁴ -FR3⁴ -CDR3⁴ -FR4⁴

wherein CDR1⁴, CDR2⁴ and CDR3⁴ represent a set of three complementarity determining regions comprising a set of the following amino acid sequences;

##STR27## and FR1⁴, FR2⁴, PR3⁴ and FR4⁴ comprise a set of the following amino acid sequences;

##STR28## and (2) a C region of an H chain of a human antibody Cγ

.