Highly active agonistic CD4 binding site anti-HIV antibodies (HAADS) comprising modified CDRH2 regions that improve contact with GP120

Patent metadata

Field	Value
Publication number	US-9890207-B2
Application number	US-201213558312-A
Country	US
Kind code	B2
Filing date	Jul 25, 2012
Priority date	Jul 25, 2011
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

Abstract

Embodiments of the present invention are directed to compositions and methods for anti-HIV (anti-CD4 binding site) potent VRC01-like (PVL) antibodies targeted to gp120 having an amino acid substitution at a residue in the anti-CD4 binding site PVL antibody that is equivalent to Phe43 in CD4, these antibodies having improved potency and breadth.

First claim

What is claimed is:

1. A composition comprising an isolated human anti-CD4 binding site (anti-CD4bs) antibody variant having a light chain and a heavy chain, the heavy chain comprising an amino acid (X) substitution at position 54 selected from G54X, T54X, or S54X according to Kabat numbering, the amino acid (X) being selected from the group consisting of alanine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, valine, histidine, arginine, glutamine, asparagine, lysine, glutamic acid, and aspartic acid, the anti-CD4bs antibody variant comprising a variant group selected from the group consisting of a VRC01 related variant group, a 3BNC117 related variant group, a VRC-PG04 related variant group, a CH31 related variant group, and a 12A12 related variant group,
the VRC01 related variant group comprising:
a complementarity determining region (CDR) 1 of the heavy chain (CDRH1) having a sequence of Gly26-Tyr27-Glu28-Phe29-(lle/Leu)30-(Asn/Asp)31-Cys32 as set forth in SEQ ID NOs: 2 and 6;
a CDR 2 of the heavy chain (CDRH2) having a sequence of SEQ ID NO: 74 Lys52-Pro52A-Arg53-Gly54-Gly55-Ala56 as set forth in SEQ ID NOs: 2 and 6;
a CDR 3 of the heavy chain (CDRH3) having a sequence selected from:
Gly95-Lys96-(Asn/Tyr)97-Cys98-(Asp/Thr)99-Tyr100-Asn100A-Trp100B-Asp100C-Phe100D-Glu101-His102 as set forth in SEQ ID NO: 2 or Gly95-Lys96-(Asn/Tyr)97-Cys98-(Asp/Thr)99-Ala100-Arg100A-Asp100B-Tyr100C-Tyr100D-Asn100E-Tryp100F-Asp100G-Phe100H-Glu101-His102 as set forth in SEQ ID NO: 6;

a CDR 1 of the light chain (CDRL1) having a sequence of Arg24-Thr25-Ser26-Gln27-(Ser/Tyr)28-Gly29-Ser30-Leu33-Ala34 as set forth in SEQ ID NOs: 1 and 5;
a CDR 2 of the light chain (CDRL2) having a sequence of Ser50-Gly51-Ser52-Thr53-Arg54-Ala55-Ala56 as set forth in SEQ ID NOs: 1 and 5; and
a CDR 3 of the light chain (CDRL3) having a sequence of Gln89-Gln90-Tyr91-Glu96-Phe97 as set forth in SEQ ID NOs: 1 and 5,

the 3BNC117 related variant group comprising:
a CDRH1 having a sequence of Gly26-Tyr27-(Asn/Glu/Lys)28-lle29-(Arg/Ser)30-Asp31-(His/Tyr)32 as set forth in SEQ ID NOs: 8, 10, 12, 14, and 16;
a CDRH2 having a sequence of Asn52-Pro52A-Lys53-Thr54-Gly55-Gln56 as set forth in SEQ ID NOs: 8, 10, 12, 14, and 16;
a CDRH3 having a sequence of Gln95-Arg96-Ser97-Asp98-(Phe/Tyr)100A-Trp100B-Asp100C-Phe100D-Asp101-Val102 as set forth in SEQ ID NOs: 8, 10, 12, 14, and 16;
a CDRL1 having a sequence of Gln24-Ala25-Asn26-Gly27-Tyr28-Leu33-Asn34 as set forth in SEQ ID NOs: 7, 9, 11, 13, and 15;
a CDRL2 having a sequence of Asp50-Gly51-Ser52-Lys53-Leu54-Glu55-(Arg/Thr)56 as set forth in SEQ ID NOs: 7, 9, 11, 13, and 15; and
a CDRL3 having a sequence of Gln89-Val90-Tyr91-Glu96-Phe97 as set forth in SEQ ID NOs: 7, 9, 11, 13, and 15,

the VRC-PG04 related variant group comprising:
a CDRH1 having a sequence of Glu26-Asp27-lle28-Phe29-Glu30-Arg31-Thr32-Glu33 as set forth in SEQ ID NOs: 20, 46, and 59;
a CDRH2 having a sequence of Lys52-(Ala/Thr)52A-Val53-(Ser/Thr)54-Gly55-Ala56 as set forth in SEQ ID NOs: 20, 46, and 59;
a CDRH3 having a sequence selected from the group of Gln95-Lys96-Phe97-Tyr98-(Ala/Thr)99-Gly100-Gly100A-Gln100B-Gly100C-Trp100D-Tyr100E-Phe100F-Asp101-Leu102 as set forth in SEQ ID NOs: 20 and 46 Gln95-Lys96-Phe97-Glu98-Ser99-Arg100-Tyr100A-(Ala/Thr)100B-Gly100C-Gly100D-Gln100E-Gly100F-Trp100G-Tyr100H-Phe100l-Asp101-Leu102 as set forth in SEQ ID NO: 59;
a CDRL1 having a sequence of Thr24-Ala25-Ala26-Ser27-Tyr28-Gly29-His30-Met33-Thr34 as set forth in SEQ ID NO: 19;
a CDRL2 having a sequence of Ala50-Thr51-Ser52-Lys53-Arg54-Ala55-Ser56 as set forth in SEQ ID NO: 19; and
a CDRL3 having a sequence of Gln89-Gln90-Leu91-Glu96-Phe97,

the CH31 related variant group comprising as set forth in SEQ ID NO: 19:
a CDRH1 having a sequence of (Asp/Glu26)-(Ala/Asp)27-Asp28-Asp28A -(Phe/Trp/Tyr)28B-Ser28C-Pro28D-(His/Tyr)28E-Trp28F-(Met/Val)28G-Asn28H-Pro29-Ala30-Pro31-Glu32-His33 as set forth in SEQ ID NOs: 22, 24, 26, 28, and 30;
a CDRH2 having a sequence of (Asn/Lys)52-Pro52A-Thr53-Asn54-Gly55-Ala56 as set forth in SEQ ID NOs: 22, 24, 26, 28, and 30;
a CDRH3 having a sequence of Ala95-Gln96-Lys97-Arg98-(Ala/Gly)99-Arg100-Ser100A-Glu100B-Trp100C-Ala100D-Tyr100E-Ala101-His102 as set forth in SEQ ID NOs: 22, 24, 26, 28, and 30;
a CDRL1 having a sequence of Gln24-Ala25-Ser26-Arg27-Gly28-lle29-Gly30-Lys31-Asp32-Leu33-Asn34 as set forth in SEQ ID NOs: 21, 23, 25, 27, and 29;
a CDRL2 having a sequence of Asp50-Ala51-Ser52-(lle/Thr/Val)53-Leu54-Glu55-Gly56 as set forth in SEQ ID NOs: 21, 23, 25, 27, and 29; and
a CDRL3 having a sequence of Gln89-Gln90-Tyr91-Glu96-Thr97 as set forth in SEQ ID NOs: 21, 23, 25, 27, and 29, and

the 12A12 related variant group comprising:
a CDRH1 having a sequence of Gly26-Tyr27-Ser28-Phe29-Thr30-Asp31-Tyr32 as set forth in SEQ ID NO: 18;
a CDRH2 having a sequence of Lys52-Pro52A-Val53-Tyr54-Gly55-Ala56 as set forth in SEQ ID NO: 18;
a CDRH3 having a sequence of Asp95-Gly96-Ser97-Gly98-Asp99-Asp100-Thr100A-Ser100B-Trp100C-His100D-Leu100E-Asp101-Pro102 as set forth in SEQ ID NO: 18;
a CDRL1 having a sequence of Gln24-Ala25-Gly26-Gln27-Gly28-lle29-Gly30-Ser31-Ser32-Leu33-Gln34 as set forth in SEQ ID NO: 17;
a CDRL2 having a sequence of Gly50-Ala51-Ser52-Asn53-Leu54-His55-Arg56 as set forth in SEQ ID NO: 17; and
a CDRL3 having a sequence of Ala89-Val90-Leu91-Glu96-Phe97 as set forth in SEQ ID NO: 17,

wherein the CDRs are defined according to the Chothia definition.

2. The composition of claim 1 , wherein the heavy chain substitution is tryptophan, tyrosine, phenylalanine, histidine, arginine, glutamine, or asparagine.

3. The composition of claim 1 , wherein the human anti-CD4bs antibody is capable of binding to gp120 at positions corresponding to 279, 280, 368, 458, and 459 according to pdb code 3U7Y.

4. A pharmaceutical composition comprising the human anti-CD4bs antibody of claim 1 or a fragment thereof, and a pharmaceutically acceptable carrier.

5. A method of inhibiting an HIV infection or an HIV-related disease, comprising:
administering a therapeutically effective amount of the composition of claim 1 to a patient.

6. A composition comprising an isolated human anti-CD4 binding site (anti-CD4bs) antibody variant having a light chain and a heavy chain, the heavy chain comprising an amino acid (X) substitution at position 54 selected from G54X, T54X, or S54X according to Kabat numbering, the amino acid (X) being selected from the group consisting of alanine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, valine, histidine, arginine, glutamine, asparagine, lysine, glutamic acid, and aspartic acid, the anti-CD4bs antibody variant comprising a variant group selected from the group consisting of a VRC01 related variant group and a 3BNC117 related variant group,
the VRC01 related variant group comprising:
a complementarity determining region (CDR) 1 of the heavy chain (CDRH1) having a sequence of Gly26-Tyr27-Glu28-Phe29-(lle/Leu)30-(Asn/Asp)31-Cys32 as set forth in SEQ ID NOs: 2 and 6;
a CDR 2 of the heavy chain (CDRH2) having a sequence of Lys52-Pro52A-Arg53-Gly54-Gly55-Ala56 as set forth in SEQ ID NOs: 2 and 6;
a CDR 3 of the heavy chain (CDRH3) having a sequence selected from:
Gly95-Lys96-(Asn/Tyr)97-Cys98-(Asp/Thr)99-Tyr100-Asn100A -Trp100B-Asp100C-Phe100D-Glu101-His102 as set forth in SEQ ID NO: 2 or Gly95-Lys96-(Asn/Tyr)97-Cys98-(Asp/Thr)99-Ala100-Arg100A-Asp100B-Tyr100C-Tyr100D-Asn100E-Tryp100F-Asp100G-Phe100H-Glu101-His102 as set forth in SEQ ID NO: 6;

a CDR 1 of the light chain (CDRL1) having a sequence of Arg24-Thr25-Ser26-Gln27-(Ser/Tyr)28-Gly29-Ser30-Leu33-Ala34 as set forth in SEQ ID NOs: 1 and 5;
a CDR 2 of the light chain (CDRL2) having a sequence of Ser50-Gly51-Ser52-Thr53-Arg54-Ala55-Ala56 as set forth i

Assignees

• Diskin Ron
• Bjorkman Pamela J
• Nussenzweig Michel
• Scheid Johannes
• California Inst Of Techn
• Univ Rockefeller

Inventors

• Diskin Ron
• Bjorkman Pamela J
• Nussenzweig Michel
• Scheid Johannes

Classifications

• A61P31/18

  for HIV · CPC title

• C07K16/1145 Primary

  Env proteins, e.g. gp41, gp110/120, gp160, V3, principal neutralising domain [PND] or CD4-binding site · CPC title

• C07K2317/55

  Fab or Fab' · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title