P G K R P E W M G W L K P R G G A V N Y A R P L Q G R V T M T R D V Y S D T A F
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- Christopher Stokes
- 5 years ago
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1 Supplementary Figure 1 VRC H H H H Q V Q L V Q S G G Q M K K P G E S M R I S C R A S G Y E F I D C T L N W I R L A CAGGTGCAGCTGGTGCAGTCTGGGGGTCAGATGAAGAAGCCTGGCGAGTCGATGAGAATTTCTTGTCGGGCTTCTGGATATGAATTTATTGATTGTACGCTAAATTGGATTCGTCTGGCC Q V R L S Q S G G Q M K K P G D S M R I S C R A S G Y E F I N C P I N W I R L A CAGGTGCGACTGTCGCAGTCTGGAGGTCAGATGAAGAAGCCTGGCGACTCGATGAGAATTTCTTGTCGGGCTTCGGGATACGAATTTATTAATTGTCCAATAAATTGGATTCGGCTGGCC Q V R L S Q S G G Q M K K P G D S M R I S C R A S G Y E F I N C P I N W I R L A CAGGTGCGACTGTCGCAGTCTGGAGGTCAGATGAAGAAGCCTGGCGACTCGATGAGAATTTCTTGTCGGGCTTCGGGATACGAATTTATTAATTGTCCAATAAATTGGATTCGGCTGGCC Q V R L S Q S G G Q M K K P G E S M R I S C Q A S G Y E F I D C T L N W V R L A CAGGTGCGTCTGTCGCAGTCTGGAGGTCAGATGAAGAAGCCTGGCGAGTCCATGAGAATTTCTTGTCAGGCTTCCGGGTATGAATTTATTGACTGTACACTAAATTGGGTTCGCCTGGCC Q V R L S Q S G G Q M K K P G E S M R I S C R A S G Y E F I D C T L N W I R L A CAGGTGCGTCTGTCGCAGTCTGGAGGTCAGATGAAGAAGCCTGGCGAGTCGATGAGAATCTCTTGTCGGGCCTCCGGATATGAATTTATTGATTGTACTCTAAATTGGATTCGCCTGGCC VRC H H H H P G K R P E W M G W L K P R G G A V N Y A R P L Q G R V T M T R D V Y S D T A F CCCGGAAAAAGGCCTGAGTGGATGGGATGGCTGAAGCCTCGGGGGGGGGCCGTCAACTACGCACGTCCACTTCAGGGCAGAGTGACCATGACTCGAGACGTTTATTCCGACACAGCCTTT P G K R P E W M G W M K P R G G A V S Y A R Q L Q G R V T M T R D M Y S E T A F CCCGGAAAAAGGCCTGAGTGGATGGGATGGATGAAGCCTAGGGGGGGGGCCGTCAGTTACGCACGTCAACTTCAGGGCAGAGTGACCATGACTCGAGACATGTATTCCGAGACAGCCTTT P G K R P E W M G W M K P R G G A V S Y A R Q L Q G R V T M T R D M Y S E T A F CCCGGAAAAAGGCCTGAGTGGATGGGATGGATGAAGCCTAGGGGGGGGGCCGTCAGTTACGCACGTCAACTTCAGGGCAGAGTGACCATGACTCGAGACATGTATTCCGAGACAGCCTTT P G R R P E W M G W L K P R G G A V N Y A R I F Q G R V T M T R D V Y S D T A F CCCGGAAGAAGGCCTGAATGGATGGGATGGCTGAAGCCTCGGGGGGGGGCCGTCAACTACGCACGTATATTTCAAGGCAGAGTGACCATGACTCGAGACGTTTATTCCGACACAGCCTTT P G R R P E W M G W L K P R G G A V N Y A R V F Q G R V T M T R D V Y S D T A F CCCGGAAGAAGGCCTGAGTGGATGGGATGGCTGAAGCCTCGGGGGGGGGCCGTCAATTACGCACGTGTATTTCAGGGCAGAGTGACCATGACTCGAGACGTTTATTCCGACACAGCCTTT VRC H H H H L E L R S L T V D D T A V Y F C T R G K N C D Y N W D F E H W G R G T P TTGGAGCTGCGCTCGTTGACAGTAGACGACACGGCCGTCTACTTTTGTACTAGGGGAAAAAACTGTGAT TACAATTGGGACTTCGAACACTGGGGCCGGGGCACCCCG L E L R S L T S D D T A V Y F C T R G K Y C T A R D Y Y N W D F E H W G Q G T P TTGGAGCTCCGTTCCTTGACATCCGACGACACGGCCGTCTATTTTTGTACTCGGGGAAAATATTGCACTGCGCGCGACTATTATAATTGGGACTTCGAACACTGGGGCCAGGGCACCCCG L E L R S L T S D D T A V Y F C T R G K Y C T A R D Y Y N W D F E H W G Q G T P TTGGAGCTCCGTTCCTTGACATCCGACGACACGGCCGTCTATTTTTGTACTCGGGGAAAATATTGCACTGCGCGCGACTATTATAATTGGGACTTCGAACACTGGGGCCAGGGCACCCCG L E L R S L T A D D T A V Y F C T R G K N C D Y N W D F E H V G P G Y P TTGGAGCTGCGCTCCTTGACAGCAGACGACACGGCCGTCTACTTTTGTACTAGGGGAAAAAACTGTGAT TACAATTGGGACTTCGAACACGTGGGGCCCGGGTACCCG L E L R S L T A D D T A V Y F C T R G K T V D Y N W D F E H V G P G T P CTGGAGCTGCGGTCCTTGACAGCAGACGACACGGCCGTCTACTTTTGTACTAGGGGAAAAACTGTAGAT TACAATTGGGACTTCGAACACGTGGGGCCGGGAACCCCG VRC H H H H V I V S S GTCATCGTCTCATCA V T V S S GTCACCGTCTCGTCA V T V S S GTCACCGTCTCGTCA V T V S P GTCACCGTCTCACCA V T V S S GTCACCGTCTCATCA Supplementary Figure 1. Alignment of 454 pyrosequencing reads. A nucleotide alignment of four heavy chain sequences with high identity to VRC01, derived from 454 pyrosequencing of of B-cell transcripts from donor 45. Amino acids are shown above each codon. Two sequences ( H and H) were identical to each other and encoded a variable region with an extended CDR H3 compared to VRC01. Upon protein expression, this heavy chain, paired with the VRC01 light chain, was highly potent and broad. The resulting mab was named VRC07. 1
2 Supplementary Figure 2 IC 50 IC 80 Virus ID Clade b12 VRC01 NIH45-46 VRC07 b12 VRC01 NIH45-46 VRC v5.c36 A > > v4.c3 A > > v5.c1 A > > v2.c20 A > v1.c1 A v3.c11 A > F1_F6_20 A BB201.B42 A BB539.2B13 A BI369.9A A > BS208.B1 A KER A > > KER A > KNH A MB201.A1 A > > MB539.2B7 A > MI369.A5 A MS208.A1 A Q23.17 A > > Q A > > Q769.d22 A > > Q769.h5 A > > Q842.d12 A > > QH209.14M.A2 A > > RW020.2 A UG037.8 A > > V1.C24 AC > V1.C4 AC > > v4.c1 AC >50 >50 >50 >50 >50 >50 > V4.C1 AC >50 >50 >50 >50 >50 >50 >50 > V3.C3 ACD V1.C10 ACD V1.C12 AD > > Q168.a2 AD > > Q461.e2 AD > > c1 AE >50 >50 >50 >50 >50 >50 >50 >50 C1080.c3 AE > > C2101.c1 AE > > > C3347.c11 AE > > C AE > > CNE3 AE > > CNE5 AE > CNE55 AE > > CNE56 AE > > CNE59 AE > M02138 AE > > R1166.c1 AE > > R2184.c4 AE > >
3 R3265.c6 AE > > TH966.8 AE > > TH AE > > AG > AG >50 >50 > >50 >50 >50 > AG > > AG > > > AG > > AG > > DJ263.8 AG > > T250-4 AG >50 >50 >50 >50 >50 >50 >50 >50 T AG > > T AG > > T AG > > T AG > > T AG > > T AG >50 >50 >50 >50 >50 >50 >50 T280-5 AG > > T33-7 AG > > B B > B > > B B >50 >50 > >50 >50 > DG B AC10.29 B ADA.DG B Bal.01 B BaL.26 B BG B > > BL01.DG B >50 >50 >50 >50 >50 >50 >50 >50 BR07.DG B BX08.16 B CAAN.A2 B > > CNE10 B > > CNE12 B > > CNE14 B CNE4 B > > CNE57 B > HO86.8 B >50 >50 >50 >50 >50 >50 >50 >50 HT593.1 B HXB2.DG B JRCSF.JB B JRFL.JB B MN.3 B PVO.04 B > > QH B QH B REJO.67 B > RHPA.7 B SC422.8 B SF162.LS B
4 SS B THRO.18 B TRJO.58 B > > TRO.11 B > > WITO.33 B > YU2.DG B CH BC CH070.1 BC > > >50 >50 > CH117.4 BC > > CH BC CNE15 BC CNE40 BC > CNE7 BC C C > > C > > C > > _V1.C16 C C > > V2.C14 C C > > C > > C > > C > > C > C > > C V4.C10 C > > V5.C3 C > > V1.C24 C > > V4.C1 C >50 >50 > >50 >50 > V1.C16 C >50 >50 >50 >50 >50 >50 >50 > V3.C10 C >50 >50 > >50 >50 > V2.C33 C V5.C14 C > V1.C35 C > > ZM C > > BR025.9 C > > CAP210.E8 C >50 >50 >50 >50 >50 >50 >50 >50 CAP244.D3 C > > CAP45.G3 C > >50 > CNE30 C CNE31 C > CNE53 C > > CNE58 C > > DU C > > DU C > > > DU C DU C >50 > >50 > DU C >50 >50 > >50 >50 >50 MW C SO18.18 C
5 TV1.29 C >50 >50 >50 >50 >50 >50 >50 >50 TZA C >50 >50 > >50 >50 >50 >50 TZBD.02 C > > ZA C > > ZM106.9 C > > ZM109.4 C > > ZM135.10a C > > ZM C > > ZM197.7 C > > ZM C > ZM215.8 C > > ZM233.6 C > > > ZM249.1 C ZM53.12 C > > ZM55.28a C > > V4.C3 CD > V2.C6 CD > > v2.c59 CD >50 >50 > >50 >50 > c1 D D > >50 >50 >50 >50 > v5.c45 D > > vrc15 D >50 > >50 > v4.c34 D > > A03349M1.vrc4a D > > NKU3006.ec1 D > UG024.2 D > > > > X2088.c9 G >50 >50 >50 >50 >50 >50 >50 >50 IC 50 IC 80 b12 VRC01 NIH45-46 VRC07 b12 VRC01 NIH45-46 VRC07 # Viruses Total # neutralized IC 50/80 <50μg/ml IC 50 <1μg/ml % neutralized IC 50/80 <50μg/ml IC 50/80 <1μg/ml Viruses neutralized 1 Median IC 50/ Geometric mean IC 50/ All viruses 2 Median IC 50/ Geometric mean IC 50/ Median and geometric mean titers are calculated only for samples with IC 50/80 <50μg/ml. 2 Median and geometric mean titers are calculated for all viruses and values >50 set equal to 100 μg/ml. Supplementary Figure 2. Comparison of VRC01, VRC07, and NIH45-46 neutralization. Neutralization of each mab against 179 viral strains was measured by the TZM-bl assay. IC 50 and IC 80 values (μg/ml) for b12, VRC01, VRC07, and NIH45-46 are shown. Values less than 0.1 μg/ml are in red; 0.1 to 1.0 μg/ml in orange; 1.0 to 10 μg/ml in yellow; 10 to 50 μg/ml in green; and values >50 μg/ml are white. 5
6 Supplementary Figure 3 a b VRC01 VRC07 NIH45-46 c Antibody VRC01-bound VRC07-bound NIH45-46-bound Heavy chain CDR H1 CDR H2 CDR H3 FR3 Total Light chain VRC VRC NIH Total Supplementary Figure 3. Comparison of VRC01, VRC07, and NIH45-46-bound gp120 core structures. (a) Antibodies were liganded to the gp120 core e from the clade A/E 93TH057 viral isolate. Overall angles of approach of VRC01 and VRC07 to gp120 resembled each other. While the variable domain of NIH45-46 recognizes gp120 similarly with that of VRC01and VRC07, the constant domain of NIH45-46 adopts a different conformation from that of VRC01 and VRC07. (b) Contact regions on gp120 by CDR H1, CDR H2, CDR H3, framework region 3 (FR3), and the light chain of each antibody are colored blue, yellow, red, cyan, and grey, respectively. (c) Binding surfaces (Å 2 ) were calculated by defining residues (Kabat numbering) for CDR H1s, residues for CDR H2s, residues for framework region 3s, residues for CDR H3s, and residues for light chains. 6
7 Supplementary Figure 4 54F 54H 54F 54H 54L 54R 54L 54R 54W 54Y 54W 54Y Supplementary Figure 4. Optimization of residue 54 on the heavy chain of VRC07. (a) VRC07 G54 variants were tested for their binding to monomeric gp120 (consensus sequence based protein for clade A1 gp120). The variants G54A, G54F, G54H, G54K, G54L, G54M, G54R, G54W, and G54Y showed increased binding to clade A1 gp120 compared to VRC01 and VRC07 G54 (dotted red line). Human IgG1 was used as a negative control. (b) To better understand the increased binding to gp120, structures of VRC07 variants with mutations at position 54, equivalents of F43 CD4, were determined. Fo-Fc electron density maps contoured at 3.5 are shown in blue mesh. (c) On a seven strain neutralization assay, VRC07-G54H improves potency by over two-fold compared to VRC07 wildtype. (d) Autoreactivity of the VRC07-G54H mutant was assessed with the HEp-2 immunofluorescence assay. Both VRC07 wildtype and VRC07-G54H score negative while VRC07- G54W is highly autoreactive. All antibodies were tested at 50 µg/ml. 7
8 Supplementary Figure 5 V5 loop Light chain N terminus 45 8
9 Supplementary Figure 5. N-terminal modifications of the light chain. (a) Analysis of VRC07-bound gp120 structure and previously reported VRC01-bound gp120 structure revealed a potential clash between the N- termini of the light chains and the V5 loop of gp120. Poor electron densities (shown in blue mesh) around amino acids E1 and I2 of the N-terminus suggest that the region is disordered. (b, c) After analyzing a variety of mutations, we identified two modifications of the N-terminus that increase potency and maintain minimal autoreactivity: a deletion of the first two amino acids (E1-I2) with or without the addition of a V3S mutation that further reduces autoreactivity. 9
10 Supplementary Figure 6 IC 50 IC 80 VRC07- VRC07- VRC07- VRC07- VRC07- VRC07- VRC07- VRC07- Virus ID Clade VRC LS 508-LS 523-LS 544-LS VRC LS 508-LS 523-LS 544-LS 0260.v5.c36 A v4.c3 A v5.c1 A v2.c20 A v1.c1 A v3.c11 A F1_F6_20 A BB201.B42 A BB539.2B13 A BI369.9A A BS208.B1 A KER A KER A KNH A MB201.A1 A MB539.2B7 A MI369.A5 A MS208.A1 A Q23.17 A Q A Q769.d22 A Q769.h5 A Q842.d12 A QH209.14M.A2 A RW020.2 A UG037.8 A V1.C24 AC V1.C4 AC v4.c1 AC >50 >50 >50 >50 >50 >50 >50 >50 >50 > V4.C1 AC >50 >50 >50 >50 >50 >50 >50 >50 >50 > V3.C3 ACD V1.C10 ACD V1.C12 AD Q168.a2 AD Q461.e2 AD c1 AE >50 >50 >50 >50 >50 >50 >50 >50 >50 >50 C1080.c3 AE C2101.c1 AE C3347.c11 AE C AE CNE3 AE CNE5 AE CNE55 AE CNE56 AE CNE59 AE M02138 AE R1166.c1 AE R2184.c4 AE R3265.c6 AE TH966.8 AE
11 TH AE AG AG > > AG AG AG AG DJ263.8 AG T250-4 AG > >50 >50 >50 >50 >50 >50 >50 T AG T AG T AG T AG T AG T AG >50 >50 >50 >50 >50 >50 >50 >50 >50 >50 T280-5 AG T33-7 AG B B B B B DG B AC10.29 B ADA.DG B Bal.01 B BaL.26 B BG B BL01.DG B >50 >50 >50 >50 >50 >50 >50 >50 >50 >50 BR07.DG B BX08.16 B CAAN.A2 B CNE10 B CNE12 B CNE14 B CNE4 B CNE57 B HO86.8 B >50 >50 >50 >50 >50 >50 >50 >50 >50 >50 HT593.1 B HXB2.DG B JRCSF.JB B JRFL.JB B MN.3 B PVO.04 B QH B QH B REJO.67 B RHPA.7 B SC422.8 B SF162.LS B SS B THRO.18 B TRJO.58 B TRO.11 B WITO.33 B
12 YU2.DG B CH BC CH070.1 BC CH117.4 BC CH BC CNE15 BC CNE40 BC CNE7 BC C C C C _V1.C16 C C V2.C14 C C C C C C C C V4.C10 C V5.C3 C V1.C24 C V4.C1 C V1.C16 C >50 >50 >50 >50 >50 >50 >50 >50 >50 > V3.C10 C > V2.C33 C V5.C14 C V1.C35 C ZM C BR025.9 C CAP210.E8 C > > CAP244.D3 C CAP45.G3 C CNE30 C CNE31 C CNE53 C CNE58 C DU C DU C DU C DU C DU C > > >50 >50 > >50 MW C SO18.18 C TV1.29 C > > > > TZA C > > > TZBD.02 C ZA C ZM106.9 C ZM109.4 C ZM135.10a C ZM C
13 ZM197.7 C ZM C ZM215.8 C ZM233.6 C ZM249.1 C ZM53.12 C ZM55.28a C V4.C3 CD V2.C6 CD v2.c59 CD c1 D D > > v5.c45 D vrc15 D v4.c34 D A03349M1.vrc4a D NKU3006.ec1 D UG024.2 D X2088.c9 G >50 >50 > >50 >50 >50 >50 >50 >50 IC 50 IC 80 VRC07- VRC07- VRC07- VRC07- VRC07- VRC07- VRC07- VRC07- VRC LS 508-LS 523-LS 544-LS VRC LS 508-LS 523-LS 544-LS # Viruses Total # neutralized IC 50/80 <50μg/ml IC 50 <1μg/ml % neutralized IC 50/80 <50μg/ml IC 50/80 <1μg/ml Viruses neutralized 1 Median IC 50/ Geometric mean IC 50/ All viruses 2 Median IC 50/ Geometric mean IC 50/ Median and geometric mean titers are calculated only for samples with IC50/80 <50 μg/ml 2 Median and geometric mean titers are calculated for all viruses and values >50 were set to 100 μg/ml. Supplementary Figure 6. Comparison of neutralization breadth and potency of lead optimized VRC07 variants. Neutralization of each mab against 179 viral strains was measured by the TZM-bl assay. IC 50 and IC 80 values (μg/ml) for VRC LS, VRC LS, VRC-523-LS, and VRC LS are shown. Values less than 0.1 μg/ml are in red; 0.1 to 1.0 μg/ml in orange; 1.0 to 10 μg/ml in yellow; 10 to 50 μg/ml in green; and values >50 μg/ml are white. 13
14 Supplementary Figure 7 a b Antibody NHP # 0 6hr 1d 2d 4d 7d 10d 14d A11E078 n/a 1 n/a 1260 n/a n/a VRC LS A11E071 n/a n/a, not available; samples were contaminated with blood. Supplementary Figure 7. mab pharmacokinetics in non-human primates. (a) 10 mg/kg of each mab was administered IV to male rhesus macaques. Antibody levels were determined by RSC3 ELISA. (b) The limit of detection was 0.15 μg/ml, and values below the limit of detection were not graphed (VRC07-G54W after day 21 and one NHP VRC LS after day 14). mab concentrations in mucosal secretions of monkeys administered VRC LS were also measured by RSC3 ELISA. Values shown are ng/ml. 14
15 Supplementary Figure 8 Supplementary Figure 8. Viral load data from passive transfer experiments. Viral loads for infected animals were determined by real-time PCR for viral RNA. 15
16 Supplementary Table 1. Crystallographic data collection and refinement statistics. 93TH057: VRC07:I30Q, G54W,S58N 93TH057: 93TH057: 93TH057: 93TH057: 93TH057: 93TH057: 93TH057: VRC07wt VRC07-G54F VRC07-G54H VRC07-G54L VRC07-G54R VRC07-G54W VRC07-G54Y PDB accession code 4OLU 4OLV 4OLW 4OLX 4OLY 4OLZ 4OM0 4OM1 Data collection Space group P P P P P P P P Cell constants c Å 67.7, 76.6, , 90.0, , 75.6, , 90.0, , 76.2, , 90.0, , 76.0, , 90.0, , 76.5, , 90.0, , 75.5, , 90.0, , 75.5, , 90.0, , 76.0, , 90.0, 90.0 Wavelength (Å) Resolution (Å) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) R merge 13.1 (51.3) 12.6 (70.9) 9.0 (27.1) 7.5 (63.5) 14.7 (50.6) 9.3 (75.1) 12.0 (56.6) 9.1 (44.4) I / I 16.9 (2.0) 12.7 (1.5) 14.2 (1.8) 32.9 (1.7) 13.3 (1.8) 22.0 (1.7) 14.6 (1.3) 23.1 (2.3) Completeness (%) 91.4 (71.4) 94.8 (83.6) 91.1 (57.5) 90.2 (57.5) 81.9 (31.9) 73.5 (40.8) 91.4 (53.6) 90.7 (50.7) Redundancy 5.4 (3.8) 4.1 (2.8) 3.7 (2.2) 5.4 (3.5) 4.9 (1.7) 8.4 (5.0) 5.2 (1.7) 1.7 (1.3) Refinement Resolution (Å) Unique reflections 47,884 34,630 25,962 44,429 37,881 44,229 43,008 53,056 R work / R free (%) 20.0/ / / / / / / /22.5 No. atoms Protein 6,035 6,042 6,041 6,039 6,042 6,082 6,043 6,075 Ligand/ion Water B-factors (Å 2 ) Protein Ligand/ion Water R.m.s. deviations Bond lengths (Å) Bond angles ( ) Ramachandran Most favored regions (%) Allowed regions (%) Disallowed regions (%) Values in parentheses are for highest-resolution shell 16
17 Supplementary Table 2. VRC01-like optimization. Chain Type of mutation Name Mutations Included in lead candidates Heavy Chain Structure-guided G54A G54A G54C G54D G54E G54F G54C G54D G54E G54F G54H G54I G54K G54L G54M G54N G54P G54Q G54R G54S G54T G54V G54W G54Y I30R I30Q S58N D100bF E46W N100eV Q62H Q64H R61F S58W W100fQ N35L Y100dW N100eT R53H R53N W50Y CDRH2-M1 CDRH2-M2 G54H G54I G54K G54L G54M G54N G54P G54Q G54R G54S G54T G54V G54W G54Y I30R I30Q S58N D100bF E46W N100eV Q62H Q64H R61F S58W W100fQ N35L, Y100dW, N100eT R53H R53N W50Y V57A, Y59A V57G, Y59G VRC LS VRC LS VRC LS VRC LS 17
18 Solubility hph01 F79H, V89T Germline reversion chh01 Hmut1 Hmut2 Hmut3 NIH4546ghvH01 NIH4546ghvH02 NIH4546ghvH05.3 ghvh01 ghvh02 E28K, E76K, D85K I30E, N31D I30E N31D R3Q, S5V, G9A, Q10E, M11V, E16A, M18V, R19K, L20V, R23K, I37V, L39Q, R43Q, R44G, P45L, S75I, D76S, F79Y, L80M, R82AS, S82BR, T83R, F91Y, T93A, R109Q, A111T, P112L R3Q, S5V, G9A, Q10E, M11V, E16A, M18V, R19K, L20V, R23K, I37V, L39Q, R43Q, D76S, F79Y, L80M, S82BR, T83R, F91Y, T93A, R109Q, A111T, P112L R3Q, I37V, T93A R3Q, S5V, G9A, Q10E, M11V, D16A, M18V, R19K, I20V, R23K, I37V, L39Q, K43Q, R44G, P45L, S75I, E76S, F79Y, L80M, R82AS, S82BR, T83R, F91Y, T93A, P108L R3Q, S5V, G9A, Q10E, M11V, D16A, M18V, R19K, I20V, R23K, I37V, L39Q, K43Q, E76S, F79Y, L80M, S82BR, T83R, F91Y, T93A, P108L VRC01-07ghvH03 G9A, Q10E, M11V, E16A, M18V, R19K, I20V, R23K, I37V, L39Q, K43Q, D76S, F79Y, L80M, S82BR, T83R, V84S, F91Y, T93A, N97Y, D99T, Y100A insert RDYY after 100 R105Q, P108L, I110T ghvh04.1 ghvh04.2 ghvh05 ghvh05.1 ghvh05.2 R3Q, S5V, G9A, M11V, D16A, M18V, R19K, I20V, R23K, I37V, L39Q, K43Q, E76S, F79Y, S82BR, F91Y, T93A, P108L R3Q, S5V, G9A, M11V, M18V, R19K, I20V, R23K, I37V, K43Q, E76S, F79Y, S82BR, F91Y, T93A, P108L R3Q, S5M, M18V, R19K, I20V, R23K, I37V, K43Q, E76S, F79Y, S82BR, F91Y, T93A, P108L R3Q, I20V, R23K, I37V, K43Q, E76S, F79Y, S82BR, F91Y, T93A R3Q, R23K, I37V, K43Q, E76S, F79Y, F91Y, T93A ghvh05.3 ghvh ghvh ghvh ghvh ghvh ghvh R3Q, I37V, T93A I37V, T93A R3Q, T93A R3Q, I37V T93A I37V R3Q VRC LS VRC LS 18
19 VRC LS Fc LS M428L, N434S VRC LS VRC LS VRC LS Light Chain Structure-guided 1aa del E1-del 2aa del 3aa del 4aa del EI-del-V3A EI-del-V3E EI-del-V3G EI-del-V3K EI-del-V3S EI-del-F97H EI-del-F97K EI-del-F97S EI-del-V3E F97H EI-del-V3E F97S G GG GGG GGGG A AA AAA AAAA E1-del, I2-del E1-del, I2-del, V3-del E1-del, I2-del, V3-del, L4-del E1-del, I2-del, V3A E1-del, I2-del. V3E E1-del, I2-del, V3G E1-del, I2-del, V3K E1-del, I2-del, V3S E1-del, I2-del, F97H E1-del, I2-del, F97H E1-del, I2-del, F97S E1-del, I2-del, V3E, F97H E1-del, I2-del, V3E, F97S E1G E1G, I2G E1G, I2G, V3G E1G, I2G, V3G, L4G E1A E1A, I2A E1A, I2A, V3A E1A, I2A, V3A, L4A VRC LS VRC LS VRC LS VRC LS Solubility hpl01 I20T, W67S, N72T hpl02 I20T, W67S, N72T, V106Q, I108N VRC LS hpl02.1 hpl02.2 hpl03 hpl04 hpl05 hpl06 chl01 I20T, W67S, N72F, V106Q, I108N I20T, W67S, V106Q, I108N W67S, N72T I20Q, W67N, N72T I20Q, W67N, N72T, V106Q, I108N I20E, S63K, S65E, W67E, D70E, N72R, T74R, V106Q, I108N N72T, E79K Glycosylation N72T N72T N72F N72E N72S N72F N72E N72S 19
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