Species | IMGT gene name | IMGT IGHG CH domain | IMGT amino acid changes on IGHG CH domain | IMGT engineered variant nomenclature | Effects on binding | Modification of effector properties | IMGT notes | IMGT description of AA changes on IGHG and correspondence with Eu numbering |
---|---|---|---|---|---|---|---|---|
Homo sapiens | IGHG1 | CH2 | E1.4>P | Homsap IGHG1v1 CH2 P1.4 | Prevents FcγRI binding [1] | Amino acid change (Homsap IGHG2-like). | CH2 Glu E1.4>Pro P (233) | |
L1.3>V | Homsap IGHG1v2 CH2 V1.3 | Decreases FcγRI binding [1] | LLGG (Homsap IGHG1)>VLGG. | CH2 Leu L1.3>Val V (234) | ||||
L1.2>A | Homsap IGHG1v3 CH2 A1.2 | Prevents FcγRI binding [1] | LLGG (Homsap IGHG1)>LAGG. | CH2 Leu L1.2>Ala A (235) | ||||
P114>A | Homsap IGHG1v4 CH2 A114 | Reduces ADCC [2] | CH2 Pro P114 (329) is conserved in the four Homsap IGHG. | CH2 Pro P114>Ala A (329) | ||||
K109>W | Homsap IGHG1v5 CH2 W109 | Reduces ADCC [6] | CH2 Lys 109>Trp W (326) |
Species | IMGT gene name | IMGT IGHG CH domain | IMGT amino acid changes on IGHG CH domain | IMGT engineered variant nomenclature | Effects on binding | Modification of effector properties | IMGT notes | IMGT description of AA changes on IGHG and correspondence with Eu numbering |
---|---|---|---|---|---|---|---|---|
Homo sapiens | IGHG1 | CH2 | S85.4>A / E118>A / K119>A | Homsap IGHG1v6 CH2 A85.4, A118, A119 | Increases FcγRIIIa binding [3] | Enhances ADCC [3] | CH2 Ser S85.4>Ala A (298)/Glu E118>Ala A (333)/Lys K119>Ala A (334) | |
S3>D / l117>E | Homsap IGHG1v7 CH2 D3, E117 | Increases FcγRIIIa binding [4] | Enhances ADCC [4] | CH2 Ser S3>Asp D (239)/lle l117>Glu E (332) | ||||
S3>D / A115>L / I117>E | Homsap IGHG1v8 CH2 D3, L115, E117 | Increases FcRIIIa binding [4] Decreases FcRIIb binding [4] |
Enhances ADCC [4] | CH2 Ser S3>Asp D (239)/Ala A115>Leu L (330)/IIe I117>Glu E (332) | ||||
CH2 and CH3 | CH2 F7>L / R83>P / Y85.2>L / V88>I / CH3 P83>L | Homsap IGHG1v9 CH2 L7, P83, L85.2, I88; CH3 L83 | Enhances ADCC (100% increase) [14] | CH2 Phe F7>Leu L (243)/Arg R83>Pro P (292)/Tyr Y85.2>Leu L (300)/Val V88>IIe I (305)/CH3 Pro P83>Leu L (396) | ||||
CH2 | L1.3>Y / L1.2>Q / G1.1>W / S3>M / H30>D / D34>E / S85.4>A | Homsap IGHG1v10 CH2 Y1.3, Q1.2, W1.1, M3, D30, E34, A85.4 | Increases FcγIIIa binding (F158 by >2000-fold, V158 by >1000-fold) (association of H chain 1 (IGHG1*01v10) and H chain 2 (IGHG1*01v11)) [15] | Enhances ADCC [15] | CH2 Leu L1.3>Tyr Y (234)/Leu L1.2>Gln Q (235)/Gly G1.1>Trp W (236)/Ser S3>Met M (239)/His H30>Asp D (268)/Asp D34>Glu E (270)/Ser S85.4>Ala A (298) | |||
D34>E / K109>D / A115>M / K119>E | Homsap IGHG1v11 CH2 E34, D109, M115, E119 | CH2 Asp D34>Glu E (270)/Lys K109>Asp D (326)/Ala A115>Met M (330)/Lys K119>Glu E (334) | ||||||
G1.1>A / S3>D / A115>L / I117>E | Homsap IGHG1v12 CH2 A1.1, D3, L115, E117 | Increases FcγRIIIa affinity [5] | CH2 Gly G1.1>Ala A(236)/Ser S3>D(239) Ala A115>Leu L(330)/Ile I117>E(332) 5d6d FCGR3A: Fc complex | |||||
IGHG2 | CH2 | VAG->LLGG (1.3 / 1.2 / 1.1 / 1) | Homsap IGHG2v1 CH2 L1.3, L1.2, G1.1, G1 | Confers FcγRI binding (WT does not show any binding capacity) [1] | VAG- > LLGG (Homsap IGHG1-like) | VAG>L1.3, L1.2, G1.1, G1 (234-237) | ||
IGHG4 | CH2 | F1.3>L | Homsap IGHG4v1 CH2 L1.3 | Increases FcγRI affinity [1] | FLGG > LLGG (Homsap IGHG1-like) | Phe F1.3>Leu L(234) | ||
Mus musculus | IGHG2B | CH2 | E1.2>L | Musmus IGHG2Bv1 CH2 L1.2 | Increases FcγRI affinity [5] | LEGG > LLGG (Homsap IGHG1-like) |
Species | IMGT gene name | IMGT IGHG CH domain | IMGT amino acid changes on IGHG CH domain | IMGT engineered variant nomenclature | Effects on binding | Modification of effector properties | IMGT description of AA changes on IGHG and correspondence with Eu numbering |
---|---|---|---|---|---|---|---|
Homo sapiens | IGHG1 | CH2 | G1.1>A / S3>D / I117>E | Homsap IGHG1v13 CH2 A1.1, D3, E117 | Increases FcγRIIa binding [16] Increases FcγRIIa/FcγRIIb binding ratio [16] | Enhances ADCP (phagocytosis of antibody-coated target cells by macrophages) [16] | CH2 Gly G1.1>Ala A (236)/Ser S3>Asp D (239)/IIe I117>Glu E (332) Variants with G1.1>A have a 70>fold greater FcγRIIa affinity and 15-fold improvement in FcγRIIa/FcγRIIb ratio [16] |
Species | IMGT gene name | IMGT IGHG CH domain | IMGT amino acid changes on IGHG CH domain | IMGT engineered variant nomenclature | Effects on binding | Modification of effector properties | IMGT notes | IMGT description of AA changes on IGHG and correspondence with Eu numbering |
---|---|---|---|---|---|---|---|---|
Homo sapiens | IGHG1 | CH2 | K109>W | Homsap IGHG1v5 CH2 W109 | Increases C1q binding [6] | Enhances CDC [6] | CH2 Lys K109>Trp W(326) | |
E118>S | Homsap IGHG1v15 CH2 S118 | Increases C1q binding [6] | Enhances CDC [6] | CH2 Glu E118>Ser S(333) | ||||
K109>W / E118>S | Homsap IGHG1v16 CH2 W109, S118 | Increases C1q binding [6] | Enhances CDC [6] | CH2 Lys K109>Trp W (326)/Glu E118>Ser S (333) | ||||
IgG1-G3 chimere (IGHG1 CH1-hinge - IGHG3 CH2-CH3) | Increases C1q binding [17] | Enhances CDC [17] | CH2 Lys K38>Gln Q(274)/Asn N40>Lys K(276)/Tyr Y85.2>Phe F(300)(1) | |||||
S29>E / H30>F / S107>T | Homsap IGHG1v17 CH2 E29, F30, T107 | Increases C1q binding [18] | Enhances CDC [18] | CH2 Ser S29>Glu E (267)/His H30>Phe F (268)/Ser S107>Thr T (324) | ||||
S29>E | Homsap IGHG1v35 CH2 E29 | Increases C1q binding [18] | Enhances CDC [18] | CH2 Ser S29>Glu E (267) | ||||
CH3 | CH3 E1>R / E109>G / S120>Y favors IgG1 hexamerization | Homsap IGHG1v18 CH3 R1, G109, Y120 | Increases C1q binding [19] | Enhances CDC [19] | CH3 Glu E1>Arg R (345)/Glu E109>Gly G (430)/Ser S120>Tyr Y (440) (the triple mutant IgG1-005-RGY (IGHG1v18) form IgG1 hexamers) [19] |
|||
IGHG4 | CH2 | S116>P | Homsap IGHG4v2 CH2 P116 | Enhances CDC [8] | P116 is found in Homsap IGHG1, IGHG2, and IGHG3, that is in the IGHG other than IGHG4 |
Species | IMGT gene name | IMGT IGHG CH domain | IMGT amino acid changes on IGHG CH domain | IMGT engineered variant nomenclature | Effects on binding | Modification of effector properties | IMGT description of AA changes on IGHG and correspondence with Eu numbering |
---|---|---|---|---|---|---|---|
Homo sapiens | IGHG1 | CH2 | D34>A | Homsap IGHG1v19 CH2 A34 | Reduces C1q binding [2] | Reduces CDC [2] | CH2 Asp D34>Ala A (270) |
K105>A | Homsap IGHG1v20 CH2 A105 | Reduces C1q binding [2] | Reduces CDC [2] | CH2 Lys K105>Ala A (322) | |||
P114>A | Homsap IGHG1v4 CH2 A114 | Reduces C1q binding [2] | Reduces CDC [2] | CH2 Pro P114>Ala A (329) | |||
S3>D / A115>L / I117>E | Homsap IGHG1v8 CH2 D3, L115, E117 | Ablates CDC [4] | CH2 Ser S3>Asp D (239)/Ala A115>L (330)/ Ile I117>Glu E (332) | ||||
Mus musculus | IGHG2B | CH2 | E101>A | Musmus IGHG2Bv2 CH2 A101 | Reduces C1q binding [7] | Reduces CDC [7] | CH2 E101, K103 and K105 form a common core in the interactions of IgG and C1q [7] |
K103>A | Musmus IGHG2Bv3 CH2 A103 | Reduces C1q binding [7] | Reduces CDC [7] | CH2 E101, K103 and K105 form a common core in the interactions of IgG and C1q [7] | |||
K105>A | Musmus IGHG2Bv4 CH2 A105 | Reduces C1q binding [7] | Reduces CDC [7] | CH2 E101, K103 and K105 form a common core in the interactions of IgG and C1q [7] |
Species | IMGT gene name | IMGT IGHG CH domain | IMGT amino acid changes on IGHG CH domain | IMGT engineered variant nomenclature | Effects on binding | Modification of effector properties | IMGT notes | IMGT description of AA changes on IGHG and correspondence with Eu numbering |
---|---|---|---|---|---|---|---|---|
Homo sapiens | IGHG1 | CH2 | L1.2>E | Homsap IGHG1v23 CH2 E1.2 | Reduces C1q binding [20] Reduces FcγR binding [20] |
Reduces CDC [20] Reduces FcγR effector properties [20] |
CH2 Leu L1.2>Glu E (235) | |
L1.3>A / L1.2>A | Homsap IGHG1v14 CH2 A1.3, A1.2 | Reduces C1q binding [21] Reduces FcγR binding [21] |
Reduces CDC [21] Reduces FcγR effector properties [21] |
CH2 Leu L1.3>Ala A (234)/Leu L1.2>Ala A (235) | ||||
N108>S / L113>F | Homsap IGHG1v38 CH2 S108, F113 | Abrogates C1q and FcγRIII binding, increases FcγRII binding, retains FcγRI high affinity binding [35] | anti-TLR4 Hu 15C1 humanized mAb [35] | CH2 Asn N108>Ser S (325)/Leu L113>Phe F (328) | ||||
L1.3>F / L1.2>E / P116>S | Homsap IGHG1v39 CH2 F1.3, E1.2, S116 | Reduces C1q binding [20] Reduces FcγR effector properties [24] |
CH2 Leu L1.3>Phe F (234)/Leu L1.2>Glu E (235)/Pro P116>Ser S (331) | |||||
L1.3>A / L1.2>A / P116>S | Homsap IGHG1v40 CH2 A1.3, A1.2, S116 | Reduces C1q binding Reduces FcγR effector properties |
CH2 Leu L1.3>Ala A (234)/Leu L1.2>Ala A (235)/Pro P116>Ser S (331) | |||||
L1.3>F / L1.2>E | Homsap IGHG1v41 CH2 F1.3, E1.2 | Reduces C1q binding [20] Reduces FcγR effector properties [24] |
CH2 Leu L1.3>Phe F (234)/Leu L1.2>Glu E (235) | |||||
IGHG2 | CH2 | H30>Q / V92>L / A115>S / P116>S | Homsap IGHG2v2 CH2 Q30, L92, S115, S116 | Reduces C1q binding [23] Reduces FcγR binding [23] |
Reduces CDC [23] Reduces FcγR effector properties [23] |
IgG2m4 (IGHG2v2) is based on the G2 isotype with AA changes from G4 [23] | CH2 His H30>Gln Q (268)/Val V92>Leu L (309)/Ala A115>Ser S (330)/Pro P116>Ser S (331) | |
V1.2>A / G1>A / P2>S / H30>A / V92>L / A115>S / P116>S | Homsap IGHG2v3 CH2 A1.2, A1, S2, A30, L92, S115, S116 | Reduces C1q binding [24] Reduces FcγR binding [24] |
Reduces CDC [24] Reduces FcγR effector properties [24] Undetectable ADCC, CDC, ADCP [24] |
L92, S115 and S116, three AA changes are from G4 [24] | CH2 Val V1.2>Ala A (235)/Gly G1>Ala A (237)/Pro P2>Ser S (238)/His H30>Ala A (268)/Val V92>Leu L (309)/Ala A115>Ser S (330)/Pro P116>Ser S (331) | |||
IgG2-G4 chimere | eculizumab | Reduces C1q binding [22] Reduces FcγR binding [22] |
Reduces CDC [22] Reduces FcγR effector properties [22] |
|||||
IGHG4 | CH2 | L1.2>E | Homsap IGHG4v3 CH2 E1.2 | Reduces C1q binding [20] Reduces FcγR binding [20] |
Reduces CDC [20] Reduces FcγR effector properties [20] |
CH2 Leu L1.2>Glu E(235) | ||
F1.3>A / L1.2>A | Homsap IGHG4v4 CH2 A1.3, A1.2 | Reduces C1q binding [21] Reduces FcγR binding [21] |
Reduces CDC [21] Reduces FcγR effector properties [21] |
CH2 Phe F1.3>Ala A (234)/Leu L1.2>Ala A (235) |
Species | IMGT gene name | IMGT IGHG CH domain | IMGT amino acid changes on IGHG CH domain | IMGT engineered variant nomenclature | Effects on half-life | IMGT notes | IMGT description of AA changes on IGHG and correspondence with Eu numbering |
---|---|---|---|---|---|---|---|
Homo sapiens | IGHG1 | CH2 | M15.1>Y / S16>T / T18>E | IGHG1v21 CH2 Y15.1, T16, E18 | Increases FCGRT (FcRn) binding [30] | 10-fold increase at pH 6.0 [30], 4-fold increases half-life in a cynomolgus pK study [31]. T18>E amino acid change provides 2 novel salt bridges between the Fc and ΒM2 of FCGRT IMGT/3Dstructure-DB : 4n0f, 4n0u [29]. A change of IGHG1 CH2 His H93 (310) into any other amino acid (excluding Cys) leads to an undetectable binding to FCGRT (FcRn) at pH 6.0 [29] | CH2 Met M15.1>Tyr Y(252), Ser S16>T(254), Thr T18>E(256) |
CH2-CH3 | M15.1>Y / S16>T / T18>E (CH2) + H113>K / N114>F / Y116>H (CH3) |
IGHG1v22 CH2 Y15.1, T16, E18, CH3 K113, F114, H116 | Increases FCGRT (FcRn) binding [30] | CH2 Met M15.1>Tyr Y(252), Ser S16>T(254), Thr T18>E(256), CH3 His H113>K(433), Asn N114>F(434), Tyr Y116>H(436) | |||
CH3 | M107>L / N114>S | IGHG1v24 CH3 L107, S114 | Increases FCGRT (FcRn) binding [32] (11-fold increase in affinity at pH 6.0 [32]) Increases reduction in tumor burden in human FCGRT (FcRn) transgenic tumor-bearing mice treated with an anti-EGFR or an anti-VEGF antibody [32] | From 3D structure it is postulated that N114>S allows additional hydrogen bonds with FCGRT (FcRn) [29] IMGT/3Dstructure-DB : 4n0f, 4n0u | CH3 Met M107>Leu L(428)/Asn N114>Ser S(434) | ||
IGHG2 | CH2 | T14>Q | IGHG2v4 CH2 Q14 | Increases FCGRT (FcRn) binding [10] | 4-fold increase in affinity at pH6.0 (no binding at pH 7.5) [10] | CH2 Thr T14>Gln Q(250) | |
CH3 | M107>L | IGHG2v5 CH3 L107 | Increases FCGRT (FcRn) binding [10] | 8-fold increase in affinity at pH6.0 (no binding at pH 7.5) [10], ~1.8-fold increase half-life in rhesus monkey pK study | CH3 Met M107>Leu L (428) | ||
CH2-CH3 | T14>Q + M107>L | IGHG2v6 CH2 Q14, CH3 L107 | Increases FCGRT (FcRn) binding [10] | 27-fold increase in affinity at pH6.0 (no binding at pH 7.5)[10], ~1.9-fold increase half-life in rhesus monkey pK study | CH2 Thr T14>Gln Q(250)/CH3 Met M107>Leu L (428) | ||
IGHG3 | CH3 | R115>H | IGHG3v1 CH3 H115 | Extended half life [11] | CH3 Arg R115>His H (435) | ||
IGHG4 | CH2 | M15.1>Y / S16>T / T18>E | IGHG4v21 CH2 Y15.1, T16, E18 | Increases FCGRT (FcRn) binding [30] | CH2 Met M15.1>Tyr Y(252), Ser S16>Thr T(254), Thr T18>Glu E(256) | ||
CH2-CH3 | S16>T / V91>P + N114>A | IGHG4v22 CH2 T16, P91, CH3 A114 | Increases FCGRT (FcRn) binding | CH2 Ser S16>Thr T(254), Val V91>Pro P(308), CH3 Asn N111>Ala A(434) |
Species | IMGT gene name | IMGT IGHG hinge or CH domain | IMGT amino acid changes on IGHG hinge or CH domain | IMGT engineered variant nomenclature | Effects on half-IG exchange | IMGT Notes |
---|---|---|---|---|---|---|
Homo sapiens | IGHG4 | hinge | S10>P | Homsap IGHG4v5 h P10 | Reduces half-IG exchange [12] | PSCP > PPCP (IGHG1-like) |
CH3 | R88>K | Homsap IGHG4v6 CH3 K88 | Reduces half-IG exchange [13] | FFLYSRLT > FFLYSKLT (IGHG1-like) |
Species | IMGT gene name | IMGT IGHG CH domain | IMGT amino acid changes on IGHG CH domain | IMGT engineered variant nomenclature | Effects on binding | Modification of effector properties | IMGT Notes | IMGT description of AA changes on IGHG and correspondence with Eu numbering |
---|---|---|---|---|---|---|---|---|
Homo sapiens | IGHG1 | CH2 | S29>E / L113>F | Homsap IGHG1v25 CH2 E29, F113 | Increases FcγRIIb binding (400-fold) [33] | Inhibits by downstream ITIM signaling in B cells [34] | obexelimab XmAb5871 | Ser S29>Glu E(267)/Leu L113>Phe F(328) |
Species | IMGT gene name | IMGT IGHG CH domain | IMGT amino acid changes on IGHG CH domain | IMGT engineered variant nomenclature | Effects on molecular interaction | IMGT Notes | IMGT description of AA changes on IGHG and correspondence with Eu numbering |
---|---|---|---|---|---|---|---|
Homo sapiens | IGHG1 | CH3 | E109>G | Homsap IGHG1v34 | CH3 Glu 109>Gly G(430) |
Species | IMGT gene name | IMGT IGHG CH domain | IMGT amino acid changes on IGHG CH domain | IMGT engineered variant nomenclature | Effects on molecular interaction | IMGT Notes | IMGT description of AA changes on IGHG and correspondence with Eu numbering |
---|---|---|---|---|---|---|---|
Homo sapiens | IGHG1 | CH3 | T22>Y / Y86>T | Homsap IGHG1v26 CH3 Y22 | Knob of knobs-into-holes interactions between the CH3 of the two different gamma1 chains [28] | The T22>Y change creates the knob | CH3 Thr T22>Tyr Y(366) |
Homsap IGHG1v31 CH3 T86 | Hole of knobs-into-holes interactions between the CH3 of the two different gamma1 chains [28] | The Y86>T change, in the partner CH3 domain, creates the hole | CH3 Tyr Y86>Thr T(407) | ||||
Homo sapiens | IGHG1 | CH3 | T22>W / T22>S, L24>A, Y86>V | Homsap IGHG1v32 CH3 W22 | Knob of knobs-into-holes interactions between the CH3 of the two different gamma1 chains | The T22>W change creates the knob | CH3 Thr T22>Trp W(366) |
Homsap IGHG1v33 S22, A24, V86 | Hole of knobs-into-holes interactions between the CH3 of the two different gamma1 chains | The T22>S, L24>A, and Y86>V changes, in the partner CH3 domain, creates the hole | CH3 Thr T22>Ser S(366), Leu L24>Ala A(368), Tyr Y86>V(407) |
Species | IMGT gene name | IMGT IGHG CH domain | IMGT amino acid changes on IGHG hinge or CH domain | IMGT engineered variant nomenclature | Effects on molecular interaction | IMGT Notes | IMGT description of AA changes on IGHG and correspondence with Eu numbering |
---|---|---|---|---|---|---|---|
Homo sapiens | IGHG1 | hinge | C5>S | Homsap IGHG1v37 h S5 | No disulfide bridge inter H-L | hinge Cys C5>Ser S(220) |
Species | IMGT gene name | IMGT IGHG CH domain | IMGT amino acid changes on IGHG CH domain | IMGT engineered variant nomenclature | Effects on molecular interaction | IMGT Notes | IMGT description of AA changes on IGHG and correspondence with Eu numbering |
---|---|---|---|---|---|---|---|
Homo sapiens | IGHG1 | CH2 | N84.4>A | Homsap IGHG1v29 | CH2 Asn 84.4>Ala A(297) | ||
Homo sapiens | IGHG1 | CH2 | N84.4>G | Homsap IGHG1v30 | CH2 Asn 84.4>Gly G(297) | ||
Homo sapiens | IGHG1 | CH2 | N84.4>Q | Homsap IGHG1v36 | CH2 Asn 84.4>Gln Q(297) | ||
Homo sapiens | IGHG4 | CH2 | N84.4>Q | Homsap IGHG4v36 | CH2 Asn 84.4>Gln Q(297) |
Species | IMGT gene name | IMGT IGHG CH domain | IMGT amino acid changes on IGHG CH domain | IMGT engineered variant nomenclature | Effects on molecular interaction | IMGT Notes | IMGT description of AA changes on IGHG and correspondence with Eu numbering |
---|---|---|---|---|---|---|---|
Homo sapiens | IGHG1 | CH2 | S3>C | Homsap IGHG1v27 CH2 C3 | CH2 Ser S3>Cys C(239) | ||
Homo sapiens | IGHG1 | CH2 | 3^4 ins^C | Homsap IGHG1v28 CH2 insC3A | CH2 3^4 ins^Cys C(239^240) |