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Amino acid positions involved in ADCC, ADCP, CDC, half-life and half-IG exchange

Citing this table: Lefranc, M.-P. and Lefranc, G., The Immunoglobulin FactsBook, Academic Press, London, UK (458 pages), 2001, ISBN:012441351X

1. Structural and biological properties of human immunoglobulins

2. Human immunoglobulin (IG) chain characteristics

3. IG interchain disulfide bridges per monomer

4. Lysines and cysteines of the Homo sapiens IGHG1, IGKC and IGLC1 and positions in the C-DOMAIN

6. IMGT engineered variant nomenclature: IGHG variants

7. Homo sapiens IGHG1 amino acids involved in the interactions with the C1q, FcγR and FCGRT

Amino acids in the IGHG constant regions of the IG heavy chains are frequently engineered to modify the effector properties of the therapeutic monoclonal antibodies.
Amino acids changes at positions involved in antibody-dependent cellular (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), half-life increase, half-IG exchange, B cell inhibition by coengagement of antigen and FcγR on the same cell and knobs-into-holes reported in the literature are described in the tables below with the IMGT engineered variant nomenclature.



IMGT engineered variant nomenclature has been set up for an easier comparison between engineered antibodies. The IMGT engineered variant name comprises the species, the gene name, the letter 'v' with a number, and then the domain(s) with AA change(s) defined by the letter of the novel AA and position in the domain. The IMGT engineered variants are described in the table below, classified on the effects on antibody-dependent cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), half-life increase, half-IG exchange, B cell inhibition by coengagement of antigen and FcγR on same cell, and knobs-into-holes. For a list of the IGHG variants per gene, see IGHG engineered variant nomenclature: IGHG variants.
IMGT engineered variants are classified by comparison with the allele *01 of the gene and, if the effects are independent on the alleles, as a references for the description of the amino acid (AA) changes for the other alleles. In those cases, the same variant (v) number is therefore used for any allele of the same gene in the same species.
If consequences of the AA changes are different depending on alleles, the allele (identified by an asterisk followed by a number, for example *01) is included in the IMGT engineered variant nomenclature, for example IGHG1*01 instead of IGHG1.
Headers of the tables include:
IMGT gene name: based on the IMGT-ONTOLOGY CLASSIFICATION axiom.
IMGT IGHG CH domain: based on the IMGT-ONTOLOGY DESCRIPTION axiom.
IMGT amino acid (AA) changes on IGHG CH domain: described using the IMGT unique numbering for C-DOMAIN, a major concept of the IMGT-ONTOLOGY NUMEROTATION axiom.

Effects on binding, Effects on half-life, Effects on half-IG exchange, Modification of effector properties: data from the literature (references quoted).
IMGT description of AA changes on IGHG and correspondence with Eu numbering: correspondence between the IMGT description of AA changes on IGHG and the Eu numbering (between parentheses).


Antibody-dependent cellular cytotoxicity (ADCC)

ADCC reduction

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)
G1.1>del Homsap IGHG1v47 CH2 delG1.1 Eliminates FcγRI, FcγRIIA, FcγRIIIA binding [44]
Increases FcγRIIb binding		 Reduces ADCC [44] CH2 Gly G1.1>del (236)
E1.4>P / L1.3>V / L1.2>A / G1.1>del Homsap IGHG1v50 CH2 P1.4, V1.3, A1.2, delG1.1 Decreases FcγR binding Reduces ADCC Amino acid change (Homsap IGHG2-like). CH2 Glu E1.4>Pro P (233)/Leu L1.3>Val V (234)/Leu L1.2>Ala A (235)/Gly G1.1>del (236)
G1.1>R / L113>R Homsap IGHG1v52 CH2 R1.1, R113 Abrogates FcγR binding Reduces ADCC CH2 Gly G1.1>Arg R (231)/Leu L113>Arg R (328)
D27>A Homsap IGHG1v66 CH2 A27 Reduces FcγR binding Reduces ADCC CH2 Asp D27>Ala A (265)
D27>S Homsap IGHG1v67 CH2 S27 Reduces FcγR binding Reduces ADCC CH2 Asp D27>Ser S (265)
V37>E Homsap IGHG1v72 CH2 E37 Reduces FcγRIIIa binding [48]
Enhances FcγRIIa and FcγRIIb binding [48]		 Reduces ADCC [40] CH2 Val V37>Glu E (273)

ADCC enhancement

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-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 [45] Enhances ADCC[45] CH2 Gly G1.1>Ala A(236)/Ser S3>D(239) Ala A115>Leu L(330)/Ile I117>E(332) 5d6d FCGR3A: Fc complex
G1.1>A (236) / S3>D (239) / I117>E (332) Homsap IGHG1v13 CH2 A1.1, D3, E117 Increases FcγRIIIa affinity
Increases FcγRIIa binding [16]
Increases FcγRIIa/FcγRIIb binding ratio [16]		 Enhances ADCC and ADCP CH2 G1.1>A (236)/S3>D (239)/I117>E (332)
G1.1>A / A115>L / I117>E Homsap IGHG1v45 CH2 A1.1, L115, E117 Increases FcγRIIIa affinity Enhances ADCC and ADCP CH2 Gly G1.1>Ala A (236)/Ala A115>Leu L (330)/Ile I117>Glu E (332)
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)

Antibody-dependent cellular phagocytosis (ADCP)

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, A115>L, I117>E Homsap IGHG1v12 CH2 A1.1, D3, L115, E117 Increases FcγRIIa binding [45] Enhances ADCP (NK cell activation)[45] CH2 Gly G1.1>Ala A (236)/Ser S3>Asp D (239)/Ala A115>Leu L (330)/Ile I117>Glu E (332)
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]
G1.1>A / A115>L / I117>E Homsap IGHG1v45 CH2 A1.1, L115, E117 Increases FcγRIIIa binding Enhances ADCC and ADCP (NK cell activation) CH2 Gly G1.1>Ala A (236)/Ala A115>Leu L (330)/Ile I117>Glu E (332)

Complement-dependent cytotoxicity (CDC)

CDC enhancement

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)
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]
Increases FcγRIIb binding [33]		 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]
IGHG1-IGHG3 CH2 K38>Q / N40>K / Y85.2>F Homsap IGHG1G3v1 CH2 Q38, K40, F85.2 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)
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

CDC reduction

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]

Reduced CDC and ADCC

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)
L1.3>A / L1.2>A / G1>A Homsap IGHG1v14-1 CH2 A1.3, A1.2, A1 Reduces C1q binding [38]
Reduces FcγR effector properties [38]		 Reduces CDC [38]
Reduces ADCC [38]		 CH2 Leu L1.3>Ala A (234)/Leu L1.2>Ala A (235)/Gly G1>Ala A (237)
L1.3>A / L1.2>A / P114>A Homsap IGHG1v14-4 CH2 A1.3, A1.2, A114 Reduces C1q binding
Reduces FcγR binding		 Reduces CDC
Reduces FcγR effector properties		 CH2 Leu L1.3>Ala A (234)/Leu L1.2>Ala A (235)/Pro P114>Ala A (329)
L1.3>A / L1.2>A / L113>R Homsap IGHG1v14-48 CH2 A1.3, A1.2, R113 Reduces C1q binding
Reduces FcγR binding		 Reduces CDC
Reduces FcγR effector properties		 CH2 Leu L1.3>Ala A (234)/Leu L1.2>Ala A (235)/Leu L113>Arg R (328)
L1.3>A / L1.2>A / P114>G Homsap IGHG1v14-49 CH2 A1.3, A1.2, G114 Reduces C1q binding
Reduces FcγR binding		 Reduces CDC
Reduces FcγR effector properties		 CH2 Leu L1.3>Ala A (234)/Leu L1.2>Ala A (235)/Pro P114>Gly G (329)
L1.3>A / L1.2>A / D27 > S Homsap IGHG1v14-67 CH2 A1.3, A1.2, S27 Reduces C1q binding
Reduces FcγR binding		 Reduces CDC
Reduces FcγR effector properties		 Combines two IMGT engineered variants: Homsap G1v14 and G1v67 CH2 Leu L1.3>Ala A (234)/Leu L1.2>Ala A (235)/Asp D27>Ser S (265)
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)
L1.3>A / L1.2>E / G1>A Homsap IGHG1v43 CH2 A1.3, E1.2, A1 Reduces C1q binding
Reduces FcγR effector properties		 Reduces CDC
Reduces ADCC		 CH2 Leu L1.3>Ala A (234)/Leu L1.2>Glu E (235)/Gly G1>AlaA (237)
L1.3>A / L1.2>E / G1>A / A115>S / P116>S Homsap IGHG1v43-60 CH2 A1.3, E1.2, A1, S115, S116 Reduces C1q binding [39]
Reduces FcγR effector properties [39]		 Reduces CDC [39]
Reduces ADCC [39]		 Combines two IMGT engineered variants: Homsap G1v43 and G1v60 CH2 Leu L1.3>Ala A (234)/Leu L1.2>Ala A (235)/Gly G1>Ala A (237)/Ala A115>S Ser (330)/Pro P116>S Ser (331)
L113>R Homsap IGHG1v48 CH2 R113 Reduces C1q binding
Reduces FcγR effector properties		 Reduces CDC
Reduces ADCC		 CH2 Leu L113>Arg R (328)
P114>G Homsap IGHG1v49 CH2 G114 Reduces C1q binding [46]
Reduces FcγR effector properties [46]		 Reduces CDC [46]
Reduces ADCC [46]		 CH2 Pro P114>Gly G (329)
S29>K Homsap IGHG1v51 CH2 K29 Reduces C1q binding
Reduces FcγR effector properties		 Reduces CDC
Reduces ADCC		 CH2 Ser S29>Lys K (267)
L1.3>F / L1.2>Q / K105>Q Homsap IGHG1v53 CH2 F1.3, Q1.2, Q105 Reduces C1q binding
Reduces FcγR effector properties		 Reduces CDC
Reduces ADCC		 CH2 Leu L1.3>Phe F (234)/Leu L1.2>Gln Q (235)/Lys K105>Gln Q (322)
L1.3>S / L1.2>T / G1.1>R Homsap IGHG1v59 CH2 S1.3, T1.2, R1.1 Reduces C1q binding
Reduces FcγR effector properties		 Reduces CDC
Reduces ADCC		 CH2 Leu L1.3>Ser S (234)/Leu L1.2>Thr T (235)/Gly G1.1>Arg R (236)
A115>S / P116>S Homsap IGHG1v60 CH2 S115, S116 Reduces C1q binding
Reduces FcγR effector properties		 Reduces CDC
Reduces ADCC		 CH2 Ala A115>Ser S (330)/Pro P116>Ser S (331)
P2>S Homsap IGHG1v63 CH2 S2 Reduces C1q binding
Reduces FcγR effector properties		 Reduces CDC
Reduces ADCC		 CH2 Pro P2>Ser S (238)
E1.4>del / L1.3>del / L1.2>del Homsap IGHG1v65 CH2 delE1.4, delL1.3, delL1.2 Reduces C1q binding
Reduces FcγR effector properties		 Reduces CDC
Reduces ADCC		 CH2 Glu E1.4>del (233)/Leu L1.3>del (234)/Leu L1.2>del (235)
D27>A / P116>G Homsap IGHG1v71 CH2 A27, G116 Reduces C1q binding [2]
Reduces FcγR effector properties [37]		 Reduces CDC [2]
Reduces ADCC [37]		 CH2 Asp D27>Ala A (265)/Pro P116>Gly G (331)
h-CH2 (h) C5>S / C11>S / C14>S + (CH2) P2>S Homsap IGHG1v70 h S5, S11, S14; CH2 S2 Reduces C1q binding
Reduces FcγR binding		 Reduces CDC
Reduces FcγR effector properties		 Combines three IMGT engineered variants: Homsap G1v63 (with G1v37 - no H-L), G1v61 (no H-H h11) and G1v62 (no H-H h14) h Cys C5>Ser S (220)/Cys C11>Ser S (226)/Cys C14>Ser S (229)/ CH2 Pro P2>Ser S (238)
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)
F85.2>Y / 92>L / T339>A Homsap IGHG2v7 CH2 Y85.2, L92, A339 Low C1q binding [49]
Low FcγR binding [49]		 Low CDC [49]
Low ADCC [49]		 Reduces acid-induced aggregation [49] CH2 Phe F85.2>Tyr Y (300)/Val V92>Leu L (309)/Thr T339>Ala A (339)
IGHG2-IGHG4 CH2 E1.4>del / F1.3>P / L1.2>V / G1.1>A Homsap IGHG2G4v1 CH2 delE1.4, P1.3, V1.2, A1.1 Reduces C1q binding [22]
Reduces FcγR binding [22]		 Reduces CDC [22]
Reduces FcγR effector properties [22]		 Eculizumab: The heavy chain is the chimeric IGHG2*01 CH1-hinge-IGHG4*01 CH2-CH3. The CH2 and CH3 are from IGHG4*01, except for the CH2 positions 1.6-1.1 (AP.PVA) with del 1.4 and amino acids P1.3, V1.2 and A1.1 being from IGHG2*01. The changes are shown in comparison to the IGHG4*01 amino acids at the same positions as E1.4, F1.3, L1.2 and G1.1. CH2 E1.4>del (233)/F1.3>P (234)/L1.2>V (235)G1.1>A (236)
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)
E1.4>del / F1.3>P / L1.2>V / G1.1>A Homsap IGHG4v7 CH2 del 1.4, P1.3, V1.2, A1.1 Reduces FcγR binding EFLG 1.4-G1.1> -PVA (Homsap IGHG2-like) CH2 Glu E1.4>del (233)/Phe F1.3>Pro P (234)/Leu L1.2>Val V (235)/Gly G1.1>Ala A (236)
E1.4>P, F1.3>V, L1.2>A, D27>A, L92>V Homsap IGHG4v37 CH2 P1.4, V1.3, A1.2, A27, V92 Reduces FcγR binding [41] Reduces CDC [42]
Reduces ADCC[41,[42]		 CH2 Glu E1.4>Pro P (233)/ Phe F1.3>Val V (234)/ Leu L1.2>Ala A (235)/ Asp D27>Ala A (265)/ Leu L92>Val V (309)
E1.4>P, F1.3>V, L1.2>A, G1.1>del Homsap IGHG4v38 CH2 P1.4, V1.3, A1.2, delG1.1 Reduces FcγR binding [43] Reduces CDC [43]
Reduces ADCC[43]		 CH2 Glu E1.4>Pro P (233)/ Phe F1.3>Val V (234)/ Leu L1.2>Ala A (235)/ Gly G1.1>del (236)
L1.2>E / P114>G Homsap IGHG4v3-49 CH2 E1.2, G114 Reduces C1q binding [46]
Reduces FcγR binding [46]		 Reduces CDC [46]
Reduces ADCC[46]		 CH2 Leu L1.2>Glu E (235)/Pro P114>Gly G (329)
P114>G Homsap IGHG4v49 CH2 G114 Reduces C1q binding [46]
Reduces FcγR binding [46]		 Reduces CDC [46]
Reduces ADCC[46]		 CH2 Pro P114>Gly G (329)
CH3 H115>R / Y116>F / L125>P Homsap IGHG4v8 CH3 R115, F116, P125 Abrogates binding to Protein A (R115, F116), P125 (Homsap IGHG3 G3-like). Purification of engineered antibodies CH3 His H115>Arg R (435)/Tyr T116>Phe F (436)/Leu L125>Pro P (445)

Half-life increase

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 Homsap 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 (CH2) M15.1>Y / S16>T / T18>E
+ (CH3) H113>K / N114>F / Y116>H		 Homsap 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 Homsap 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)
H113>K / N114>F Homsap IGHG1v46 CH3 K113, F114 Increases FCGRT (FcRn) binding (increased affinity at pH 6.0) CH3 His H113>Lys K (433)/Asn N114>Phe F (434)
CH2-CH3 (CH2) T14>Q + (CH3) M107>L Homsap IGHG1v42 CH2 Q14, CH3 L107 Increases FCGRT (FcRn) binding [30] CH2 Thr T14>Gln Q(250)/CH3 Met M107>Leu L (428)
IGHG2 CH2 T14>Q Homsap 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)
H93>A Homsap IGHG2v8-1 CH2 Q14 Abrogates FCGRT binding at pH 6.0 [10] Homsap G2v8 any amino acid replacement of H93 except cystein [10]. Number 1 of G2v8-1 is for A CH2 His H93> Ala A (310)
CH3 M107>L Homsap 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 (CH2) T14>Q + (CH3) M107>L Homsap 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 Homsap IGHG3v1 CH3 H115 Extended half-life [11] CH3 Arg R115>His H (435)
IGHG4 CH2 M15.1>Y / S16>T / T18>E Homsap 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 (CH2) S16>T / V91>P + (CH3) N114>A Homsap IGHG4v22 CH2 T16, P91, CH3 A114 Expected to increase FCGRT (FcRn) binding [36] CH2 Ser S16>Thr T(254), Val V91>Pro P(308), CH3 Asn N111>Ala A(434)
CH3 M107>L / N114>S Homsap IGHG4v24 CH3 L107, S114 Increases FCGRT (FcRn) binding (increased affinity at pH 6.0) CH3 Met M107>Leu L (428)/Asn N114>Ser S (434)

Half-IG exchange

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)
F85.1>L / R88>K Homsap IGHG4v10 CH3 L85.1, K88 Reduces half-IG exchange of bispecific IgG4 antibodies GSFFLYSRLTVD > GSFLLYSKLTVD

B cell inhibition by coengagement of antigen and FcγR on same cell

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)

Hexamerisation

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 E109>Gly G(430)

Knobs-into-holes and Enhancement of heteropairing H-H of bispecific antibodies

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)
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)
T6>V, T22>L, K79>L, T81>W / T6 > V, L7 > Y, F85.1 > A, Y86 > V Homsap IGHG1v68 CH3 V6, L22, L79, W81 Enhances, with G1v69, the heteropairing H-H of bispecific antibodies CH3 Thr T6>Val V (350)/Thr T22>Leu L (366)/ Lys K79>Leu L (392)/Thr T81>Trp W(394)
Homsap IGHG1v69 V6, Y7, A85.1, V86 Enhances, with G1v68, the heteropairing H-H of bispecific antibodies CH3 T6>V (350)/L7>Y (351)/F85.1>A (405)/Y86>V (407)

No disulfide bridge

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)
C11>S Homsap IGHG1v61 h S11 No disulfide bridge inter H-H h11 hinge Cys C11>Ser S(226)
C14>S Homsap IGHG1v62 h S14 No disulfide bridge inter H-H h14 hinge Cys C14>Ser S(229)

No glycosylation site

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)
N84.4>G Homsap IGHG1v30 CH2 Asn 84.4>Gly G(297)
N84.4>Q Homsap IGHG1v36 CH2 Asn 84.4>Gln Q(297)
N84.4>Q Homsap IGHG4v36 CH2 Asn 84.4>Gln Q(297)

Additional disulfide bridge

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 R83>C / V85>C Homsap IGHG1v54 Stabilizes CH2 in the absence of N84.4 (297) glycosylation CH2 Arg R83>Cys C (292)/Val V85>Cys C (302)

Site-specific drug attachment engineered cysteine

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)
3^4 ins^C Homsap IGHG1v28 CH2 insC3A CH2 3^4 ins^Cys C(239^240)
E36>C Homsap IGHG1v64 CH2 C36 CH2 Glu E36>Cys C (272)
CH2-CH3 (CH1) Y85.2>F (pAMF) + (CH3) F85.2>F (pAMF) Homsap IGHG1v56 CH1 F85.2; CH3 F85.2 Modified Phenylalanine for conjugation (produced in Escherichia coli, non glycosylated) CH1 Y85.2>F (pAMF) (180)/CH3 F85.2>F (pAMF) (404)
CH3 S122>C Homsap IGHG1v44 CH3 C122 CH3 Ser S122>Cys C (442)
L123>C Homsap IGHG1v55 CH3 C123 CH3 Leu L123>Cys C (443)

Note :
  • (1) The amino acid changes correspond to differences in CH2 between IGHG1*01 (K38, N40, Y85.2) and IGHG3*01 (Q38, K40, F85.2).
  • (2) L1.2 is from G1v23 [20], F1.3 and S116 are from G4 [24].


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    • Created:
    11/12/2012
    Last updated:
    Wednesday, 12-Jun-2024 16:02:12 CEST
    Authors:
    Karima Cherouali, Mélissa Cambon, Souphatta Sasorith and Marie-Paule Lefranc
    Editor:
    Chantal Ginestoux, Karima Cherouali, Mélissa Cambon and Marie-Paule Lefranc