IMGT Education

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

• Category: Effector
• #1 ADCC reduction
• #2 ADCC enhancement
• #3 ADCC and ADCP enhancement
• #4 CDC enhancement
• #5 CDC reduction
• #6 ADCC and CDC reduction
• Dual effect: ADCC reduction, CDC enhancement
• Dual effect: ADCC enhancement, CDC reduction
• #7 B cell inhibition
• #8 No N-glycosylation site (CH2 N84.4)
• Category: Half-life
• #9 Half-life increase
• #9 Half-life decrease
• Category: Physicochemical properties
• #10 Biophysical optimization
• #10 Epitope Supression
• Category: Structure
• #11 Additional inter H-L and/or H-H disulfide bridge
• #12 Prevention of IgG4 half-IG exchange
• #13 Hexamerisation
• #14 Heteropairing H-H enhancement
• #15 Suppression of inter H-L and/or H-H disulfide bridge
• #16 Site-specific drug attachment
• #17 Heteropairing H-L enhancement
• #18 Control of bispecific H-H heteropairing
• Category: Hybrid
• #19 Hybrid mAbs


IMGT engineered variant nomenclature has been established for an easier comparison between engineered antibodies. The IMGT engineered variant name comprises the the property and function type, the antibody isotype, and a variant identifier consisting of the letter 'v' followed by a number (e.g., 1-G1v1). This is followed by the domain(s) with AA change(s) defined by the letter of the novel AA and its position within the domain (e.g., CH2 P1.4), based on the IMGT unique numbering system. The engineered variants are described in the table below into five categories: 'Effector', 'Half-life', 'Structure', 'Physicochemical properties', and 'Hybrid', encompassing a total of 19 variant types. For a list of the Fc variants per gene, see Fc engineered variant nomenclature: Fc 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 G1*01 instead of G1.
Headers of the tables include:
IMGT gene name: based on the IMGT-ONTOLOGY CLASSIFICATION axiom.
IMGT C domain: based on the IMGT-ONTOLOGY DESCRIPTION axiom.
IMGT amino acid (AA) changes C domains: 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 and correspondence with Eu numbering: correspondence between the IMGT description of AA changes and the Eu numbering (between parentheses).




Category: Effector

#1 ADCC reduction

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on binding	Modification of effector properties	IMGT notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH2	E1.4>P	1-G1v1 CH2 P1.4	Prevents FccRI binding [1]	Reduces ADCC [1]	Amino acid change (Homsap IGHG2-like).	CH2 Glu E1.4>Pro P (233)
			E1.4>P / L1.3>V / L1.2>A	1-G1v1-2-3 CH2 P1.4, V1.3, A1.2		Reduces ADCC [52]		CH2 Glu E1.4>Pro P (233)/ Leu L1.3>Val V (234)/ Leu L1.2>Ala A(235)
			L1.3>V	1-G1v2 CH2 V1.3	Decreases FcγRI binding [1]	Reduces ADCC [1]	LLGG (Homsap IGHG1)>VLGG.	CH2 Leu L1.3>Val V (234)
			L1.2>A	1-G1v3 CH2 A1.2	Prevents FcγRI binding [1]	Reduces ADCC [1]	LLGG (Homsap IGHG1)>LAGG.	CH2 Leu L1.2>Ala A (235)
			G1.1>del	1-G1v47 CH2 delG1.1	Eliminates FcγRI, FcγRIIA, FcγRIIIA binding [36] Increases FcγRIIb binding	Reduces ADCC [36]		CH2 Gly G1.1>del (236)
			E1.4>P / L1.3>V / L1.2>A / G1.1>del	1-G1v50 CH2 delE1.4, P1.3, V1.2, A1.1	Decreases FcγR binding [75]	Reduces ADCC [75]	Amino acid change (Homsap IGHG2-like).	CH2 Glu E1.4>del (233)/ Leu L1.3>P Pro (234)/ Leu L1.2>V val (235), Gly G1.1>A Ala (236)
			E1.4>P / L1.3>V / L1.2>A / G1.1>del / D27>G / A110>Q / A115>S	1-G1v50-79 CH2 delE1.4, P1.3, V1.2, A1.1, G27, Q110, S115	Decreases FcγR binding [113]	Reduces ADCC [113]	Amino acid change (Homsap IGHG2-like).	CH2 Glu E1.4>del (233)/ Leu L1.3>P Pro (234)/ Leu L1.2>V val (235)/ Gly G1.1>A Ala (236)/ Asp D27>Gly G (265)/ Ala A110>Gln Q (327)/ Ala A115>Ser S (330)
			G1.1>R / L113>R	1-G1v52 CH2 R1.1, R113	Abrogates FcγR binding [59]	Reduces ADCC [59]		CH2 Gly G1.1>Arg R (236)/Leu L113>Arg R (328)
			D27>A	1-G1v66 CH2 A27	Reduces FcγR binding [75]	Reduces ADCC [75]		CH2 Asp D27>Ala A (265)
			D27>A / P116>G	1-G1v66-80 CH2 A27, G116		Reduces ADCC		CH2 Asp D27>Ala A (265)/ Pro P116>Gly G (331)
			D27>S	1-G1v67 CH2 S27	Reduces FcγR binding [75]	Reduces ADCC [75]		CH2 Asp D27>Ser S (265)
			D27>G / A110>Q / A115>S	1-G1v79 CH2 G27, Q110, S115		Reduces ADCC [113]		CH2 Asp D27>Gly G (265)/ Ala A110>Gln Q (327)/ Ala A115>Ser S (330)
			P116>G	1-G1v80 CH2 G116		Reduces ADCC [113]		CH2 Pro P116>Gly G (331)
			E31>R	1-G1v101 CH2 R31		Reduces ADCC		CH2 Glu E31>R Arg (269)
			V37>E	1-G1v106 CH2 E37	Reduces FcγRIIIa binding [48] Enhances FcγRIIa and FcγRIIb binding [48]	Reduces ADCC [48]		CH2 Val V37>Glu E (273)
	IGHG4	CH2	D27>A	1-G4v66 CH2 A27		Reduces ADCC [113]		CH2 Asp D27>Ala A (265)




#2 ADCC enhancement

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on binding	Modification of effector properties	IMGT notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH2	S85.4>A / E118>A / K119>A	2-G1v6 CH2 A85.4, A118, A119	Increases FcγRIIIa binding [4]	Enhances ADCC [4]		CH2 Ser S85.4>Ala A (298)/Glu E118>Ala A (333)/Lys K119>Ala A (334)
			S3>D / l117>E	2-G1v7 CH2 D3, E117	Increases FcγRIIIa binding [5]	Enhances ADCC [5]		CH2 Ser S3>Asp D (239)/lle l117>Glu E (332)
			L1.3>Y / L1.2>Q / G1.1>W / S3>M / H30>D / D34>E / S85.4>A	2-G1v10 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)) [7]	Enhances ADCC [7]		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	2-G1v11 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)
			P11>I / A124>Q	2-G1v103 CH2 I11, Q124		Enhances ADCC [64]		CH2 Pro P11>I Ile (247)/ Ala A124>Gln Q (339)
		CH2-CH3	(CH2) F7>L / R83>P / Y85.2>L / V88>I / (CH3) P83>L	2-G1v9 CH2 L7, P83, L85.2, I88, CH3 L83		Enhances ADCC (100% increase) [6]		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 L1.2>V / F7>L / R83>P / Y85.2>L ; CH3 P83>L	2-G1v9-1 CH2 V1.2, L7, P83, L85.2, CH3 L83		Enhances ADCC[63]		CH2 Leu L1.2>Val V(235) / Phe F7>Leu L (243) / Arg R83>Pro P (292) / Tyr Y85.2>Leu L (300); CH3 Pro P83>Leu L (396)
		CH3	T81>M	2-G1v102 CH3 M81		Enhances ADCC		CH3 Thr T81>Met M (394)
	IGHG2	CH2	^1.4P, P1.3>L, V1.2>L, A1.1>G	2-G2v1 CH2 ^1.4P, L1.3, L1.2, G1.1	Confers FcγRI binding (WT does not show any binding capacity) [1]	Enhances ADCC [1]		CH2 ins ^1.4P Pro (233)/ Pro P1.3>L Leu (234)/ Val V1.2>L Leu (235)/ Ala A1.1>G Gly (236)
			S3>D / G110>A / I117>E	2-G2v7-1 CH2 D3, A110, E117		Enhances ADCC [86]	CH2 Ser S3>Asp D (239)/ Gly G110>Ala A (327)/ Ile I117>Glu E (332)
	IGHG4	CH2	F1.3>L	2-G4v1 CH2 L1.3	Increases FcγRI affinity [1]	Enhances ADCC [1]	FLGG > LLGG (Homsap IGHG1-like)	Phe F1.3>Leu L(234)
Mus musculus	IGHG2B	CH2	E1.2>L	2-G2Bv1 CH2 L1.2	Increases FcγRI affinity [100]	Enhances ADCC [100]	LEGG > LLGG (Homsap IGHG1-like)




#3 ADCC and ADCP enhancement

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on binding	Modification of effector properties	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH2	G1.1>A / S3>D / A115>L / I117>E	3-G1v12 CH2 A1.1, D3, L115, E117	Increases FcγRIIIa and FcγRIIa binding [8]	Enhances ADCC and ADCP (NK cell activation)[8]	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	3-G1v13 CH2 A1.1, D3, E117	Increases FcγRIIIa and FcγRIIa binding [9] Increases FcγRIIa/FcγRIIb binding ratio [9]	Enhances ADCC and ADCP [9]	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 [9]
			G1.1>A / A115>L / I117>E	3-G1v45 CH2 A1.1, L115, E117	Increases FcγRIIIa affinity [34]	Enhances ADCC and ADCP (NK cell activation) [34]	CH2 Gly G1.1>Ala A (236)/ Ala A115>Leu L (330)/ Ile I117>Glu E (332)
			T85.3>A	3-G1v104 CH2 A85.3	Increases binding to FcγRIIa and moderate binding to FcγRIIIa [37]	Enhances ADCC and ADCP [37]	CH2 Thr T85.3>Ala A (299)




#4 CDC enhancement

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on binding	Modification of effector properties	IMGT notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH2	E118>S	4-G1v15 CH2 S118	Increases C1q binding [3]	Enhances CDC [3]		CH2 Glu E118>Ser S (333)
			K109>W / E118>S	4-G1v16 CH2 W109, S118	Increases C1q binding [3]	Enhances CDC [3]		CH2 Lys K109>Trp W (326)/Glu E118>Ser S (333)
			S29>E / H30>F / S107>T	4-G1v17 CH2 E29, F30, T107	Increases C1q binding [15]	Enhances CDC [15]		CH2 Ser S29>Glu E (267)/His H30>Phe F (268)/Ser S107>Thr T (324)
			S29>E	4-G1v35 CH2 E29	Increases C1q binding [15] Increases FcγRIIb binding [15]	Enhances CDC [15]		CH2 Ser S29>Glu E (267)
		CH3	E1>R / E109>G / S120>Y	4,10,13-G1v18 CH3 R1, G109, Y120	Increases C1q binding [16]	Enhances CDC [16]	favors IgG hexamerization	CH3 Glu E1>Arg R (345)/Glu E109>Gly G (430)/Ser S120>Tyr Y (440) (the triple mutant IgG1-005-RGY (G1v18) form IgG1 hexamers) [16]
			CH3 E109>G	13-G1v34 CH3 G109	Increases C1q binding [15]	Enhances CDC [15]	favors IgG hexamerization	CH3 Glu E109>Gly G (430)
	IGHG1-IGHG3	CH2	Hybrid G1 CH1-h-G3 CH2-CH3	19-G1G3v1	Increases C1q binding [17]	Enhances CDC [17]	Amino acids Q38, K40 (CH2) and F85.2 (CH3) are from IGHG3*01
	IGHG4	CH2	S116>P	4-G4v2 CH2 P116		Enhances CDC [88]	P116 is found in Homsap IGHG1, IGHG2, and IGHG3, that is in the IGHG other than IGHG4	CH2 Ser S116>Pro P (331)




#5 CDC reduction

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on binding	Modification of effector properties	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH2	D34>A	5-G1v19 CH2 A34	Reduces C1q binding [2]	Reduces CDC [2]	CH2 Asp D34>Ala A (270)
			K105>A	5-G1v20 CH2 A105	Reduces C1q binding [2]	Reduces CDC [2]	CH2 Lys K105>Ala A (322)
			A115>V	5-G1v120 CH2 V115	Reduces C1q binding [114]	Reduces CDC [114]	CH2 Ala A115>Val V (330)
	IGHG2	CH2	P116>S	5-G2v9 CH2 S116	Reduces C1q binding [114]	Reduces CDC [114]	CH2 Pro P116>S Ser (331)
			K105>A	5-G2v20 CH2 A105	Reduces C1q binding [2]	Reduces CDC [2]	CH2 Lys K105>A Ala (322)
Mus musculus	IGHG2B	CH2	E101>A	Musmus 5-G2Bv2 CH2 A101	Reduces C1q binding [101]	Reduces CDC [101]	CH2 Glu E101>A Ala (318) CH2 E101, K103 and K105 form a common core in the interactions of IgG and C1q [101]
			K103>A	Musmus 5-G2Bv3 CH2 A103	Reduces C1q binding [101]	Reduces CDC [101]	CH2 Lys K103>A Ala (320) CH2 E101, K103 and K105 form a common core in the interactions of IgG and C1q [101]
			K105>A	Musmus 5-G2Bv4 CH2 A105	Reduces C1q binding [101]	Reduces CDC [101]	CH2 Lys K105>A Ala (322) CH2 E101, K103 and K105 form a common core in the interactions of IgG and C1q [101]




#6 ADCC and CDC reduction

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on binding	Modification of effector properties	IMGT notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1
		CH2	L1.2>A / G1>A	6-G1v3-1 CH2 A1.2, A1	Reduces C1q binding [61] Reduces FcγR binding [61]	Reduces CDC [61] Reduces ADCC [61]		CH2 Leu L1.2>Ala A (235)/ Gly G1>Ala A (237)
			P114>A	6-G1v4 CH2 A114	Reduces C1q binding Reduces FcγR binding	Reduces ADCC Reduces CDC [2]	CH2 Pro P114 (329) is conserved in the four Homsap IGHG.	CH2 Pro P114>Ala A (329)
			P114>R	6-G1v4-2 CH2 R114	Reduces C1q binding [2] Reduces FcγR binding [2]	Reduces ADCC [2] Reduces CDC [2]	CH2 Pro P114 (329) is conserved in the four Homsap IGHG.	CH2 Pro P114>Arg R (329)
			D27>A / P114>A	6-G1v4-66 CH2 A27, A114	Reduces C1q binding [41] Reduces FcγR binding [41]	Reduces ADCC [41] Reduces CDC [41]		CH2 Asp D27>Ala A (265)/ Pro P114>Ala A (329)
			L1.3>A / L1.2>A	6-G1v14 CH2 A1.3, A1.2	Reduces C1q binding [10] Reduces FcγR binding [10]	Reduces CDC [10] Reduces ADCC [10]		CH2 Leu L1.3>Ala A (234)/ Leu L1.2>Ala A (235)
			L1.3>A / L1.2>A / G1>A	6-G1v14-1 CH2 A1.3, A1.2, A1	Reduces C1q binding [11] Reduces FcγR binding [11]	Reduces CDC [11] Reduces ADCC [11]		CH2 Leu L1.3>Ala A (234)/Leu L1.2>Ala A (235)/Gly G1>Ala A (237)
			L1.3>A / L1.2>A / G1>A / K105>A	6-G1v14-1-20 CH2 A1.3, A1.2, A1, A105	Reduces C1q binding [58] Reduces FcγR binding [58]	Reduces CDC [58] Reduces ADCC [58]		CH2 L1.3>Ala A (234)/ Leu L1.2>Ala A (235)/ Gly G1>Ala A (237)/ Lys K105>Ala A (322)
			L1.3>A / L1.2>A / P114>A	6-G1v14-4 CH2 A1.3, A1.2, A114	Reduces C1q binding [12] Reduces FcγR binding [12]	Reduces CDC [12] Reduces ADCC [12]		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	6-G1v14-48 CH2 A1.3, A1.2, R113	Reduces C1q binding Reduces FcγR binding	Reduces CDC [75] Reduces ADCC [75]		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	6-G1v14-49 CH2 A1.3, A1.2, G114	Abrogates C1q binding [13] Abrogates FcγR binding [13]	Reduces CDC [13] Reduces ADCC [13]		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	6-G1v14-67 CH2 A1.3, A1.2, S27	Reduces C1q binding [14] Reduces FcγR binding [14]	Reduces CDC [14] Reduces ADCC [14]		CH2 Leu L1.3>Ala A (234)/ Leu L1.2>Ala A (235)/ Asp D27>Ser S (265)
			L1.2>E	6-G1v23 CH2 E1.2	Reduces C1q binding [19] Reduces FcγR binding [19]	Reduces CDC [19] Reduces ADCC [19]		CH2 Leu L1.2>Glu E (235)
			N108>S / L113>F	6-G1v38 CH2 S108, F113	Abrogates C1q and FcγRIII binding, increases FcγRII binding, retains FcγRI high affinity binding [29]	Reduces CDC [29] Reduces ADCC [29]	anti-TLR4 Hu 15C1 humanized mAb [29]	CH2 Asn N108>Ser S (325)/ Leu L113>Phe F (328)
			L1.3>F / L1.2>E / P116>S	6-G1v39 CH2 F1.3, E1.2, S116	Reduces C1q binding [96] Reduces FcγR binding [96]	Reduces CDC [96] Reduces ADCC [96]		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	6-G1v40 CH2 A1.3, A1.2, S116	Reduces C1q binding [31] Reduces FcγR binding [31]	Reduces CDC [31] Reduces ADCC [31]		CH2 Leu L1.3>Ala A (234)/ Leu L1.2>Ala A (235)/ Pro P116>Ser S (331)
			L1.3>F / L1.2>E	6-G1v41 CH2 F1.3, E1.2	Reduces C1q binding [75] Reduces FcγR binding [75]	Reduces CDC [75] Reduces ADCC [75]		CH2 Leu L1.3>Phe F (234)/ Leu L1.2>Glu E (235)
			L1.3>F / L1.2>E / D27>A	6-G1v41-66 CH2 F1.3, E1.2, A27	Reduces C1q binding [59] Reduces FcγR binding [59]	Reduces CDC [59] Reduces ADCC [59]		CH2 Leu L1.3>Phe F (234)/ Leu L1.2>Glu E (235)/ Asp D27>Ala A (265)
			L1.3>A / L1.2>E / G1>A	6-G1v43 CH2 A1.3, E1.2, A1	Reduces C1q binding [11] Reduces FcγR effector properties [11]	Reduces CDC [11] Reduces ADCC [11]		CH2 Leu L1.3>Ala A (234)/Leu L1.2>Glu E (235)/Gly G1>AlaA (237)
			L1.3>A / G1>A	6-G1v43-1 CH2 A1.3, A1		Reduces CDC [41] Reduces ADCC [41]		CH2 Leu L1.3>Ala A (234)/ Gly G1>Ala A (237)
			L1.3>A / L1.2>E	6-G1v43-2 CH2 A1.3, E1.2		Reduces CDC [72] Reduces ADCC [72]		CH2 Leu L1.3>Ala A (234)/ Leu L1.2>Glu E (235)
			L1.3>A / L1.2>E / G1>A / A115>S / P116>S	6-G1v43-60 CH2 A1.3, E1.2, A1, S115, S116	Reduces C1q binding [32] Reduces FcγR binding [32]	Reduces CDC [32] Reduces ADCC [32]		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	6-G1v48 CH2 R113	Reduces C1q binding Reduces FcγR binding	Reduces CDC [75] Reduces ADCC [75]		CH2 Leu L113>Arg R (328)
			P114>G	6-G1v49 CH2 G114	Reduces C1q binding [12] Reduces FcγR binding [12]	Reduces CDC [12] Reduces ADCC [12]		CH2 Pro P114>Gly G (329)
			E1.4>del / L1.3>P / L1.2>A / G1.1>A / P114>A	6-G1v50-1-4 CH2 delE1.4, P1.3, A1.2, A1.1, A114	Reduces C1q binding Reduces FcγR binding	Reduces CDC Reduces ADCC		CH2 Glu E1.4>del (233)/ Leu L1.3>Pro P (234)/ Leu L1.2>Ala A (235)/ Gly G1.1>Ala A (236)/ Pro P114>Ala A (329)
			E1.4>del / L1.3>P / L1.2>V / G1.1>A / P114>A	6-G1v50-4 CH2 delE1.4, P1.3, V1.2, A1.1, A114	Reduces C1q binding Reduces FcγR binding	Reduces CDC Reduces ADCC		CH2 Glu E1.4>del (233)/ Leu L1.3>Pro P (234)/ Leu L1.2>Val V (235)/ Gly G1.1>Ala A (236)/ Pro P114>Ala A (329)
			E1.4>del / L1.3>P / L1.2>V / G1.1>A / S29>K	6-G1v50-51 CH2 delE1.4, P1.3, V1.2, A1.1, K29		Reduces CDC Reduces ADCC		CH2 Glu E1.4>del (233)/ Leu L1.3>Pro P (234) / Leu L1.2>Val V (235) / Gly G1.1>Ala A (236) / Ser S29>Lys K (267)
			S29>K	6-G1v51 CH2 K29	Reduces C1q binding [75] Reduces FcγR binding [75]	Reduces CDC [75] Reduces ADCC [75]		CH2 Ser S29>Lys K (267)
			L1.3>F / L1.2>Q / K105>Q	6-G1v53 CH2 F1.3, Q1.2, Q105	Reduces C1q binding [38] Reduces FcγR binding [38]	Reduces CDC [38] Reduces ADCC [38]		CH2 Leu L1.3>Phe F (234)/ Leu L1.2>Gln Q (235)/ Lys K105>Gln Q (322)
			L1.3>A / L1.2>Q / K105>Q	6-G1v53-1 CH2 A1.3, Q1.2, Q105	Reduces C1q binding [57] Reduces FcγR binding [57]	Reduces CDC [57] Reduces ADCC [57]		CH2 Leu L1.3>Ala A (234)/ Leu L1.2>Gln Q (235)/ Lys K105>Gln Q (322)
			L1.3>S / L1.2>T / G1.1>R	6-G1v59 CH2 S1.3, T1.2, R1.1	Abrogates C1q binding [41] Abrogates FcγR binding [41]	Reduces CDC [41] Reduces ADCC [41]	Undetectable ADCC and CDC	CH2 Leu L1.3>Ser S (234)/ Leu L1.2>Thr T (235)/ Gly G1.1>Arg R (236)
			L1.2>G / G1.1>R	6-G1v59-1 CH2 G1.2, R1.1		Reduces CDC [62] Reduces ADCC [62]		CH2 Leu L1.2>Gly G (235)/ Gly G1.1>Arg R (236)
			L1.2>R / G1.1>R / S3>K	6-G1v59-2 CH2 R1.2, R1.1, K3		Reduces CDC [67] Reduces ADCC [67]		CH2 Leu L1.2>Arg R (235)/ Gly G1.1>Arg R (236)/ Ser S3>Lys K (239)
			A115>S / P116>S	6-G1v60 CH2 S115, S116	Reduces C1q binding [41] Reduces FcγR binding [41]	Reduces CDC [41] Reduces ADCC [41]		CH2 Ala A115>Ser S (330)/ Pro P116>Ser S (331)
			A110>G / A115>S / P116>S	6-G1v60-1 CH2 G110, S115, S116	Reduces C1q binding Reduces FcγR binding	Reduces CDC Reduces ADCC		CH2 A Ala110>G Gly (327)/ Ala A115>Ser S (330)/ Pro P116>Ser S (331)
			P2>S	6-G1v63 CH2 S2	Reduces C1q binding Reduces FcγR binding	Reduces CDC [75] Reduces ADCC [75]		CH2 Pro P2>Ser S (238)
			E1.4>del / L1.3>del / L1.2>del	6-G1v65 CH2 delE1.4, delL1.3, delL1.2	Reduces C1q binding [43] Reduces FcγR binding [43]	Abolishes CDC [43] Abolishes ADCC [43]		CH2 Glu E1.4>del (233)/ Leu L1.3>del (234)/ Leu L1.2>del (235)
			L1.3>A / L1.2>A / G1>A / P2>S / H30>A / A115>S / P116>A	6-G1v97 CH2 A1.3, A1.2, A1, S2, A30, S115, S116	Reduces C1q binding Reduces FcγR binding	Abrogates CDC, ADCC and ADCP[113]		CH2 Leu L1.3>Ala A (234)/ Leu L1.2>Ala A (235)/ Gly G1>Ala A (237)/ Pro P2>Ser S (238)/ His H30>Ala A (268)/ Ala A115>Ser S (330)/ Pro P116>Ser S (331)
			CH2 E31>R / K105>A	1,5-G1v101-20 CH2 R31, A105		Reduces CDC [53] Reduces ADCC [53]		CH2 E Glu31>Arg R (269)/ K Lys105>A Ala (322)
	IGHG2	CH2	H30>Q / V92>L / A115>S / P116>S	6-G2v2 CH2 Q30, L92, S115, S116	Reduces C1q binding [78] Reduces FcγR binding [78]	Reduces CDC [78] Reduces FcγR effector properties [78]	IgG2m4 (6-G2v2) is based on the G2 isotype with AA changes from G4 [78]	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	6-G2v3 CH2 A1.2, A1, S2, A30, L92, S115, S116	Reduces C1q binding Reduces FcγR [30]	Reduces CDC, ADCC and ADCP[30]		CH2 Val V1.2>Al 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)
			V1.2>A / G1>A	6-G2v3-1 CH2 A1.2, A1	Reduces C1q binding Reduces FcγR [116]	Reduces CDC and ADCC[116]		CH2 Val V1.2>Al A (235)/ Gly G1>Ala A (237)
			F85.2>Y / 92>L / T339>A	6,10-G2v7 CH2 Y85.2, L92, A339	Low C1q binding [80] Low FcγR binding [80]	Low CDC [80] Low ADCC [80]	Reduces acid-induced aggregation [80]	CH2 Phe F85.2>Tyr Y (300)/ Val V92>Leu L (309)/ Thr T339>Ala A (339)
			A115>S / P116>S	6-G2v60 CH2 S115, S116	Reduces C1q binding [81] Reduces FcγR binding [81]	Reduces CDC [81] Reduces ADCC [81]		CH2 Ala A115>Ser S (330)/ Pro P116>Ser S (P331)
			D27>A / A115>S / P116>S	6-G2v60-66 CH2 A27, S115, S116	Reduces C1q binding [46][81] Reduces FcγR binding [46][81]	Reduces CDC [46][81] Reduces ADCC [46][81]		CH2 Asp D27>Ala A (265)/ Ala A115>Ser S (330)/ Pro P116>Ser S (P331)
	IGHG2-IGHG4	CH2	Hybrid G2 CH1-h-CH2 N-terminus-G4 CH2-CH3	19-G2G4v1	Reduces C1q binding [111] Reduces FcγR binding [111]	Reduces CDC [111] Reduces FcγR effector properties [111]	Eculizumab: The heavy chain is a hydrid of IGHG2*01 CH1-hinge-CH2 N-terminus domains and IGHG4*01 CH2-CH3 domains. 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.	CH2 (233-236)
			Hybrid G2 CH1-h-CH2-G4 CH3	19-G2G4v2	Reduces C1q binding Reduces FcγR binding	Reduces CDC Reduces FcγR effector properties	Nemolizumab: The heavy chain is a hybrid of IGHG2*01 CH1-hinge-CH2 domains and IGHG4*01 CH3 domain.
	IGHG4	CH2	L1.2>E	6-G4v3 CH2 E1.2	Reduces C1q binding [19] Reduces FcγR binding [19]	Reduces CDC [19] Reduces ADCC [19]		CH2 Leu L1.2>Glu E (235)
			L1.2>E / P114>G	6-G4v3-49 CH2 E1.2, G114	Reduces C1q binding [12] Reduces FcγR binding [12]	Reduces CDC [12] Reduces ADCC[12]		CH2 Leu L1.2>Glu E (235)/ Pro P114>Gly G (329)
			F1.3>A / L1.2>A	6-G4v4 CH2 A1.3, A1.2	Reduces C1q binding [10] Reduces FcγR binding [10]	Reduces CDC [10] ADCC [10]		CH2 Phe F1.3>Ala A (234)/ Leu L1.2>Ala A (235)
			L1.2>A	6-G4v4-1 CH2 A1.2	Reduces C1q binding [115] Reduces FcγR binding [115]	Reduces CDC [115] ADCC [115]		CH2 Leu L1.2>Ala A (235)
			E1.4>P / F1.3>V / L1.2>A / D27>A	6,1-G4v9-66 CH2 P1.4, V1.3, A1.2, A27	Reduces C1q binding [95]Reduces FcγR binding [95]	Reduces CDC [95] Reduces ADCC[95],[112]		CH2 Glu E1.4>Pro P (233)/ Phe F1.3>Val V (234)/ Leu L1.2>Ala A (235)/ Asp D27>Ala A (265)
			E1.4>del / F1.3>P / L1.2>V / G1.1>A	6-G4v7 CH2 E1.4del, P1.3, V1.2, A1.1	Reduces C1q binding [75] Reduces FcγR binding [75]	Reduces CDC [75] Reduces ADCC [75]		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	6-G4v9 CH2 P1.4, V1.3, A1.2	Reduces C1q binding [113] Reduces FcγR binding [113]	Reduces CDC [113] Reduces ADCC [113]		CH2 Glu E1.4>Pro P (233)/ Phe F1.3>Val V (234)/ Leu L1.2>Ala A (235)
			F1.3>A / L1.2>A / G1>A / P2>S	6-G4v34 CH2 A1.3, A1.2, A1, S2		Reduces CDC [113] Reduces ADCC[113]		CH2 Phe F1.3>Ala A (234)/ Leu L1.2>Ala A (235)/ Gly G1>Ala A (237)/ Pro P2>Ser S (238)
			F1.3>A / L1.2>A / G1.1>del / G1>A / P2>S	6-G4v35 CH2 A1.3, A1.2, delG1.1, A1, S2		Reduces CDC [113] Reduces ADCC[113]		CH2 Phe F1.3>Ala A (234)/ Leu L1.2>Ala A (235)/ Gly G1.1>del (236)/ Gly G1>Ala A (237)/ Pro P2>Ser S (238)
			P114>G	6-G4v49 CH2 G114	Reduces C1q binding [12] Reduces FcγR binding [12]	Reduces CDC [12] Reduces ADCC[12]		CH2 Pro P114>Gly G (329)
	IGHG4-IGHG1	CH2	Hybrid G4 CH1-h-CH2-G1 CH3	19-G4G1v1	Reduces C1q binding Reduces FcγR binding	Reduces CDC Reduces ADCC	Vixarelimab: The heavy chain is a hybrid of IGHG4*01 CH1-hinge-CH2 domains and IGHG1*01 CH3 doamin.




Dual effect: ADCC reduction, CDC enhancement

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on binding	Modification of effector properties	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH2	K109>W	1,4-G1v5 CH2 W109	Increases C1 binding [3]	Enhances CDC [3] Reduces ADCC [3]	CH2 Lys K109>Trp W (326)
			L1.3>A / L1.2>A / K109>A / E118>S	1,4-G1v5-2 CH2 A1.3, A1.2, A109, S118	Increases C1q binding [113]	Enhances CDC [113] Reduces ADCC [113]	CH2 Leu L1.3>Ala A (234)/ Leu L1.2>Ala A (235)/ Lys K109>Ala A (326)/ Glu E118>Ser S (333)




Dual effect: ADCC enhancement, CDC reduction

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on binding	Modification of effector properties	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH2	S3>D / A115>L / I117>E	2,5-G1v8 CH2 D3, L115, E117	Increases FcRIIIa binding [5] Decreases FcRIIb binding [5]	Enhances ADCC [5] Ablates CDC [5]	CH2 Ser S3>Asp D (239)/ Ala A115>Leu L (330)/ IIe I117>Glu E (332)




#7 B cell inhibition

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on binding	Modification of effector properties	IMGT Notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH2	S29>E / L113>F	7-G1v25 CH2 E29, F113	Increases FcγRIIb binding (400-fold) [21]	Inhibits by downstream ITIM signaling in B cells	obexelimab XmAb5871	CH2 Ser S29>Glu E(267)/ Leu L113>Phe F(328)
			P2>D	6,7-G1v63-2 CH2 D2	Increases FcγRIIb binding [113]	Inhibits by downstream ITIM signaling in B cells [113]	Reduces ADCC and CDC	CH2 Pro P2>Asp D (238)
			E1.4>D / G1>D / P2>D / H30>D / P35>G / A115>R	6,7-G1v63-3 CH2 D1.4, D1, D2, D30, G35, R115	Increases FcγRIIb binding [113]	Inhibits by downstream ITIM signaling in B cells [113]	Reduces ADCC and CDC	CH2 Glu E1.4>Asp D (233)/ Gly G1>Asp D (237)/ Pro P2>Asp D (238)/ His H30>Asp D (268)/ Pro P35>Gly G (271)/ Ala A115>Arg R (330)
			L1.2>W / G1.1>N / H30>D / A115>K	7-G1v85 CH2 W1.2, N1.1, D30, K115	Increases FcγRIIb binding [113]	Inhibits by downstream ITIM signaling in B cells [113]		CH2 Leu L1.2>Trp W (235)/ Gly G1.1>Asn N (236)/ His H30>Asp D (268)/ Ala A115>Lys K (330)
			L1.3>Y / P2>D / V26>I / A115>K	7-G1v86 CH2 Y1.3, D2, I26, K115	Increases FcγRIIb binding [113]	Inhibits by downstream ITIM signaling in B cells [113]	Reduces ADCC and CDC	CH2 Leu L1.3>Tyr Y (234)/ Pro P2>Asp D (238)/ Val V26>Ile I (264)/ Ala A115>Lys K (330)
		CH3	S85.3>P	7-G1v105 CH3 P85.3	Increases FcγRIIb binding [74]	Inhibits by downstream ITIM signaling in B cells [74]		CH3 Ser S85.3>Pro P (403)




#8 No N-glycosylation site (CH2 N84.4)

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on binding	Modification of effector properties	IMGT Notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH2	N84.4>A	8-G1v29 CH2 A84.4	Reduces FcγR binding	Reduces ADCC [25]		CH2 Asn 84.4>Ala A (297)
			N84.4>G	8-G1v30 CH2 G84.4	Reduces FcγR binding	Reduces ADCC [25]		CH2 Asn 84.4>Gly G (297)
			N84.4>H	8-G1v30-1 CH2 H84.4	Reduces FcγR binding	Reduces ADCC [37]		CH2 Asn 84.4>His H (297)
			N84.4>Q	8-G1v36 CH2 Q84.4	Reduces FcγR binding	Reduces ADCC [25]		CH2 Asn 84.4>Gln Q (297)
			N84.4>S	8-G1v36-1 CH2 S84.4	Reduces FcγR binding	Reduces ADCC [49]		CH2 Asn 84.4>Ser S (297)
	IGHG2	CH2	N84.4>Q	8-G2v36 CH2 Q84.4	Reduces FcγR binding	Reduces ADCC [83]		CH2 Asn 84.4>Gln Q (297)
	IGHG4	CH2	N84.4>G	8-G4v30 CH2 G84.4	Reduces FcγR binding	Reduces ADCC		CH2 Asn 84.4>Gly G (297)
			N84.4>Q	8-G4v36 CH2 Q84.4	Reduces FcγR binding	Reduces ADCC [12]		CH2 Asn 84.4>Gln Q(297)




Category: Half-life

#9 Half-life increase

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on half-life	IMGT notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH2	M15.1>Y / S16>T / T18>E	9-G1v21 CH2 Y15.1, T16, E18	Increases FCGRT (FcRn) binding at pH 6.0 [17]	10-fold increase at pH 6.0 [17], 4-fold increases half-life in a cynomolgus pK study [17]. T18>E amino acid change provides 2 novel salt bridges between the Fc and ΒM2 of FCGRT IMGT/3Dstructure-DB : 4n0f, 4n0u [113]. 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 [113]	CH2 Met M15.1>Tyr Y (252)/ Ser S16>Thr T (254)/, Thr T18>Glu E (256)
		CH2-CH3	(CH2) M15.1>Y / S16>T / T18>E (CH3) H113>K / N114>F / Y116>H	9-G1v22 CH2 Y15.1, T16, E18, CH3 K113, F114, H116	Increases FCGRT (FcRn) binding at pH 6.0 [18]		CH2 Met M15.1>Tyr Y (252)/ Ser S16>Thr T (254)/ Thr T18>Glu E (256)/ CH3 His H113>Lys K (433)/ Asn N114>Phe F (434)/ Tyr Y116>His H (436)
			(CH2) T14>Q / (CH3) M107>L	9-G1v42 CH2 Q14, CH3 L107	Increases FCGRT (FcRn) binding at pH 6.0 [28]		CH2 Thr T14>Gln Q (250)/ CH3 Met M107>Leu L (428)
		CH3	M107>L / N114>S	9-G1v24 CH3 L107, S114	Increases FCGRT (FcRn) binding at pH 6.0 [20] (11-fold increase in affinity at pH 6.0 [20])	Increases reduction in tumor burden in human FCGRT (FcRn) transgenic tumor-bearing mice treated with an anti-EGFR or an anti-VEGF antibody [20] From 3D structure it is postulated that N114>S allows additional hydrogen bonds with FCGRT (FcRn) [113] IMGT/3Dstructure-DB : 4n0f, 4n0u	CH3 Met M107>Leu L (428)/ Asn N114>Ser S (434)
			M107>V	9-G1v24-1 CH3 V107	Increases FCGRT (FcRn) binding at pH 6.0 [56]		CH3 Met M107>Val V (428)
			H113>K / N114>F	9-G1v46 CH3 K113, F114	Increases FCGRT (FcRn) binding at pH 6.0 [35]		CH3 His H113>Lys K (433)/ Asn N114>Phe F (434)
			M107>L / N114>A	9-G1v78 CH3 L107, A114	Increases FCGRT (FcRn) binding at pH 6.0 [60]		CH3 Met M107>Leu L (428)/ Asn N114>Ala A (434)
			M107>L / N114>A / Y116>T	9-G1v78-1 CH3 L107, A114, T116	Increases FCGRT (FcRn) binding at pH 6.0 [113]		CH3 Met M107>Leu L (428)/ Asn N114>Ala A (434)/ Tyr Y116>Thr T (436)
			N114>A	9-G1v78-2 CH3 A114	Increases FCGRT (FcRn) binding at pH 6.0 [113]		CH3 Asn N114>Ala A (434)
			H115>K	9-G1v78-3 CH3 K115	Increases FCGRT (FcRn) binding at pH 6.0 [54]		CH3 His H115>Lys K (435)
	IGHG2	CH2	T14>Q	9-G2v4 CH2 Q14	Increases FCGRT (FcRn) binding at pH 6.0[79]	4-fold increase in affinity at pH 6.0 (no binding at pH 7.5) [79]	CH2 Thr T14>Gln Q (250)
		CH2-CH3	(CH2) T14>Q / (CH3) M107>L	9-G2v6 CH2 Q14, CH3 L107	Increases FCGRT (FcRn) binding at pH 6.0 [79]	27-fold increase in affinity at pH 6.0 (no binding at pH 7.5) [79], ~1.9-fold increase half-life in rhesus monkey pK study	CH2 Thr T14>Gln Q (250)/ CH3 Met M107>Leu L (428)
		CH3	M107>L	9-G2v5 CH3 L107	Increases FCGRT (FcRn) binding at pH 6.0 [79]	8-fold increase in affinity at pH 6.0 (no binding at pH 7.5) [79], ~1.8-fold increase half-life in rhesus monkey pK study	CH3 Met M107>Leu L (428)
	IGHG3	CH3	R115>H	9-G3v1 CH3 H115	Increases FCGRT (FcRn) binding at pH 6.0 [77]		CH3 Arg R115>His H (435)
	IGHG4	CH2	M15.1>Y / S16>T / T18>E	9-G4v21 CH2 Y15.1, T16, E18	Increases FCGRT (FcRn) binding [93]		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	9-G4v22 CH2 T16, P91, CH3 A114	Expected to increase FCGRT (FcRn) binding at pH 6.0 [94]		CH2 Ser S16>Thr T (254)/ Val V91>Pro P (308)/ CH3 Asn N111>Ala A(434)
			(CH2) T14>Q / (CH3) M107>L	9-G4v42 CH2 Q14, CH3 L107	Increases FCGRT (FcRn) binding at pH 6.0		CH2 Thr T14>Gln Q (250)/ CH3 Met M107>Leu L (428)
		CH3	M107>L / N114>S	9-G4v24 CH3 L107, S114	Increases FCGRT (FcRn) binding (increased affinity at pH 6.0) [93]		CH3 Met M107>Leu L (428)/ Asn N114>Ser S (434)
			M107>L / N114>A	9-G4v78 CH3 L107, A114	Increases FCGRT (FcRn) binding at pH 6.0		CH3 Met M107>Leu L (428)/ Asn N114>Ala A (434)




#9 Half-life decrease

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on half-life	IMGT notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH2	R17>K	9-G1v77-2 CH2 K17	Reduced half-life [104]		CH2 Arg R17>Lys K (255)
		CH2-CH3	(CH2) M15.1>Y / S16>T / T18>E / (CH3) H113>K / N114>F	9-G1v22-1 CH2 Y15.1, T16, E18, CH3 K113, F114	Enhances FCGRT binding without pH dependency Reduced half-life [69]		CH2 Met M15.1>Tyr Y (252)/ Ser S16>Thr T (254)/ Tyr T18>Glu E (256)/ CH3 His H113>Lys K (433)/ Asn N114>Phe F (434)
			(CH2) I15.2>A / H93>A / (CH3) H115>A	9-G1v77-1 CH2 A15.2, A93, CH3 A115	Reduced half-life [55]		CH2 Ile I15.2>Ala A (253)/ His H93>Ala A (310)/ CH3 His H115>Ala A (435)
		CH3	H115>A	9-G1v77 CH3 A115	Reduced half-life [113]		CH3 His H115>Ala A (435)
	IGHG2	CH2	H93>A	9-G2v8-1 CH2 A93	Abrogates FCGRT binding at pH 6.0 Reduced half-life [47]		CH2 His H93>Ala A (310)
	IGHM	J-CHAIN	Y103>A	9-Jchain-v1 J-CHAIN A103	Reduces IGHM binding Reduced half-life, faster clearence		CH2 Tyr Y103>Ala A (103)




Category: Physicochemical properties

#10 Biophysical optimization

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes C domain	IMGT engineered variant nomenclature	Effects on molecular interaction	IMGT Notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH1-CH2-CH3	(CH1) N114>D / (CH2) Q84.2>E / (CH3) N44>D, Q97>E, N100>D	10-G1v108 CH1 D114, CH2 E84.2, CH3 D44, E97, D100	Fc heterodimer with one chain remaining unmutated [65]	Enhances H-H heteropairing of bispecific antibodies	CH1 Asn N114>Asp D (208)/ CH2 Gln Q84.2>Glu E (295)/ CH3 Asn N44>Asp D (384)/ Gln Q97>Glu E (418)/ Asn N100>Asp D (421)
		CH1	CH1 G16>E	10-G1v100-1 CH1 E16	pI engineering	Reduces pI for thermal stability	CH1 Gly G16>E Glu (137)
		CH2	T14>V / T90>P	10-G1v87 CH2 V14, P90	Improves CH2 thermal stability [113]		CH2 Thr T14>Val V (250)/ Thr T90>Pro P (307)
		CH2-CH3	(CH2) Q94>R / (CH3) P1.2>R	10-G1v88 CH2 R94, CH3 R1.2	pI engineering [113]	Increases pI for enhanced uptake of immune complexes	CH2 Gln Q94>Arg R (311)/ CH3 Pro P1.2>Arg R (343)
			(CH2) Q94>R / (CH3) D92>K	10-G1v88-1 CH2 R94, CH3 K92	pI engineering [113]	Increases pI for enhanced uptake of immune complexes	CH2 Gln Q94>Arg R (311)/ CH3 Asp D92>Lys K (413)
		CH3	H115>R / Y116>F	10-G1v83 CH3 R115, F116	Abrogates Protein A binding [97]	The CH3 F116 change (instead of Y) minimizes potential immunogenicity, R coexists with F in IGHG3	CH3 His H115>Arg R (435)/ Tyr Y116>Phe F (436)
			H115>R	10-G1v83-1 CH3 R115	Abrogates Protein A binding [98]		CH3 His H115>Arg R (435)
	IGHG4	CH1-CH2	(CH1) K100>Q / (CH2) F84.3>Y	18,10,9-G4v11 CH1 Q100, CH2 Y84.3	pI engineering [103]	Reduces pI for Fc heterodimer purification [103]	CH1 Lys K100>Gln Q (196)/ CH2 Phe F84.3>Tyr Y (296)
		CH3	H115>R / Y116>F / L125>P	10-G4v8 CH3 R115, F116, P125	Abrogates Protein A binding [75]	The CH3 F116 change (instead of Y) minimizes potential immunogenicity, R coexists with F in IGHG3 In IgG4, the mutation CH3 L125>P is required to incorporate residue from human IgG1 (CH3 P125 (445))	CH3 His H115>Arg R (435)/ Tyr Y116>Phe F (436)/ Leu L125>Pro P (445)
			L125>P	10-G4v8-1 CH3 P125	Reduces Acid-induced aggregation [105]		CH3 Leu L125>Pro P (445)
			H115>R / Y116>F	10-G4v83 CH3 R115, F116	Abrogates Protein A binding [97]		CH3 His H115>Arg R (435)/ Tyr Y116>Phe F (436)
			H115>R	10-G4v83-1 CH3 R115	Abrogates Protein A binding [103]		CH3 His H115>Arg R (435)
		CH3-CHS	(CH3) L125>P / (CHS) G1>del / K2>del	10-G4v8-3 CH3 P125, CHS delG1, delK2	Reduces C-terminal heterogeneity of IgG4 antibodies [103]	SLSLGK > SLSP--	CH3 Leu L125>Pro P (445)/ CHS Gly G1>del (446)/ Lys K2>del (447)
	IGLC	C-LAMBDA2	S45>G / T82>K	10-LC2v1 C-LAMBDA2 G45, K82	Improves stability for domain stabilization [106]		C-LAMBDA2 Ser S45>Gly G (152)/ Thr T82>Lys K (163)




#10 Epitope Supression

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on molecular interaction	IMGT Notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH3	Q118>R / S120>E	10-G1v89 CH3 R118, E120	Supresses Rheumatoid factor (RF) binding [73]	Fc-engineered antibodies with enhanced FcRn binding may also increase binding to rheumatoid factor (RF), an autoantibody in rheumatoid arthritis. The R118 and E120 mutations in the CH3 domain help to reduce RF binding without affecting FcRn affinity	CH3 Gln Q118>Arg R (438)/ Ser S120>Glu E (440)
	IGHG2	CH2	F84.3>A / N84.4>Q	8,10-G2v36-104 CH2 A84.3, Q84.4	Eliminates T-cell epitope in aglycosylated antibodies [83] Reduces ADCC [83]	The CH2 F84.3>A may prevent the exposure of T cell epitopes created by CH2 N84.4>Q aglycosylation, reducing immunogenicity [83]	CH2 Phe F84.3>Ala A (296)/ Asn N84.4>Q Gln (297)
	IGHG4	CH3	Q118>R / S120>E	10-G4v89 CH3 R118, E120	Supresses Rheumatoid factor (RF) binding [73]	The R118 and E120 mutations in the CH3 domain help to reduce RF binding [73]	CH3 Gln Q118>Arg R (438)/ Ser S120>Glu E (440)

Category: Structure

#11 Additional inter H-L and/or H-H disulfide bridge

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on molecular interaction	IMGT Notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH1	K12>C	11-G1v93 CH1 C12	Adds inter H-L disulfide bridge		CH1 Lys K12>C Cys (K133C)
			S94>C	11-G1v94 CH1 C94	Adds inter H-H disulfide bridge	An extra disulfide bridge in the CH1 domain reduces its flexibility	CH1 Ser S94>C Cys (S191C)
		CH2	R83>C / V85>C	11-G1v54 CH2 C83, C85	Adds inter H-H disulfide bridge [39]	Stabilizes CH2 in the absence of N84.4 (297) glycosylation [39]	CH2 Arg R83>Cys C (292)/ Val V85>Cys C (302)
			R83>C / N84.4>A / V85>C	11,8-G1v54-29 CH2 C83, A84.4, C85	Adds inter H-H disulfide bridge for domain stabilization [39]	Stabilizes CH2 in the absence of N84.4 (297) glycosylation [39]	CH2 Arg R83>Cys C (292)/ Asn N84.4>Ala A (297)/ Val V85>Cys C (302)
			R83>C / N84.4>G / V85>C	11,8-G1v54-30 CH2 C83, G84.4, C85	Adds inter H-H disulfide bridge for domain stabilization [39]	Stabilizes CH2 in the absence of N84.4 (297) glycosylation [39]	CH2 Arg R83>Cys C (292)/ Asn N84.4>Gly G (297)/ Val V85>Cys C (302)
			R83>C / N84.4>Q / V85>C	11,8-G1v54-36 CH2 C83, Q84.4, C85	Adds inter H-H disulfide bridge for domain stabilization [39]	Stabilizes CH2 in the absence of N84.4 (297) glycosylation [39]	CH2 Arg R83>Cys C (292)/ Asn N84.4>Gln Q (297)/ Val V85>Cys C (302)
	IGHG1_IGKC	CH1_C-KAPPA	(CH1) F81>C / V84>C (C-KAPPA) Q79>C / S81>C	11-G1v84 CH1 C81, C84	Adds inter H-L disulfide bridge [104]	Stabilizes bispecific antibodies	CH1 Phe F81>Cys C (170)/ Val V84>Cys C (173)
				11-KCv84 C-KAPPA C79, C81			C-KAPPA Gln Q79>Cys C (160)/ Ser S81>Cys C (S162)
	IGKC	C-KAPPA	F121>C/ C126>S	11-KCv37 C-KAPPA C121, S126	Adds inter H-L disulfide bridge and supresses inter H-L disulfide bridge	Creation of H-L disulfide bridge via C121 (F209C)	C-KAPPA Phe F121>C Cys (209)/ Cys C126>S Ser (214)
	IGHV-IGLV/IGKV	VH - V-LAMBDA	(VH) G49>C / (VL) G120>C	11-scFv-v1 C49 (VH)-C120 (VL)	Adds disulfide bridge for domain stabilization	Additional dissulfide bond to stabilize the scFv	VH Gly G49>C Cys (49)/ V-LAMBDA Gly G120>C Cys (120)
		V-LAMBDA - VH	(VL) G120>C / (VH) G49>C	11-scFv-v2 C120 (VL)-C49 (VH)	Adds disulfide bridge for domain stabilization	Additional dissulfide bond to stabilize the scFv	VL Gly G120>C Cys (120)/ VH Gly G49>C Cys (49)




#12 Prevention of IgG4 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	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG4	hinge	S10>P	12-G4v5 h P10	Reduces IgG4 half-IG exchange [90]	PSCP > PPCP (IGHG1-like)	h Ser S10>Pro P (228)
		CH3	CH3 R88>K	12-G4v6 CH3 K88	Reduces IgG4 half-IG exchange [91]	FFLYSRLT > FFLYSKLT (IGHG1-like)	CH3 Arg R88>Lys K (409)




#13 Hexamerisation

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on molecular interaction	IMGT Notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH3	E1>R / E109>G / S120>Y	4,10,13-G1v18 CH3 R1, G109, Y120	Hexamerization	Increases C1q binding [16] Enhances CDC [16]	CH3 Glu E1>Arg R (345)/Glu E109>Gly G (430)/Ser S120>Tyr Y (440) (the triple mutant IgG1-005-RGY (G1v18) form IgG1 hexamers) [16]
			E109>G	13-G1v34 CH3 G109	Hexamerization	Increases C1q binding [27] Enhances CDC [27]	CH3 Glu E109>Gly G (430)
			E1>R	10,13-G1v98 CH3 R1	Hexamerization		CH3 Glu E1>Arg R (345)




#14 Heteropairing H-H enhancement

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on molecular interaction	IMGT Notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH3	T22>Y Y86>T	14-G1v26 CH3 Y22	Knob of knobs-into-holes interactions between the CH3 of the two different gamma1 chains [22]	The T22>Y change creates the knob	CH3 Thr T22>Tyr Y (366)
				14-G1v31 CH3 T86	Hole of knobs-into-holes interactions between the CH3 of the two different gamma1 chains [22]	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	14-G1v32 CH3 W22	Knob of knobs-into-holes interactions between the CH3 of the two different gamma1 chains [26]	The T22>W change creates the knob	CH3 Thr T22>Trp W (366)
				14-G1v33 CH3 S22, A24, V86	Hole of knobs-into-holes interactions between the CH3 of the two different gamma1 chains [26]	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>Val V (407)
			T6>V / T22>L / K79>L / T81>W T6>V / L7>Y / F85.1>A / Y86>V	14-G1v68 CH3 V6, L22, L79, W81	Enhances H-H heteropairing of bispecific antibodies [44]		CH3 Thr T6>Val V (350)/ Thr T22>Leu L (366)/ Lys K79>Leu L (392)/ Thr T81>Trp W (394)
				14-G1v69 CH3 V6, Y7, A85.1, V86			CH3 Thr T6>Val V (350)/ Leu L7>Tyr Y (351)/ Phe F85.1>Ala A (405)/ Tyr Y86>Val V (407)
			L7>D / L24>E L7>K / T22>K	14-G1v72 CH3 D7, E24	Enhances H-H heteropairing of bispecific antibodies [66]	Heterodimerization by electrostatic steering attraction, avoiding homodimerization of CH3 domains by electrostatic repulsion	CH3 Leu L7>Asp D (351)/ Leu L24>Glu E (368)
				14-G1v73 CH3 K7, K22			CH3 Leu L7>Lys K (351)/ Thr T22>Lys K (366)
			L7>E / Y86>L / K88>V T22>L / D84.2>R	14-G1v72-1 CH3 E7, L86, V88	Enhances H-H heteropairing of bispecific antibodies [68]		CH3 Leu L7>Glu E (351)/ Tyr Y86>Leu L (407)/ Lys K88>Val V (409)
				14-G1v73-1 CH3 L22, R84.2			CH3 Tyr T22>Leu L (366)/ Asp D84.2>Arg R (399)
			K79>D / K88>D E12>K / E84.2>K	14-G1v72-2 CH3 D79, D88	Enhances H-H heteropairing of bispecific antibodies [70]	Heterodimerization by electrostatic steering attraction, avoiding homodimerization of CH3 domains by electrostatic repulsion	CH3 Lys K79>Asp D (392)/ Lys K88>Asp D (409)
				14-G1v73-2 CH3 K12, K84.2			CH3 Glyu E12>Lys K (356)/ Glu E84.2>Lys K (399)
			S10>C Y5>C	14-G1v74 CH3 C10	Enhances H-H heteropairing for domain stabilization [50]	Heterodimerization by electrostatic steering attraction, avoiding homodimerization of CH3 domains by electrostatic repulsion	CH3 Ser S10>Cys C (354)
				14-G1v75 CH3 C5			CH3 Tyr Y5>Cys C (349)
			F85.1>K K88>A	14-G1v82-3 CH3 K85.1	Enhances H-H heteropairing of bispecific antibodies [66]		CH3 Phe F85.1>Lys K (405)
				14-G1v82-4 CH3 A88			CH3 Lys K88>Ala A (409)
			K16>E, K88>W Q3>R, D84.2>V, F85.1>T	14-G1v90 CH3 E16, W88	Knob of knobs-into-holes interactions between the CH3 of the two different gamma1 chains	The T22>S, L24>A, F85.1>K and Y86>V changes, in the partner CH3 domain, create the hole	CH3 Lys K16>E Glu (360)/ Lys K88>Trp W (409)
				14-G1v91 CH3 R3, V84.2, T85.1	Hole of knobs-into-holes interactions between the CH3 of the two different gamma1 chains	The T22>W and K88>A changes create the knob	CH3 Gln Q3>Arg R (347)/ Asp D84.2>Val V (399)/ Phe F85.1>Tyr T (405)
		h-CH3	(h) D6>E / (CH3) L24>E (h) D6>R / (CH3) K88>R	14-G1v99-1 h E6, CH3 E24	Enhances H-H heteropairing of bispecific antibodies	Heterodimerization by electrostatic steering attraction, avoiding homodimerization of CH3 domains by electrostatic repulsion	h Asp D6>E Glu (221)/ CH3 Leu L24>E Glu (368)
				14-G1v99-2 h R6, CH3 R88			h Asp D6>Arg R (221)/ CH3 Lys K88>Arg R (409)
	IGHG2	h-CH3	(h) C5>E / P10>E / (CH3) L24>E (h) C5>R / E7>R / P10>R / (CH3) K88>R	14-G2v72-1 h E5, E10, CH3 E24	Enhances H-H heteropairing of bispecific antibodies [82]	Heterodimerization by electrostatic steering attraction, avoiding homodimerization of CH3 domains by electrostatic repulsion	h Cys C5>Glu E (220)/ Pro P10>Glu E (228)/ CH3 Leu L24>Glu E (368)
				14-G2v73-1 h R5, R7, R10, CH3 R88			h Cys C5>Arg R (220)/ Glu E7>Arg R (224)/ Pro P10>Arg R (228)/ CH3 Lys K88>Arg R (409)
		CH3	K26>E / K88>E E13>K / D84.2>K	14-G2v72-2 CH3 E26, E88	Enhances H-H heteropairing of bispecific antibodies [85]	Heterodimerization by electrostatic steering attraction, avoiding homodimerization of CH3 domains by electrostatic repulsion	CH3 Lys K26>Glu E (370)/ Lys K88>Glu E (409)
				14-G2v73-2 CH3 K13, K84.2			CH3 Glu E13>Lys K (357)/ Asp D84.2>Lys K (399)
	IGHG4	CH3	E12>K K119>E	14-G4v12 CH3 K12	Enhances H-H heteropairing of bispecific antibodies [103]	Heterodimerization by electrostatic steering attraction, avoiding homodimerization of CH3 domains by electrostatic repulsion	CH3 Glu E12>Lys K (356)
				14-G4v13 CH3 E119			CH3 Lys K119>Glu E (439)
			T22>W T22>S /L24>A / Y86>V	14-G4v32 CH3 W22	Knob of knobs-into-holes interactions between the CH3 of the two different gamma1 chains [26]	The T22>W change creates the knob	CH3 Thr T22>Trp W (366)
				14-G4v33 CH3 S22, A24, V86	Hole of knobs-into-holes interactions between the CH3 of the two different gamma1 chains [26]	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>Val V (407)




#15 Suppression of inter H-L and/or H-H disulfide bridge

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on molecular interaction	IMGT Notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	hinge	C5>S	15-G1v37 h S5	Supresses inter H-H disulfide bridge [108]		hinge Cys C5>Ser S (220)
			C5>G	15-G1v37-1 h G5	Supresses inter H-H disulfide bridge [104]		hinge Cys C5>Gly G (220)
			C11>S	15-G1v61 h S11	Supresses inter H-H disulfide bridge (h11) [75]		hinge Cys C11>Ser S (226)
			C14>S	15-G1v62 h S14	Supresses inter H-H disulfide bridge (h14) [75]		hinge Cys C14>Ser S (229)
			C5>S / C11>S / C14>S	15-G1v70 h S5, S11, S14	Supresses inter H-H disulfide bridges [45]		hinge Cys C5>Ser S (220)/ Cys C11>Ser S (226)/ Cys C14>Ser S (229)
	IGHG2	CH1	C10>S	15-G2v97 CH1 S10	Supresses inter H-H disulfide bridge		hinge Cys C10>Ser S (131)
		hinge	C4>S	15-G2v37 h S4	Supresses inter H-L disulfide bridge [84]		hinge Cys C4>Ser S (219)
	IGHG4	CH1	C10>S	15-G4v97 CH1 S10	Supresses inter H-H disulfide bridge		hinge Cys C10>Ser S (131)
	IGKC	C-KAPPA	C126>S	15-KCv36 C-KAPPA S126	Supresses inter H-L disulfide bridge [108]		C-KAPPA Cys C126>S Ser (214)
Mus musculus	IGKC	C-KAPPA	C126>S	Musmus 15-KCv36 C-KAPPA S126	Supresses inter H-L disulfide bridge		C-KAPPA Cys C126>Ser S (214)




#16 Site-specific drug attachment

Species	IMGT gene name	IMGT C domain	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on molecular interaction	IMGT Notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH1	A1.4>C	16-G1v27-1 CH1 C1.4	Site-specific drug attachment [109]	Engineered cysteine for site-specific conjugation [109]	CH2 Ala A1.4>Cys C (118)
			CH1 A1.4>(pAF)F	16-G1v56-1 CH1 F(pAF)1.4	Site-specific drug attachment [99]	The modified amino acid para-acetylphenylalanine (pAF) is a non-natural phenylalanine variant that facilitates site-specific conjugation in antibody-drug conjugates (ADCs) [99]	CH1 Ala A85.2>F (pAF) (118)
		CH2	S3>C	16-G1v27 CH2 C3	Site-specific drug attachment [23]	Engineered cysteine for site-specific conjugation [23]	CH2 Ser S3>Cys C (239)
			3^4 ins^C	16-G1v28 CH2 insC3A	Site-specific drug attachment [24]	Reduces Fcγ effector proporties [24]	CH2 3^4 ins^Cys C(239^240)
			E36>C	16-G1v64 CH2 C36	Site-specific drug attachment [42]	Engineered cysteine for site-specific conjugation [42]	CH2 Glu E36>Cys C (272)
			D27>C	16-G1v76 CH2 C27	Site-specific drug attachment	Engineered cysteine for site-specific conjugation Reduces FcγR binding	CH2 Asp D27>Cys C (265)
		CH1-CH3	(CH1) Y85.2>(pAMF)F / (CH3) F85.2>(pAMF)F	16-G1v56 CH1 F(pAMF)85.2, CH3 F(pAMF)85.2	Site-specific drug attachment [40]	The modified amino acid p-azidomethyl-L-phenylalanine (pAMF) is a non-natural phenylalanine variant that facilitates site-specific conjugation in antibody-drug conjugates (ADCs)	CH1 Tyr Y85.2>F (pAMF) (180)/ CH3 Phe F85.2>F (pAMF) (404)
		CH3	S122>C	16-G1v44 CH3 C122	Site-specific drug attachment [33]	Engineered cysteine for site-specific conjugation [33]	CH3 Ser S122>Cys C (442)
			L123>C	16-G1v55 CH3 C123	Site-specific drug attachment [33]	Engineered cysteine for site-specific conjugation [33]	CH3 Leu L123>Cys C (443)
			F85.2>(pAMF)F	16-G1v56-2 CH3 F(pAMF)85.2	Site-specific drug attachment [112]	The modified amino acid p-azidomethyl-L-phenylalanine (pAMF) is a non-natural phenylalanine variant that facilitates site-specific conjugation in antibody-drug conjugates (ADCs) [112]	CH3 Phe F85.2>F (pAMF) (404)
	IGHG1-IGKC	CH2 - C-KAPPA	(CH2) K81>C (C-KAPPA) K93>C	16-G1v81 CH2 C81	Site-specific drug attachment [89]	Engineered cysteine for site-specific conjugation [89]	CH2 Lys K81>Cys C (290)/ C-KAPPA Lys K93>Cys C (183)
				16-KCv93 C-KAPPA C93




#17 Heteropairing H-L enhancement

Species	IMGT gene name	IMGT IGHG CH and IGKC/IGLC domains	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on molecular interaction	IMGT Notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1_IGKC	CH1_C-KAPPA	(CH1) K26>E / K119>E (C-KAPPA) E12>R / Q13>K	17-G1v57 CH1 E26, E119	Enhances H-L heteropairing of bispecific antibodies [75]		CH1 Lys K26>Glu E (147)/ Lys K119>Glu E (213)
				17-KCv57 C-KAPPA R12, K13			C-KAPPA Glu E12>Arg R (123)/ Gln Q13>Lys K (124)
			(CH1) K26>D (C-KAPPA) S20>K	17-G1v57-3 CH1 D26	Enhances H-L heteropairing of bispecific antibodies [104]		CH1 Lys K26>Asp D (147)
				17-KCv57-3 C-KAPPA K20			C-KAPPA Ser S20>Lys K (131)
			(CH1) L7>E / K26>T / Q84.2>E (C-KAPPA) S20>R / V22>G / S86>R	17-G1v68-1 CH1 E7, T26, E84.2	Enhances H-L heteropairing of bispecific antibodies [76]		CH1 Leu L7>Glu E (128)/ Lys K26>Thr T (147)/ Gln Q84.2>Glu E (175)
				17-KCv68-1 C-KAPPA R20, G22, R86			C-KAPPA Ser S20>Arg R (131)/ Val V22>Gly G (133)/ Ser S86>Arg R (176)
		VH-CH1_VK - C-KAPPA	(VH) Q44>E, CH1 S86>K (V-KAPPA) Q44>K, (C-KAPPA) V22>E	17-G1v84-1 VH E44, CH1 K86	Enhances H-L heteropairing of bispecific antibodies		VH Gln Q44>Glu E (44)/ CH1 Ser S86>Lys K (183)
				17-Kv84-1 V-KAPPA K44, C-KAPPA E22			V-KAPPA Gln Q44>Lys K (44)/ C-KAPPA Val V22>Glu E (133)
			(VH) Q44>K, (CH1) S86>E (V-KAPPA) Q44>E, (C-KAPPA) V22>K	17-G1v84-2 VH K44, CH1 E86	Enhances H-L heteropairing of bispecific antibodies		VH Gln Q44>Lys K (44)/ CH1 Ser S86>Glu E (183)
				17-Kv84-2 V-KAPPA E44, C-KAPPA K22			V-KAPPA Gln Q44>Glu E (44)/ C-KAPPA Val V22>Lys K (133)
			(VH) Q44>E, (CH1) G77>E (V-KAPPA) Q44>K, (C-KAPPA) S3>K	17-G1v92-1 VH E44, CH1 E77	Enhances H-L heteropairing of bispecific antibodies		VH Gln Q44>Glu E (44)/ CH1 Gly G77>Glu E (166)
				17-Kv92-1 V-KAPPA K44, C-KAPPA K3			V-KAPPA Gln Q44>Lys K (44)/ C-KAPPA Ser S3>Lys K (114)
			(VH) Q44>K, (CH1) G77>K (V-KAPPA) Q44>E, (C-KAPPA) S3>E	17-G1v92-2 VH K44, CH1 K77	Enhances H-L heteropairing of bispecific antibodies		VH Gln Q44>Lys K (44)/ CH1 Gly G77>Lys K (166)
				17-Kv84-2 V-KAPPA E44, C-KAPPA E3			V-KAPPA Gln Q44>Glu E (44)/ C-KAPPA Ser S3>Glu E (114)
	IGHG1_IGLC	CH1_C-LAMBDA2	(CH1) S86>K (C-LAMBDA2) S86>E / Q88>E / T124>A	17-G1v69-1 CH1 K86	Enhances H-L heteropairing of bispecific antibodies		CH1 Ser S86>Lys K (183)
				17-LC2v69-1 C-LAMBDA2 E86, E88, A124			C-LAMBDA2 Ser S86>Glu E (176)/ Gln Q88>Glu E (178)/ Thr T124>Ala A (212)
		CH1-h_C-LAMBDA2	(CH1) F5>C / (h) C5>V (C-LAMBDA2) S10>C / C126>V	17-G1v58 CH1 C5, h V5	Enhances H-L heteropairing of bispecific antibodies [75]		CH1 Phe F5>Cys C (126)/ h Cys C5>Val V (220)
				17-LC2v58 C-LAMBDA2 C10, V126			C-LAMBDA2 Ser S10>Cys C (121)/ Cys C126>Val V (214)
	IGHG1_IGHV	CH1_C-LAMBDA2	(CH1) S86>K (C-LAMBDA2) S86>E / Y88>E / T124>A	17-G1v69-1 CH1 K86	Enhances H-L heteropairing of bispecific antibodies [112]		CH1 Ser S86>Lys K (183)
				17-LC2v69-1 C-LAMBDA2 E86, E88, A124			C-LAMBDA2 Ser S86>Glu E (176)/ Tyr Y88>Glu E (178)/ Thr T124>Ala A (212)
	IGHG4_IGKC	CH1_C-KAPPA	(CH1) Q84.2>K (C-KAPPA) S20>E, T90>E	17-G4v57-1 CH1 K84.2	Enhances H-L heteropairing of bispecific antibodies		CH1 Gln Q84.2>Lys K (180)
				17-KCv57-1 C-KAPPA E20, E90			C-KAPPA Ser S20>Glu E (131)/ Thr T90>Glu E (180)
	IGHG4_IGLC	CH1_C-LAMBDA2	(CH1) K26>E, Q84.2>E (C-LAMBDA2) T20>K, S90>K	17-G4v57-2 CH1 E26, E84.2	Enhances H-L heteropairing of bispecific antibodies		CH1 Lys K26>Glu E (147)/ Gln Q84.2>Glu E (175)
				17-LC2v57-2 C-LAMBDA2 K20, K90			C-LAMBDA2 Thr T20>Lys K (131)/ Ser S90>Ly K (180)
	IGKC	C-KAPPA	R1.4>A, T1.3>S	17-KCv96 C-KAPPA A1.4, S1.3	Enhances H-L heteropairing of bispecific antibodies		C-KAPPA Arg R1.4>Ala A (108)/ Thr T1.3>Ser S (109)




#18 Control of bispecific H-H heteropairing

Species	IMGT gene name	IMGT IGHG CH and IGKC/IGLC domains	IMGT amino acid changes on C domain	IMGT engineered variant nomenclature	Effects on molecular interaction	IMGT Notes	IMGT description of AA changes and correspondence with Eu numbering
Homo sapiens	IGHG1	CH3	F85.1>L K88>R	18-G1v82-1 CH3 L85.1	Control H-H heteropairing of bispecific antibodies [51]		CH3 Phe F85.1>Leu L (405)
				18-G1v82-2 CH3 R88			CH3 Lys K88>Arg R (409)
			L24>D / K26>S E13>Q / S20>K	18-G1v82-5 CH3 D24, S26	Control H-H heteropairing of bispecific antibodies [65]	Enhances Fc heterodimer purification [65]	CH3 Leu L24>Asp D (368)/ Lys K26>Ser S (370)
				18-G1v82-6 CH3 Q13, K20			CH3 Glu E13>Gln Q (357)/ Ser S20>Lys K (364)
			D84.2>R / K88>E	18-G1v82-7 CH3 R84.2, E88	Control H-H heteropairing of bispecific antibodies [104]	Expression of two different antibodies in a single cell Heteropairing H-H reduction [104]	CH3 Asp D84.2>Arg R (399)/ Lys K88>Glu E (409)
	IGHG4	CH3	F85.1>L / R88>K	18-G4v10 CH3 L85.1, K88	Control H-H heteropairing of bispecific antibodies [92]	Reduces half-IG exchange of bispecific IgG4 antibodies [92]	CH3 Phe F85.1>Leu L (405)/Arg R88>Lys K (409)




Category: Hybrid

#19 Hybrid mAbs

Species	IMGT gene name	IMGT engineered variant nomenclature	CH domains isotype	Effects on molecular interaction	IMGT Note
Homo sapiens	IGHG1-IGHG2	19-G1G2v1	G1 CH1-h-CH2 N-terminus G2 CH2-CH3	Improves mAb stability [107]	The tafasitamab protein sequence is identical to the IgG1 isotype in the Fab and hinge regions and at the N-terminus of the CH2 domain (235-242) and is identical to the IgG2 isotype in the CH2 (243-344) and CH3 domains.
		19-G1G2v2	G2 CH1 G1 hinge G2 CH2-CH3	Improves mAb stability and flexibility [110]	Using an IgG1 hinge improves antibody flexibility (abituzumab)
	IGHG1-IGHG3	19-G1G3v1	G1 CH1-h G3 CH2-CH3	Increases C1q binding [87]	CDC enhancement
	IGHG1-IGHG4	19-G1G4v1	G1 CH1-h G4 CH2-CH3	Reduces effector functions and improves stability
		19-G1G4v2	G4 CH1-h-CH2 G1 CH3	Reduces effector functions	vixarelimab
		19-G1G4v3	G4 CH1 G1 h	Improves stability
	IGHG2-IGHG4	19-G2G4v1	G2 CH1-h-CH2 N-terminus G4 CH2-CH3	Reduces effector functions [111]
		19-G2G4v2	G2 CH1-h-CH2 G4 CH3	Reduces effector functions [111]	nemolizumab



More information:
• ADCC and CDC (IMGT Lexique)
• Correspondence between C numberings (IMGT Scientific chart)
• Half-IG exchange (The IMGT Biotechnology page)
• IGHG CH properties and antibody engineering (IMGT Lexique)
• IMGT description of mutations
• Knobs-into-holes amino acid changes (The IMGT Biotechnology page)
• Protein display : house mouse (Mus musculus) IGHC (IMGT Repertoire)
• Protein display : human (Homo sapiens) IGHC (IMGT Repertoire)
• The Immunoglobulin FactsBook (FactsBook) (IMGT Index)


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Created:

11/12/2012

Last updated:

Thursday, 07-Aug-2025 21:00:49 CEST

Authors:

Taciana Manso, Karima Cherouali, Mélissa Cambon, Souphatta Sasorith and Marie-Paule Lefranc

Editor:

Chantal Ginestoux, Taciana Manso, Karima Cherouali, Mélissa Cambon and Marie-Paule Lefranc

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