## 5.4. IMGT® Structure and Amino Acid Databases

### 5.4.1. IMGT/3Dstructure-DB

IMGT/3Dstructure-DB [57–59], on the IMGT® Web site at http://www.imgt.org, provides IMGT annotations and contact analysis of three-dimensional structure data of IG, TR, MH, and RPI and their complexes. The 'PDB code' (four letters and/or numbers, e.g., 1n8z) is used as 'IMGT entry ID' for the 3D structures obtained from the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB) [297]. The IMGT/3Dstructure-DB card (per entry) provides eight search/display options: 'Chain details', 'Contact analysis', 'Paratope and epitope' [298,299], '3D visualization Jmol or QuickPDB', 'Renumbered IMGT files', 'IMGT numbering comparison', 'References and links', 'Printable card'.

'Chain details' provides detailed IMGT annotation which includes the IMGT gene and allele identification (CLASSIFICATION), region and domain delimitations (DESCRIPTION) and amino acid (AA) positions according to the IMGT unique numbering. The closest IMGT genes and alleles expressed in the AA sequences of the 3D structures are identified by aligning the AA sequences of the 3D structures with the IMGT domain reference directory. The '1n8z' comprises the trastruzumab Fab chains (L-KAPPA '1n8z_A' and the VH-CH1 '1n8z_B' (Figure 30). The Fab is in complex with the *Homo sapiens* ERRB2 (erb-b2 receptor tyrosine kinase 2, HER2, NEU, CD340) (Ligand '1n8z_C') [300].

<figure><img src="image_39.png" /></figure>

(A)

<caption>Figure 30. *Cont.*</caption>
<figure><img src="image_40.png" /><figcaption>(B)</figcaption></figure>

**Figure 30.** Chain details of the trastuzumab Fab '1n8z' in IMGT/3Dstructure-DB [57–59]. (A). L-KAPPA chain (1b8z_A). The chain sequence is identified as containing a V-KAPPA (V-REGION in green and J-REGION in orange) and a C-KAPPA (blue). (B). VH-CH1 chain (1n8z_B). The chain sequence is identified as containing a VH (V-REGION in green, N-AND-D-REGION in red and J-REGION in orange) and a CH1 (in blue). (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).

'Contact analysis' includes the 'Domain pair contacts' and the contacts between amino acids at given positions or 'IMGT Residue@Position'. Domain pair contacts between the trastuzumab Fab V-KAPPA [D1] 1n8z_A and ERBB2 ('(Ligand)' 1n8z_C) and between the trastuzumab Fab VH [D1] 1n8z_B and ERBB2 ('(Ligand)' 1n8z_C) are shown in Figure 31. An 'IMGT Residue@Position' is defined by the IMGT position numbering in a domain (or if not characterized, in the chain), the AA name (3-letter and between parentheses 1-letter abbreviation), the IMGT domain description and the IMGT chain ID, e.g., '57-TYR (Y)-VH-1n8z_B'. Its characteristics are reported in an IMGT Residue@Position card (or 'R@P') which includes (i) general information (PDB file numbering, IMGT file numbering, residue full name and formula), (ii) structural information 'IMGT LocalStructure@Position' (secondary structure, Phi and Psi angles (in degrees) and accessible surface area (ASA) (in square angstrom)) and (iii) detailed contact analysis. Contact analysis of IG/antigen complexes, is provided with detailed and standardized description of paratope/epitope in crystal structures.
## IMGT/3Dstructure-DB Domain pair contacts

### Contacts of

Domain Chain
V-KAPPA [D1] 1n8z_A

with

Domain Chain
(Ligand) 1n8z_C

### Summary:

<table><thead><tr><th rowspan="2">Residue<br>pair contacts</th><th colspan="3">Number of residues</th><th colspan="3">Atom pair contact types</th></tr><tr><th>Total</th><th>From 1</th><th>From 2</th><th>Total</th><th>Polar</th><th>Hydrogen</th><th>Nonpolar</th></tr></thead><tbody><tr><td>22</td><td>22</td><td>11</td><td>11</td><td>193</td><td>23</td><td>4</td><td>170</td></tr></tbody></table>

### List of the Residue@Position pair contacts:

Click 'R@P' for IMGT Residue@Position cards

<table><thead><tr><th rowspan="2">Order<br>IMGT<br>Num</th><th rowspan="2">Residue</th><th rowspan="2">Domain</th><th rowspan="2">Chain</th><th rowspan="2">Order<br>IMGT<br>Num</th><th rowspan="2">Residue</th><th rowspan="2">Domain</th><th rowspan="2">Chain</th><th colspan="4">Atom pair contact types</th></tr><tr><th>Total</th><th>Polar</th><th>Hydrogen</th><th>Nonpolar</th></tr></thead><tbody><tr><td>R@P 28</td><td>ASP D</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 572</td><td>GLU E</td><td>(Ligand)</td><td>1n8z_C</td><td>3</td><td>3</td><td>0</td><td>0</td></tr><tr><td>R@P 36</td><td>ASN N</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 555</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td><td>1</td><td>0</td><td>0</td><td>1</td></tr><tr><td>R@P 36</td><td>ASN N</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 570</td><td>ASP D</td><td>(Ligand)</td><td>1n8z_C</td><td>8</td><td>3</td><td>1</td><td>5</td></tr><tr><td>R@P 36</td><td>ASN N</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 572</td><td>GLU E</td><td>(Ligand)</td><td>1n8z_C</td><td>5</td><td>1</td><td>0</td><td>4</td></tr><tr><td>R@P 36</td><td>ASN N</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 574</td><td>ALA A</td><td>(Ligand)</td><td>1n8z_C</td><td>5</td><td>1</td><td>0</td><td>4</td></tr><tr><td>R@P 36</td><td>ASN N</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 576</td><td>GLN Q</td><td>(Ligand)</td><td>1n8z_C</td><td>9</td><td>4</td><td>1</td><td>5</td></tr><tr><td>R@P 37</td><td>THR T</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 576</td><td>GLN Q</td><td>(Ligand)</td><td>1n8z_C</td><td>10</td><td>2</td><td>0</td><td>8</td></tr><tr><td>R@P 37</td><td>THR T</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 577</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td><td>1</td><td>0</td><td>0</td><td>1</td></tr><tr><td>R@P 38</td><td>ALA A</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 555</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td><td>5</td><td>0</td><td>0</td><td>5</td></tr><tr><td>R@P 55</td><td>TYR Y</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 577</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td><td>2</td><td>0</td><td>0</td><td>2</td></tr><tr><td>R@P 56</td><td>SER S</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 577</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td><td>6</td><td>0</td><td>0</td><td>6</td></tr><tr><td>R@P 66</td><td>PHE F</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 577</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td><td>26</td><td>0</td><td>0</td><td>26</td></tr><tr><td>R@P 66</td><td>PHE F</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 578</td><td>CYS C</td><td>(Ligand)</td><td>1n8z_C</td><td>6</td><td>0</td><td>0</td><td>6</td></tr><tr><td>R@P 66</td><td>PHE F</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 579</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td><td>6</td><td>0</td><td>0</td><td>6</td></tr><tr><td>R@P 107</td><td>HIS H</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 555</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td><td>18</td><td>2</td><td>0</td><td>16</td></tr><tr><td>R@P 107</td><td>HIS H</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 556</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td><td>14</td><td>1</td><td>0</td><td>13</td></tr><tr><td>R@P 108</td><td>TYR Y</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 553</td><td>LYS K</td><td>(Ligand)</td><td>1n8z_C</td><td>15</td><td>1</td><td>1</td><td>14</td></tr><tr><td>R@P 108</td><td>TYR Y</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 555</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td><td>19</td><td>0</td><td>0</td><td>19</td></tr><tr><td>R@P 108</td><td>TYR Y</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 556</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td><td>12</td><td>2</td><td>0</td><td>10</td></tr><tr><td>R@P 109</td><td>THR T</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 556</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td><td>6</td><td>0</td><td>0</td><td>6</td></tr><tr><td>R@P 114</td><td>THR T</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 544</td><td>ASP D</td><td>(Ligand)</td><td>1n8z_C</td><td>12</td><td>3</td><td>1</td><td>9</td></tr><tr><td>R@P 114</td><td>THR T</td><td>V-KAPPA [D1]</td><td>1n8z_A</td><td>R@P 556</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td><td>4</td><td>0</td><td>0</td><td>4</td></tr></tbody></table>

(A)

<caption>Figure 31. *Cont.*</caption>
<table><thead><tr><th>Contacts of</th><th>Domain</th><th>Chain</th><th>with</th><th>Domain</th><th>Chain</th></tr></thead><tbody><tr><td></td><td>VH [D1]</td><td>1n8z_B</td><td></td><td>(Ligand)</td><td>1n8z_C</td></tr></tbody></table>

Summary:

<table><thead><tr><th rowspan="2">Residue pair contacts</th><th colspan="3">Number of residues</th><th colspan="3">Atom pair contact types</th></tr><tr><th>Total</th><th>From 1</th><th>From 2</th><th>Total</th><th>Polar</th><th>Hydrogen</th><th>Nonpolar</th></tr></thead><tbody><tr><td>25</td><td>21</td><td>10</td><td>11</td><td>210</td><td>27</td><td>2</td><td>183</td></tr></tbody></table>

List of the Residue@Position pair contacts:

Click 'R@P' for IMGT Residue@Position cards

<table><thead><tr><th rowspan="2">Order</th><th colspan="3">Order</th><th colspan="3">Atom pair contact types</th></tr><tr><th>Residue</th><th>Domain</th><th>Chain</th><th>Residue</th><th>Domain</th><th>Chain</th></tr></thead><tbody><tr><td>R@P 38</td><td>TYR Y</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 542</td><td>GLU E</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 38</td><td>TYR Y</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 557</td><td>PHE F</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 55</td><td>ARG R</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 542</td><td>GLU E</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 55</td><td>ARG R</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 544</td><td>ASP D</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 55</td><td>ARG R</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 556</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 55</td><td>ARG R</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 557</td><td>PHE F</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 57</td><td>TYR Y</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 542</td><td>GLU E</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 64</td><td>TYR Y</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 541</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 64</td><td>TYR Y</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 542</td><td>GLU E</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 65</td><td>THR T</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 542</td><td>GLU E</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 66</td><td>ARG R</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 542</td><td>GLU E</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 66</td><td>ARG R</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 544</td><td>ASP D</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 66</td><td>ARG R</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 545</td><td>GLN Q</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 107</td><td>TRP W</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 556</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 107</td><td>TRP W</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 557</td><td>PHE F</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 111</td><td>GLY G</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 554</td><td>ASP D</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 111</td><td>GLY G</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 563</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 111</td><td>GLY G</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 565</td><td>ILE I</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 111</td><td>GLY G</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 567</td><td>LYS K</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 112</td><td>PHE F</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 565</td><td>ILE I</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 112</td><td>PHE F</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 567</td><td>LYS K</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 113</td><td>TYR Y</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 554</td><td>ASP D</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 113</td><td>TYR Y</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 555</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 113</td><td>TYR Y</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 556</td><td>PRO P</td><td>(Ligand)</td><td>1n8z_C</td></tr><tr><td>R@P 113</td><td>TYR Y</td><td>VH [D1]</td><td>1n8z_B</td><td>R@P 557</td><td>PHE F</td><td>(Ligand)</td><td>1n8z_C</td></tr></tbody></table>

(B)

**Figure 31.** IMGT/3Dstructure-DB Domain pair contacts [57–59]. (A). Domain pair contacts between trastuzumab Fab V-KAPPA (1n8z_A) and ERBB2 ((Ligand) 1n8z_C). (B). Domain pair contacts between trastuzumab Fab VH (1n8z_B) and ERBB2 ((Ligand) 1n8z_C). Positions in the CDR1-IMGT, CDR2-IMGT and CDR3-IMGT are represented in blue, green and bluegreen, for the V-KAPPA and in red, orange and purple, for the VH. Positions in the FR-IMGT are in yellow. 55 and 66 are anchors of the CDR2-IMGT. Clicking on 'R@P' gives access to the IMGT Residue@Position card. (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).

'Renumbered IMGT flat file' allows to view (or download) an IMGT coordinate file renumbered according to the IMGT unique numbering and to which has been added the IMGT specific information.
This IMGT information (identical to that provided in 'Chain details') is in the 'REMARK 410' lines (blue online) added in the IMGT coordinate files. Tools associated to IMGT/3Dstructure-DB include IMGT/StructuralQuery and IMGT/DomainSuperimpose, available online.

In summary, the IMGT/3Dstructure-DB provides:

(1) Identification of the closest genes and alleles, according to the IMGT gene and allele nomenclature (Section 3) (e.g., for *Homo sapiens* [2,4]) (Figure 30),

(2) IMGT/DomainGapAlign results [58,79,80],

(3) IMGT Collier de Perles [47–50] (on two layers with hydrogen bonds for V and C) created by the IMGT/Collier-de-Perles tool [51],

(4) Contact analysis between a pair of domains or between a domain and a ligand (Figure 31) (paratope/epitope description of IG/antigen (Figure 32) and TR/pMH complexes) [57–59],

(5) Renumbered IMGT files [57–59],

(6) IMGT numbering comparison [57–59].

<figure><img src="image_41.png" /><figcaption>**Figure 32.** IMGT/3Dstructure-DB paratope/epitope of trastuzumab/ERBB2 in 1n8z [57–59]. The IMGT paratope, or antigen-binding site, includes the part of the VH and VL domains that recognizes (binds to) the antigen (Ag) (epitope or antigenic determinant) [298,299]. In addition to the contacts between amino acids of the CDR1-IMGT, CDR2-IMGT and CDR3-IMGT of the V-KAPPA and VH and the antigen ERBB2 (Figure 31), framework positions which are detected as having relevant contacts with the antigen are included in the paratope. This is the case, here, of the anchor positions of the CDR2-IMGT in V-KAPPA F(66_A) (Figure 31A) and in VH R(55_B) and R(66_B) (Figure 31B). These positions are classically taken into account in V domain humanization by grafting. (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).</figcaption></figure>

In July 2020, IMGT/3Dstructure-DB contained 3985 IG structure entries (including 2152 IG/Ag complexes).

### 5.4.2. IMGT/2Dstructure-DB

IMGT/2Dstructure-DB was created as an extension of IMGT/3Dstructure-DB [57–59] to describe and analyse amino acid (AA) sequences of antibodies for which no 3D structures were available. IMGT/2Dstructure-DB uses the IMGT/3Dstructure-DB informatics frame and interface, which allow one to analyse, manage, and query IG, TR, and MH, as well as other IgSF and MhSF and engineered proteins (FPIA, CPCA), as polymeric receptors made of several chains, in contrast to the IMGT/LIGM-DB sequence database that analyses and manages sequences individually [54,55]. The AA sequences are analyzed with the IMGT® criteria of standardized identification [30,31], description [32–35], nomenclature [37,38] and numerotation [39–46].

The current IMGT/2Dstructure-DB entries include 336 AA sequences of antibodies from Kabat [118] (those for which there were no available nucleotide sequences), and AA sequences of mAb and FPIA from IMGT/mAb-DB [60] and the WHO-INN programme [86,87]. Queries can be made on an individual entry, using the Entry ID or the Molecule name. Thus a 'trastuzumab' query in 'Molecule name' allows
to retrieve 18 results: five INN from IMGT/2Dstructure-DB, and thirteen 3D structures (of which "1nz8") from IMGT/3Dstructure-DB. The same query interface is used for IMGT/2Dstructure-DB and IMGT/3Dstructure-DB.

The IMGT/2Dstructure-DB cards provide standardized IMGT information on chains and domains and IMGT Colliers de Perles on one or two layers, identical to that provided for the sequence analysis in IMGT/3Dstructure-DB, however the information on experimental structural data (hydrogene bonds in IMGT Collier de Perles on two layers, Contact analysis) is only available in the corresponding IMGT/3Dstructure-DB cards, if the antibodies have been cristallised.

### 5.4.3. IMGT/mAb-DB

IMGT/mAb-DB [60], has been developed to provide an easy access to therapeutic antibody amino acid sequences (links to IMGT/2Dstructure-DB) and structures (links to IMGT/3Dstructure-DB, if 3D structures are available). IMGT/mAb-DB data include monoclonal antibodies (mAb, INN suffix -mab, being defined by the presence of at least an IG variable domain) and fusion proteins for immune applications (FPIA, for example, a receptor or membrane ligand fused to a Fc) from the WHO INN programme [86,87]. This database also includes a few composite proteins for clinical applications (CPCA) (e.g., protein or peptide fused to a Fc for only increasing their half-life; INN prefix ef- recently adopted for these CPCA) and some related proteins of the immune system (RPI) used, unmodified, for clinical applications.

## 6. Using the IMGT Numbering for V and C-Domain for Antibody Description and Engineering

### 6.1. Antibody V-DOMAIN Humanization by IMGT-CDR Grafting

#### 6.1.1. CDR-IMGT Delimitation for Grafting

For many years, the main source of specific monoclonal antibodies [301] has been from mouse or rat species, owing to the difficulty of obtaining human monoclonal antibodies by the hybridoma methodology. The objective of antibody humanization has been to graft at the DNA level the CDR of an antibody V domain, from mouse (or other species) and of a given specificity, onto the V domain framework of a human antibody, thus preserving the specificity of the original (murine or other species) antibody while decreasing its immunogenicity [302]. The Contact analysis of IG/Ag complexes in IMGT/3Dstructure-DB [57–59] and their analysis [303] demonstrate the preponderance of the CDR-IMGT amino acids in the paratope [298] (Figure 31; Figure 32). IMGT/DomainGapAlign [58,79,80] has become the IMGT reference tool for antibody humanization design based on CDR grafting. Indeed, it precisely defines the CDR-IMGT to be grafted and helps selecting the most appropriate human FR-IMGT by providing the alignment of the amino acid sequences between the mouse (or other species) and the closest human V-DOMAIN [90–100] (IMGT® http://www.imgt.org, The IMGT Biotechnology page > Antibody humanization).

Analyses performed on humanized therapeutic antibodies underline the importance of a correct delimitation of the CDR and FR. As an example, two amino acid changes were required in the first version of the humanized VH of alemtuzumab, in order to restore the specificity and affinity of the original rat antibody. The positions of these amino acid changes (S28 > F and S35 > F) are now known to be located in the CDR1-IMGT and should have been directly grafted, but at the time of this mAb humanization they were considered as belonging to the FR according to the Kabat numbering [118]. In contrast, positions 66-74 were, at the same time, considered as belonging to the CDR according to the Kabat numbering, whereas they clearly belong to the FR2-IMGT and the corresponding sequence should have been ‘human’ instead of being grafted from the ‘rat’ sequence (IMGT® http://www.imgt.org, The IMGT Biotechnology page > Antibody humanization > Alemtuzumab).

#### 6.1.2. Amino Acid Interactions between FR-IMGT and CDR-IMGT

IMGT Colliers de Perles from crystallized 3D structures in IMGT/3Dstructure-DB [57–59] highlight two conserved hydrogen bonds between FR-IMGT and CDR-IMGT positions: FR2-IMGT 39 with
CDR2-IMGT 56 (or 57) and FR2-IMGT 40 with CDR3-IMGT 105 (Figure 21). Antibody engineering and humanization should therefore preserve these bondings which stabilize the loops. It is also worthwhile to note that, in VH CDR3, the stem of the CDR3 loop is stabilized by a conserved salt bridge between R106 (arginine contributed by the 3'V-REGION) and D116 (aspartate contributed by the 5'J-REGION of the *Homo sapiens* IGHJ2, IGHJ3, IGHJ4, IGHJ5 or IGHJ6) (IMGT® http://www.imgt.org, IMGT Repertoire (IG and TR) > 2. Proteins and alleles > 2. Alignments of alleles > IGHJ > Mammalia > human (*Homo sapiens*)).

## 6.2. *Only-Heavy-Chain Antibodies*

### 6.2.1. Dromedary IgG2 and IgG3

The dromedary or Arabian camel (*Camelus dromedarius*) IGHV3 genes belong to two sets based on four AA differences which have been linked to two antibody formats expressed in Camelidae: the conventional IG (H2L2) and the “only-heavy-chain” IG (H2, i.e., no light chain and only two identical H-gamma chains lacking CH1) [304] (IMGT® http://www.imgt.org, IMGT Repertoire (IG and TR) > 2. Proteins and alleles > 1. Protein displays > V-REGION > IGHV > Arabian camel (*Camelus dromedarius*)). The AA differences characteristic of each set are located at four FR2-IMGT positions, 42, 49, 50 and 52 (42 in the C strand, 49, 50 and 52 in the C' strand), and belong to the [GFCC'C'] sheet at the hydrophobic VH-VL interface in conventional antibodies of Camelidae as well as of any vertebrate species [1] whereas, in camelid ‘only-heavy-chain’ antibodies (no light chains, and therefore no VL), these positions are exposed to the environment with, through evolution, a selection of hydrophilic amino acids [305].

The first set of IGHV3 genes is expressed in conventional tetrameric IgG1 that constitute 25% of circulating antibodies. The second set is expressed in ‘only-heavy-chain’ IgG2 and IgG3 that constitute 75% of the circulating antibodies [304]. The respective H-gamma2 and H-gamma3 chains are both characterized by the absence of the CH1 domain owing to a splicing defect [306]. It is the absence of CH1 which is responsible for the lack of association of the light chains (see 6.1.2) (Figure 33) (IMGT® http://www.imgt.org, IMGT Repertoire (IG and TR) > 1. Locus and Genes > 7. Gene tables; ibid., IMGT Biotechnology page > Characteristics of the camelidae (camel, llama) antibody synthesis). Only-heavy-chain antibodies is a feature of the Camelidae IG as they have also been found in the Bactrian camel (*Camelus bactrianus*) of Central Asia and in the llama (*Lama glama*) and alpaca (*Vicugna pacos*) of South America. The genetic event (splicing defect) responsible for the lack of CH1 occurred in their common ancestor before the radiation between the ‘camelini’ and ‘lamini’, dating approximately 11 million years (Ma) ago.

The V domains of Camelidae ‘only-heavy-chain’ antibodies have characteristics for potential pharmaceutical applications (e.g., specificities with binding to protein clefts for those with extended CDR3, easy production and selection of single-domain format with novel specificities). They are designated as VH<sub>H</sub> domain when they have to be distinguished from conventional VH (the V sequence criterion is based on the four AA at positions 42, 49, 50 and 52, particularly 49 and 50, with E49 (or Q49) and R50 in VH<sub>H</sub>, and G49 and L50 (or P50) in VH. A more complete knowledge of the germline genes is required to identify somatic mutations from genetic polymorphisms, for the other positions. Most llama VH<sub>H</sub> have normal or long CDR3-IMGT and, as expected from Arabian camel, have E49 (or Q49) and R50 (i.e., llama anti-TNF 5m2i [8.8.16] and 5m2m [12.8.18] [307], or llama anti-HIV 5hm1 [8.7.14] [308]). However some llama VH<sub>H</sub>, defined as having no paired VL, were found unexpectedly to have the conventional G49 and L50, and to be characterized by a short CDR3-IMGT of 8 amino acids and Arg R118 (instead of J-TRP W118) (i.e., 5m2j [8.8.8] [307]). The selection of the J-REGION R118 (instead of W118, in the IGHJ 118-121 ‘W-G-X-G’ motif, G strand of the V domain) and that of the V-REGION R50 (instead of L50 or P50, in the IGHV, C' strand of the V domain) represent therefore two different evolutionary paths which make the G-F-C-C' layer of the VH<sub>H</sub> more hydrophilic (Figure 21). The term ‘nanobody’ initially used for describing a single-domain format antibody is not equivalent
to VH<sub>H</sub>, as it has been used for V domains other than VH<sub>H</sub> and for constructs containing more than one V domain and is a registered mark (VH and/or VH<sub>H</sub>) (e.g., caplacizumab, ozoralizumab) (IMGT® http://www.imgt.org, IMGT/mAb-DB > caplacizumab; ibid. ozoralizumab).

<figure><img src="image_42.png" /><figcaption>**Figure 33.** Characteristics of the immunoglobulin synthesis in Camelidae. The Arabian camel (*Camelus dromedarius*) and the llama (*Lama glama*) have three IgG subclasses: the conventional IgG1 and the non-conventional IgG2 and IgG3. IgG2 and IgG3 are characterized by the absence of light chain. This lack of light chain is itself a consequence of the absence of the CH1 domain in the H-gamma 2 and H-gamma 3 chains, due to a splicing defect of the CH1 exon (non canonical DONOR-SPLICE: not instead of ngt). (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).</figcaption></figure>

### 6.2.2. Human Heavy Chain Diseases (HCD)

The camelidae 'only-heavy-chain' antibodies synthesis is remarkably reminiscent of what is observed in human heavy chain diseases (HCD). These proliferative disorders of B lymphoid cells produce truncated monoclonal immunoglobulin heavy chains which lack associated light chains. In most HCD, the absence of the heavy chain CH1 domain by deletion or splicing defect may be responsible for the lack of assembly of the light chain [309]. Similar observations have also been reported in mouse variants [309] (IMGT® http://www.imgt.org, IMGT Education > Pathology of the immune system > Molecular defects in Immunoglobulin Heavy Chain Diseases (HCD); ibid., IMGT Lexique > Heavy Chain Diseases (HCD)).

### 6.2.3. Nurse Shark IgN

A convergence mechanism in evolution is observed in nurse shark *Ginglymostoma cirratum* ('Gincir' in the IMGT 6-letter abbreviaton code for species) IgN antibodies (or IgNAR, 'immunoglobulin new antigen receptor') [310] which are 'only-heavy-chain' antibodies (H2 homodimeric H-nu chains without CH1, and no associated light chains). The IGHV genes expressed in the Gincir H-nu chains belong to the IGHV2 subgroup and are characterized by the absence of the CDR2-IMGT owing to a deletion that encompasses position 54 to 67. The Gincir IGH genes are organized in duplicated cassettes, and those that express IgN comprise Gincir IGHV2 subgroup genes and an IGHN constant gene (IMGT® http://www.imgt.org, IMGT Repertoire (IG and TR) > 2. Proteins and alleles > 1. Protein displays > IGHV > nurse shark (*Ginglymostoma cirratum*), ibid., IGHC; ibid., > 1. Locus and genes > 7. Gene tables > IGHV > Chondrichthyes > nurse shark (*Ginglymostoma cirratum*), ibid., IGHC).
## 6.3. Contact Analysis of TR-Mimic Antibodies and TR

The IMGT unique numbering has recently allowed the contact analysis comparison between an antibody and a T cell receptor, with a same ligand [311]. Both immunoglobulin, IG Fab 3M4E5, a TR-mimic antibody, and the T cell receptor, TR 1G4_a58b61, target the NY-ESO-1 peptide SLLMWITQC presented by HLA-A*02:01 [312] (Figure 34). IMGT Colliers de Perles on one and two layers and contact analyses of the IG/pMH1 (3gjf, for Fab 3M4E5) and TR/pMH1 (2p5e, for 1G4_a58b61) complexes [311] are available in IMGT/3Dstructure-DB, based on the unique numbering V-DOMAIN for IG and TR [40–42], and the IMGT unique numbering for G-DOMAIN for MH [43]. They allow to visualize the features and differences in the antigen recognition by an antibody and a TR targeting the same p/MH antigen (Figure 34). The contacts of the NY-ESO-1 peptide SLLMWITQC with the MH1 HLA-A*02:01 groove are similar in the two peptide-HLA complexes as expected [313–315].

<figure><img src="image_43.png" /><figcaption>Figure 34. *Cont.*</figcaption></figure>
<figure><img src="image_44.png" /><figcaption>**Figure 34.** Contact analysis and IMGT Collier de Perles of a TR-mimic antibody and of a TR targeting peptide-HLA. VH and V-LAMBDA of the IG Fab 3M4E5 and V-BETA and V-ALPHA of the TR 1G4_a58b61 target the NY-ESO-1 peptide presented by HLA-A*02:01 [311,312]. From top to bottom are shown: 1. contacts with the ligand, 2. contacts with G-ALPHA1, 3. contacts with G-ALPHA2, 4. IMGT Collier de Perles on one layer, 5. IMGT Collier de Perles on two layers with hydrogen bonds, 6. contacts of the NY-ESO-1 peptide SLLMWITQC with the MH1 HLA-A*02:01 groove [313–315]. The CDR1-IMGT, CDR2-IMGT and CDR3-IMGT are represented in red, orange and purple for the IG VH and the TR V-BETA, and in blue, green, bluegreen for the IG VL, here V-LAMBDA and for the TR V-ALPHA. Three-dimensional structure PDB codes are 3gjf, for Fab 3M4E5 (IG/pMH1), and 2p5e, for 1G4_a58b61 (TR/pMH1) (IMGT® http://www.imgt.org, IMGT/3Dstructure-DB). (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).</figcaption></figure>

## 6.4. Antibody C-Domain Post-Translational Modifications, Engineering and Allotypes

The constant region of the IG heavy chain is made of several CH domains, which are analysed and described in IMGT® using the IMGT unique numbering [42,44–46]. This allows a universal standardized comparison of sequences and 3D structures between C domains of any chain, any receptor and any species. Examples of post-translational modifications (glycosylations), effector properties and engineering at the C-DOMAIN level are given in the following subsections.

### 6.4.1. N-Linked Glycosylation Sites CH2 N84.4

The N-linked glycosylation site present in the CH2 domain of the constant region of the four human IG H-gamma chains is located at CH2 N84.4. As shown in the IMGT Collier de Perles, this asparagine is localized at the DE turn (Figure 35).
A.

<figure><img src="image_45.png" /></figure>

B.

<figure><img src="image_46.png" /><figcaption>**Figure 35.** *Homo sapiens* IGHG1 CH2 and N-linked glycosylation site N84.4 [94]. (A) IMGT Collier de Perles of IGHG1 CH2 on one layer (on the left) and on two layers with hydrogen bonds (on the right). The N84.4 is at the DE turn. The identifier of the chain to which the domain belongs is 1hzh_H. The IMGT Colliers de Perles on two layers show, in the forefront, the GFC strands and, in the back, the ABED strands, linked by the CD transversal strand. The IMGT Colliers de Perles were generated by the IMGT/Collier-de-Perles tool [51] integrated in IMGT/3Dstructure-DB [57–59]. Hydrogen bonds (green</figcaption></figure>
lines) and disulfide bond between C23 and C104 (orange line) were automatically added from the experimental structural data). Amino acids are shown in the one-letter abbreviation. Positions at which hydrophobic amino acids (hydropathy index with positive value: I, V, L, F, C, M, A) and tryptophan (W) are found in more than 50% of analysed sequences are shown in blue. All proline (P) are shown in yellow. Hatched circles correspond to missing positions according to the IMGT unique numbering for C domain [42]. Arrows indicate the direction of the beta strands and their designations in 3D structures. Anchors (26, 39, 45, 77, 104, 118) are shown in squares. (B) 3D structure of the IGHG1 CH2 dimer with the two carbohydrate chains. The N84.4 at the DE turn is shown on the CH2 on the left whereas the N84.4 of the CH2 on the right is hidden behind the carbohydrates. The ribbon representation of the 3D structures was obtained using PyMOL (http://www.pymol.org). The identifiers of the H-gamma1 chains to which the CH2 domains belong are 1hzh_H and 1hzh_K (IMGT® http://www.imgt.org, IMGT/3Dstructure-DB). (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).

The human glycans are mainly classified as 'biantennary complex' structure with a core fucose (Fuc) and are often terminated with N-acetylneuraminic acid (Neu5Ac), a sialic acid (Figure 36). The largest N-linked oligosaccharide structure found in human IgG is shown in Figure 36A (left panel). The conserved heptasaccharide core is composed of two N-acetylglucosamine (GlcNAc), three mannose (Man) and two other GlcNAc residues that are β-1,2 linked to α-6 Man and α-3 Man, forming two arms. The bisecting N-acetylglucosamine (GlcNac, NAG) represents around 10% of human IgG glycoforms. The four most abundant glycans in mAb biopharmaceuticals are shown in Figure 36A (right panel). The Fc oligosaccharides are terminated by zero, one or two galactoses and are called G0, G1 or G2, respectively. For G1F, Gal can be on the α1,3-arm or on the α1,6-arm. Additional fucose (Fuc), galactose (Gal), N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) residues may be present or not, particularly depending on the expression system. Mammalian cell expression systems are the favorite methods for the commercial production of monoclonal antibodies because their protein glycosylation machinery closely resembles that in human. The current marketed antibodies are mainly expressed in CHO (Chinese Hamster Ovary), SP2/0 (mouse myeloma cells), NS0 (Non-Secreting mouse myeloma cells) and hybridomas (Figure 36B).

<figure><img src="image_47.png" /></figure>

(A)

<caption>Figure 36. Cont.</caption>
<figure><img src="image_48.png" /><figcaption>**Figure 36.** (A). Largest N-linked oligosaccharide structure found in human IgG (left panel) and most abundant glycans found in mAb biopharmaceuticals (right panel). (B). Glycosylation patterns of recombinant antibodies produced in human, CHO and NS0 cells. Symbol Nomenclature for Glycans (SNFG) is according to the NCBI Glycans page https://www.ncbi.nlm.nih.gov/glycans/snfg.html. Gal: galactose, Man: mannose, Fuc: fucose, GlcNac: N-acetylglucosamine, Neu5Ac: N-acetylneuraminic acid and Neu5Gc: N-glycolylneuraminic acid. The absence of GlcNac bisecting, in glycans of recombinant antibodies produced in hamster (CHO) and mouse (NS0) cells, is marked by a white square (IMGT® http://www.imgt.org, IMGT Lexique > Immunoglobulin (IG) or antibody glycosylation). (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).</figcaption></figure>

The graphical representation of the 36 possible structures of IG N-glycans expressed in human cells are available in the IMGT Lexique, with correspondence between the 'GA' nomenclature, based on the number of galactose (G) (0, 1 or 2) and sialic acid (A) (0, 1 or 2) at the terminal ends of the arms of the IG N-glycans, and the 'HN' nomenclature based on the number of carbohydrates in the glycan composition (H: number of hexoses, N: number of N-acetyl glucosamine), with, if present, S number of sialic acids (IMGT® http://www.imgt.org, IMGT Lexique > Immunoglobulin (IG) or antibody glycosylation).

### 6.4.2. Knobs-into-Holes

The knobs-into-holes methodology has been proposed for obtaining bispecific antibodies [309]. The aim is to increase interactions between the CH3 domain of two H-gamma1 chains that belong to antibodies with a different specificity to obtain bispecific antibodies. The two amino acids CH3 T22 (B strand) and Y86 (E strand) selected for changes belong to the [ABED] sheet, at the interface of the two *Homo sapiens* IGHG1 CH3 domains (Figure 37). Interactions of these two amino acids are described in 'Contact analysis' in IMGT/3Dstructure-DB [57–59] (Figure 37A). The knobs-into-holes methodology consists into an amino acid change on one CH3 domain (here, T22 > Y) that creates a knob, and another amino acid change on the other CH3 domain (here, Y86 > T) that creates a hole, thus favoring increased interactions between the CH3 of the two H-gamma1 chains at both positions 22 and 86 [316] (IMGT® http://www.imgt.org, The IMGT Biotechnology page > Bispecific antibodies > Knobs-into-holes amino acid changes). (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).
A.

<table><thead><tr><th colspan="5">Order</th><th colspan="5">Order</th><th colspan="4">Atom pair contact types</th></tr><tr><th>IMGT Num</th><th>Residue</th><th>Domain</th><th>Chain</th><th>IMGT Num</th><th>Residue</th><th>Domain</th><th>Chain</th><th>Total</th><th>Polar</th><th>Hydrogen</th><th>Nonpolar</th></tr></thead><tbody><tr><td>R@P</td><td>22</td><td>THR</td><td>T [D5] CH3</td><td>1hzh_H</td><td>R@P</td><td>7</td><td>LEU</td><td>L [D5] CH3</td><td>1hzh_K</td><td>3</td><td>0</td><td>0</td><td>3</td></tr><tr><td>R@P</td><td>22</td><td>THR</td><td>T [D5] CH3</td><td>1hzh_H</td><td>R@P</td><td>24</td><td>LEU</td><td>L [D5] CH3</td><td>1hzh_K</td><td>1</td><td>0</td><td>0</td><td>1</td></tr><tr><td>R@P</td><td>22</td><td>THR</td><td>T [D5] CH3</td><td>1hzh_H</td><td>R@P</td><td>86</td><td>TYR</td><td>Y [D5] CH3</td><td>1hzh_K</td><td>15</td><td>2</td><td>1</td><td>13</td></tr><tr><td>R@P</td><td>86</td><td>TYR</td><td>Y [D5] CH3</td><td>1hzh_H</td><td>R@P</td><td>21</td><td>LEU</td><td>L [D5] CH3</td><td>1hzh_K</td><td>1</td><td>1</td><td>0</td><td>0</td></tr><tr><td>R@P</td><td>86</td><td>TYR</td><td>Y [D5] CH3</td><td>1hzh_H</td><td>R@P</td><td>22</td><td>THR</td><td>T [D5] CH3</td><td>1hzh_K</td><td>13</td><td>1</td><td>1</td><td>12</td></tr><tr><td>R@P</td><td>86</td><td>TYR</td><td>Y [D5] CH3</td><td>1hzh_H</td><td>R@P</td><td>81</td><td>THR</td><td>T [D5] CH3</td><td>1hzh_K</td><td>2</td><td>0</td><td>0</td><td>2</td></tr><tr><td>R@P</td><td>86</td><td>TYR</td><td>Y [D5] CH3</td><td>1hzh_H</td><td>R@P</td><td>86</td><td>TYR</td><td>Y [D5] CH3</td><td>1hzh_K</td><td>43</td><td>0</td><td>0</td><td>43</td></tr><tr><td>R@P</td><td>86</td><td>TYR</td><td>Y [D5] CH3</td><td>1hzh_H</td><td>R@P</td><td>87</td><td>SER</td><td>S [D5] CH3</td><td>1hzh_K</td><td>4</td><td>1</td><td>0</td><td>3</td></tr><tr><td>R@P</td><td>86</td><td>TYR</td><td>Y [D5] CH3</td><td>1hzh_H</td><td>R@P</td><td>88</td><td>LYS</td><td>K [D5] CH3</td><td>1hzh_K</td><td>17</td><td>1</td><td>0</td><td>16</td></tr><tr><td>R@P</td><td>87</td><td>SER</td><td>S [D5] CH3</td><td>1hzh_H</td><td>R@P</td><td>86</td><td>TYR</td><td>Y [D5] CH3</td><td>1hzh_K</td><td>5</td><td>1</td><td>0</td><td>4</td></tr></tbody></table>

B.

<figure><img src="image_49.png" /></figure>

C.

<figure><img src="image_50.png" /><figcaption>**Figure 37.** *Homo sapiens* IGHG1 CH3 and knobs-into-holes positions [94]. (A) Contact analysis of threonine T22 and tyrosine Y86 at the interface between the two CH3 domains of the gamma1 chains. T22 and Y86 are the two positions involved in the knobs-and-holes. (B) IMGT Colliers de Perles of</figcaption></figure>
*Homo sapiens* IGHG1 CH3 on one layer (on the left) and on two layers with hydrogen bonds (on the right). T22 (in strand B) and Y86 (in strand E) are highlighted. The IMGT Colliers de Perles on two layers show, in the forefront, the GFC strands and, in the back, the ABED strands, linked by the CD transversal strand. The [ABED] sheets are at the interface between the two CH3 domains. The IMGT Colliers de Perles were generated by the IMGT/Collier-de-Perles tool [51] integrated in IMGT/3Dstructure-DB [57–59]. Hydrogen bonds (green lines) and disulfide bond between C23 and C104 (orange line) were automatically added from the experimental structural data. Amino acids are shown in the one-letter abbreviation. Positions at which hydrophobic amino acids (hydropathy index with positive value: I, V, L, F, C, M, A) and tryptophan (W) are found in more than 50% of analysed sequences are shown in blue. All proline (P) are shown in yellow. Hatched circles correspond to missing positions according to the IMGT unique numbering for C domain [42]. Arrows indicate the direction of the beta strands and their designations in 3D structures. Anchors (26, 39, 45, 77, 104, 118) are shown in squares. (C) 3D structure of the CH3 dimer showing the two amino acids T22 and Y86 involved in the knobs-and-holes amino acid changes (T22 > Y on one CH3 domain, Y86 > T on the other). The identifiers of the gamma1 chains to which the CH3 domains belong are 1hzh_H and 1hzh_K (IMGT® http://www.imgt.org, IMGT/3Dstructure-DB). (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).

### 6.4.3. Interface Ball-and-Socket-Like Joints

The comparison of the interface between the CH2 and CH3 domains from 3D structures of *Homo sapiens* IGHG2 Fc with the interface in 3D structures of IGHG1 Fc revealed that in all Fc of gamma chains the movement of the CH2 results from a pivoting around a highly conserved ball-and-socket-like joint [317]. Using the IMGT unique numbering for C-domain, the CH2 L15 side chain (last position of the A strand, next to the AB turn) (the ‘ball’) interacts with a pocket (the ‘socket’) formed by CH3 M107, H108, E109 and H115 (FG loop) (Figure 38). The interface is stabilized by two hydrogen bonds: CH2 L15 (O) and CH3 H115 (ND1), CH2 K125 (O) and CH3 Y29 (OH), and by two salt bridges: CH2 K12 (A strand) and CH3 E40 (C strand), CH2 K123 (G strand) and CH3 E109 (FG) (Figure 38). These amino acids are well conserved between the *Homo sapiens* gamma isotypes and the IGHG genes and alleles except for IGHG3 H115 that shows a polymorphism associated to different G3m allotypes [83]. This ball-and-socket-like joint is a structural feature similar but reversed to that previously described at the VH and CH1 domain interface [318], in which the VH L12, T125 and S127 form the ‘socket’ whereas the CH1 F29 and P30 form the ‘ball’ (IMGT® http://www.imgt.org, IMGT Repertoire > 2. Proteins and alleles > 1. Protein displays > C-DOMAIN with CHS, M and HINGE regions; ibid., IMGT Repertoire > 2. Proteins and alleles > 2. Alignments of alleles > IGHC; ibid., IMGT/3Dstructure-DB > query on Fab).

### 6.4.4. IGHG Alleles and Gm Allotypes

Allotypes are polymorphic markers of an IG subclass that correspond to amino acid changes and are detected serologically by antibody reagents [83]. In therapeutic antibodies (human, humanized or chimeric), allotypes may represent potential immunogenic epitopes [82], as demonstrated by the presence of antibodies in individuals immunized against these allotypes [83]. For the H-gamma chains, the allotypes are designated as Gm (for gamma marker), and for the H-gamma1 chains as G1m [83]. The allotypes G1m, G2m and G3m are carried by the constant region of the H-gamma1, H-gamma2 and H-gamma3 chains, encoded by the IGHG1, IGHG2 and IGHG3 genes, respectively.
A.

<figure><img src="image_51.png" /><figcaption>Figure 38. *Cont.*</figcaption></figure>
<figure><img src="image_52.png" /><figcaption>**Figure 38.** Contact analysis and ball-and-socket interface between *Homo sapiens* IGHG1 CH2 and CH3 [94]. (A) Contact analysis between the CH2 and CH3 domains of the Fc gamma1 (from IMGT/3Dstructure-DB, 3ave_A). The amino acids of the CH3 BC and FG loops (left column) and those of the CH2 G strand (right column) are shown in rectangles. CH2 96 and 97 correspond to the EF turn whereas other positions are from the A strand or AB turn. Arrows indicates the two hydrogen bonds (orange on line) and the two salt bridges (green online) mentioned in the text [312]. (B) The ball-and-socket-joint of the IGHG1 CH2-CH3 interface [312] is shown using the IMGT numbering, with the ball (L15) and the socket (M107, H108, E109 and H115). The interface is stabilized by two hydrogen bonds involving on CH2, L15 (O) and K125 (O) that bind on CH3, H115 (ND1) and Y29 (OH), respectively, and by two salt bridges involving on CH2, K12 (A strand) and K123 (G strand) that interact on CH3 with E40 (C strand) and E109 (FG loop), respectively. The identifier of the gamma1 chain to which the CH2 and CH3 domains belong is 3ave_A (IMGT® http://www.imgt.org, IMGT/3Dstructure-DB). (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).</figcaption></figure>

The H-gamma1 chains may express four G1m alleles (combinations of G1m allotypes): G1m3, G1m3,1, G1m17,1, and G1m17,1,2 (and in Negroid populations three additional G1m alleles, Gm17,1,27, Gm17,1,28 and Gm17,1,27,28) [83]. The correspondence between the G1m alleles and IGHG1 alleles is shown in Table 14.
<table><caption>Table 14. Correspondence between the IGHG1 alleles and G1m alleles [83,100].</caption><thead><tr><th rowspan="3">IGHG1<br>Alleles</th><th colspan="2">G1m Alleles <sup>1</sup></th><th colspan="10">IMGT Amino Acid Positions <sup>2</sup></th><th rowspan="3">Populations<br>[83]</th></tr><tr><th rowspan="2">Allotypes</th><th rowspan="2">Isoallotype <sup>3</sup></th><th colspan="3">CH1</th><th colspan="7">CH3</th></tr><tr><th>103</th><th>120</th><th>12</th><th>14</th><th>101</th><th>110</th><th>115</th><th>116</th></tr><tr><th></th><th></th><th></th><th colspan="8">G1m3 <sup>4</sup></th><th></th></tr></thead><tbody><tr><td>IGHG1*01 <sup>5</sup>,<br>IGHG1*02 <sup>5</sup>,<br>IGHG1*05 <sup>5</sup></td><td>G1m17,1</td><td></td><td>I</td><td>K</td><td>D</td><td>L</td><td>V</td><td>A</td><td>H</td><td>Y</td><td>Caucasoid<br>Negroid<br>Mongoloid</td></tr><tr><td>IGHG1*03</td><td>G1m3</td><td>nG1m1,<br>nG1m17</td><td>I</td><td>R</td><td>E</td><td>M</td><td>V</td><td>A</td><td>H</td><td>Y</td><td>Caucasoid</td></tr><tr><td>IGHG1*04</td><td>G1m17,1,27</td><td></td><td>I</td><td>K</td><td>D</td><td>L</td><td>I</td><td>A</td><td>H</td><td>Y</td><td>Negroid</td></tr><tr><td>IGHG1*05p <sup>6</sup></td><td>G1m17,1,28</td><td></td><td>I</td><td>K</td><td>D</td><td>L</td><td>V</td><td>A</td><td>R</td><td>Y</td><td>Negroid</td></tr><tr><td>IGHG1*06p <sup>6</sup></td><td>G1m17,1,27,28</td><td></td><td>I</td><td>K</td><td>D</td><td>L</td><td>I</td><td>A</td><td>R</td><td>Y</td><td>Negroid</td></tr><tr><td>IGHG1*07p <sup>6</sup></td><td>G1m17,1,2</td><td></td><td>I</td><td>K</td><td>D</td><td>L</td><td>V</td><td>G</td><td>H</td><td>Y</td><td>Caucasoid<br>Mongoloid</td></tr><tr><td>IGHG1*08p <sup>6</sup></td><td>G1m3,1</td><td>nG1m17</td><td>I</td><td>R</td><td>D</td><td>L</td><td>V</td><td>A</td><td>H</td><td>Y</td><td>Mongoloid</td></tr></tbody></table>

<footnote n="1">¹. In Negroid populations, the G1m17,1 allele frequently includes G1m27 and/or G1m28, leading to three additional G1m alleles, G1m17,1,27, G1m17,1,28 and G1m17,1,27,28 [83]. ². Amino acids corresponding to G1m allotypes are shown in bold. ³. The nG1m1 and nG1m17 isoallotypes present on the Gm1-negative and Gm-17 negative H-gamma-1 chains (and on other H-gamma chains) are shown in italics. ⁴. The presence of R120 is detected by anti-nG1m17 antibodies whereas the simultaneous presence of I103 and R120 in the H-gamma1 chains is detected by anti-Gm3 antibodies [83]. ⁵. The IGHG1*01, IGHG1*02 and IGHG1*05 alleles only differ at the nucleotide level (codon 85.1 in CH2 of *02 and *05 differs from *01, codon 19 in CH1 and codon 117 in CH3 of *05 differ from *01 and *02). ⁶. IGHG1*05p, IGHG1*06p, IGHG1*07p and IGHG1*08p amino acids are expected [83] but not yet sequenced at the nucleotide level and therefore these alleles are not shown in Alignments of alleles (IMGT® http://www.imgt.org, IMGT Repertoire > 2. Proteins and alleles > 2. Alignments of alleles > IGHC Mammalia > *Homo sapiens* IGHG1). Allotypes on CH1 include G1m17 K120 (blue) vs nG1m17, G1m3 R120 (dark blue). Allotypes on CH3 include G1m1 D12, L14 (yellow) vs nG1m1 E12 M14 (pale yellow), G1m27 I101 (green), G1m2 G110 (purple), G1m28 R115, Y116 (orange). (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).</footnote>
Amino acids involved in the expression of G1m allotypes and localized on the CH1 and CH3 domains of H-gamma1 chains are shown in IMGT Colliers de Perles on two layers and in 3D structures (Figure 39). In the CH1, the lysine at position 120 (K120) in strand G corresponds to the G1m17 allotype [83]. The isoleucine I103 (strand F) is specific of the H-gamma1 chain isotype. If an arginine is expressed at position 120 (R120), the simultaneous presence of R120 and I103 corresponds to the expression of the G1m3 allotype [83]. For isotypes other than H-gamma1, R120 corresponds to the expression of the nG1m17 isoallotype (an isoallotype or nGm is detected by antibody reagents that identify this marker as an allotype in one IgG subclass and as an isotype for other subclasses). In the CH3, the aspartate D12 and leucine L14 (strand A) correspond to G1m1, whereas glutamate E12 and methionine M14 correspond to the nG1m1 isoallotype [83]. A glycine at position 110 corresponds to G1m2, whereas an alanine does not correspond to any allotype (G1m2-negative chain).

Trastuzumab has been engineered in order to obtain the less immunogenic (being most frequent in different populations) allotype G1m17 (CH1 K120), associated to the nG1m1 (CH3 E12, M14) [319], defined using the generic description, as IGHG1\*03v, G1m3 > G1m17, nG1m1 (CH1 R120 > K, CH3 E12,M14). The G1m allotypes have been confirmed serologically [82].

A.
IGHG1 CH1

<figure><img src="image_53.png" /><figcaption>**Figure 39.** *Cont.*</figcaption></figure>
<figure><img src="image_54.png" /><figcaption>**Figure 39.** *Homo sapiens* IGHG1 and G1m allotypes [83,94]. (A) IGHG1 CH1. The IMGT Collier de Perles of IGHG1 CH1 on two layers is shown with hydrogen bonds, as green lines online (on the left). K120 (strand G) corresponds to the G1m17 allotype [83]. I103 (strand F) is specific of the H-gamma1 chain isotype. The simultaneous presence of R120 and I103 corresponds to the expression of the G1m3 allotype (not shown) [83]. For isotypes other than H-gamma1, R120 corresponds to the expression of the nG1m17 isoallotype (not shown) [83]. The 3D structure of the CH1 (on the right) shows K120 (G1m17) and the H-gamma1 specific I103 [83]. (B) IGHG1 CH3. The IMGT Collier de Perles of IGHG1 CH3 on two layers is shown with hydrogen bonds, as green lines online (on the left). D12 and L14 (strand A) correspond to the G1m1 allotype, whereas E12 and M14 (not shown) correspond to the nG1m1 isoallotype [83]. G110 (not shown) corresponds to G1m2, whereas A110 (here) does not correspond to any allotype [83]. G129 and K130 represent the CHS in secreted IG. The 3D structure of the CH3 (on the right) shows the positions 12 and 14 of the G1m1/nG1m1 allotype, and position 110 of the G1m2/-allotype. The CH1 and CH3 domains are from the b12 antibody. The b12 H-gamma1 chain is encoded by the IGHG1*01 allele and expresses the G1m17,1 allotypes, based on sequence analysis (CH1 K120, CH3 D12 and L14) [83]. The presence of an A (Ala) in CH1 121 of 1hzh_H is a PDB file error. It should be a V (Val) as in 1n0x_H, and as mentioned in the IMGT note of 1hzh(IMGT® http://www.imgt.org, IMGT/3Dstructure-DB > Entry code (PDB): 1hzh). (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).</figcaption></figure>

The H-gamma2 chains express only one allotype G2m23. G2m23 and the H-gamma2 chains are either G2m23 or G2m. (two dots indicate that a specimen was tested and found to be negative for G2m23 [83]. G2m23 is localized on CH2. Amino acid sequence and 3D structure comparisons show that the G2m23 allotype is correlated with CH2 M45.1, whereas the absence of the allotype (G2m..) is correlated with valine V45.1 [83]. The G2m23-positive H-gamma2 chains are also characterized by the presence of threonine T92 in the CH1, whereas the G2m23-negative chains and the H-gamma chains of other IgG subclasses have proline P92 in the CH1. Being located on the CH1 domain this amino acid change is not involved in the expression of the G2m23 allotype, but owing to the strong linkage on the same chain, the CH1 T92 codon has been used for the molecular characterization of the G2m23 chains [83].

The H-gamma3 chains are the most polymorphic IG chains in humans. Thirteen G3m allotypes are characterized: G3m5, G3m6, G3m10, G3m11, G3m13, G3m14, G3m15, G3m16, G3m21, G3m24, G3m26, G3m27, G3m28 [83]. Three isoallotypes (nG3m5, nG3m11, and nG3m21) have also been characterized.
Two G3m allotypes are located on the CH2 of gamma3 chains, G3m16 (W83) and G3m21 (L82), nG3m21 (P82) [83]. The other G3m allotypes form two mosaics on the CH3 [83] (Figure 40). A first mosaic includes G3m11 (S44), nG3m11 (N44), G3m10 (S44, I101)/G3m24 (S44, V101), G3m27 (I101), G3m6 (S44, E98)/G3m13 (S44, Q98). The second mosaic includes G3m26 (R115), G3m5 (R115, F116)/nG3m5 (H115, Y116)/G3m28 (R115, Y116), G3m14 (M84, R115, F116) and G3m15 (M39, H115, Y116) [83] (Figure 40). The combination of expressed allotypes correspond to haplotypes represented in the IMGT G3m allele butterfly' representation [83] (Figure 41).

<figure><img src="image_55.png" /><figcaption>**Figure 40.** G3m allotypes localizations on the gamma3 chains [83]. (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).</figcaption></figure>
<figure><img src="image_56.png" /><figcaption>**Figure 41.** IMGT G3m allele butterfly' representation [83]. The two mosaics on the CH3 domain are shown for each G3m allele (allotypes are described in [83]). The first mosaic around G3m11 is on the top with G3m27, G3m10/G3m24, G3m13/G3m6. The second mosaic is at the bottom with G3m26, G3m5/nG3m5/G3m28. Amino acids involved in the allotype expression and their position according to the IMGT unique numbering for C domain [42] are indicated. Two allotypes are on the CH2 domain, G3m16 (Trp W83) and G3m21 (Leu L82). Haplotypes to which the G3m alleles belong, are indicated between square brackets. (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).</figcaption></figure>
The therapeutical antibody omodenbamab (INN L123, 2020) is an *Homo sapiens* immunoglobulin G3-kappa, anti-*Staphylococcus aureus* SpA (Staphylococcal protein A). The C region of the H-gamma3 chains is encoded by IGHG3*01, G3m5* (G3m5,10,11,13,14,26,27) with CH3 S44 (439), M84 (452), Q98 (474), I101 (477), R115 (490) and F116 (491).

### 6.4.5. IGHG Engineered Variants and Effector Properties

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 are engineered at positions involved in antibody-dependent cellular (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), half-life increase, half-IG exchange, and B cell inhibition by coengagement of antigen and FcγR on the same cell [320,321] (IMGT® http://www.imgt.org, The IMGT Biotechnology page > Amino acid positions involved in ADCC, ADCP, CDC, half-life and half-IG exchange).

The IMGT engineered variant nomenclature (Table 15) has been set up for an easier comparison between engineered antibodies [311]. The IMGT engineered variant name comprises the species, the gene name, the letter 'v' with a number (e.g., *Homo sapiens* IGHG1v1), and then the domain(s) with AA change(s) defined by the letter of the novel AA and position in the domain, e.g., CH2, P1.4. In Table 15, correspondence with the Eu numbering is shown between parentheses, whereas in antibody descriptions (i.e., INN proposed and recommended lists), positons between parentheses are those in the antibody chains. The 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 reference for the description of the amino acid (AA) changes for the other alleles. In those cases, the same variant (v) number is used for any allele of the same gene in the same species.
<table><caption>**Table 15.** IMGT engineered variant nomenclature [311]. *Homo sapiens* IGHG variants involved in ADCC, ADCP, CDC, half life increase, half-IG exchange, B cell inhibition, and knobs-into-holes are shown. In mAb description, the Eu numbering between parentheses is replaced by the amino position in the antibody gamma chain. Amino acid changes and bibliographical references are quoted at The IMGT Biotechnology page (IMGT® http://www.imgt.org The IMGT Biotechnology page > Amino acid positions involved in ADCC, ADCP, CDC, half-life and half-IG exchange). Properties modifications include: ADCC or CDC enhancement (pale green), ADCP enhancement (dark green), ADCC or CDC reduction (pale orange), B cell inhibition (orange), Half-life increase (pale blue), Hald-IG exchange reduction, Hole or Knob in knobs-into-holes interaction, Favors hexamerisation, Site-specific drug attachment, No N-glycosylation site, No disulfide bridge inter H-L (yellow).</caption><thead><tr><th rowspan="2">Species and<br>IMGT Gene<br>Name</th><th rowspan="2">IMGT<br>Engineered<br>Variant<br>Nomenclature</th><th colspan="4">IGHG Gene Variant Description</th><th colspan="3">Property Modifications</th></tr><tr><th>CH2</th><th>AA and IMGT Position in<br>CH2 of IGHG Gene<br>Variant</th><th>CH3</th><th>AA and IMGT<br>Position in<br>CH3 of IGHG<br>Gene Variant</th><th>ADCC<br>Enhancement or<br>Reduction, ADCP<br>Enhancement, B<br>Cell Inhibition</th><th>CDC<br>Enhancement<br>or Reduction</th><th>Half-IG Exchange<br>Reduction, Half-Life<br>Increase,<br>Knobs-into-Holes</th></tr></thead><tbody><tr><td rowspan="13">CDC enhnHomo<br>sapiens<br>IGHG1</td><td>IGHG1v1</td><td>CH2</td><td>P1.4 (233)</td><td></td><td></td><td>ADCC reduction</td><td></td><td></td></tr><tr><td>IGHG1v2</td><td>CH2</td><td>V1.3 (234)</td><td></td><td></td><td>ADCC reduction</td><td></td><td></td></tr><tr><td>IGHG1v3</td><td>CH2</td><td>A1.2 (235)</td><td></td><td></td><td>ADCC reduction</td><td></td><td></td></tr><tr><td>IGHG1v4</td><td>CH2</td><td>A114 (329)</td><td></td><td></td><td>ADCC reduction</td><td>CDC reduction</td><td></td></tr><tr><td>IGHG1v5</td><td>CH2</td><td>W109 (326)</td><td></td><td></td><td>ADCC reduction</td><td>CDC<br>enhancement</td><td></td></tr><tr><td>IGHG1v6</td><td>CH2</td><td>A85.4 (298), A118 (333),<br>A119 (334)</td><td></td><td></td><td>ADCC<br>enhancement</td><td></td><td></td></tr><tr><td>IGHG1v7</td><td>CH2</td><td>D3 (239), E117 (332)</td><td></td><td></td><td>ADCC<br>enhancement</td><td></td><td></td></tr><tr><td>IGHG1v8</td><td>CH2</td><td>D3 (239), L115 (330), E117<br>(332)</td><td></td><td></td><td>ADCC<br>enhancement</td><td>CDC reduction</td><td></td></tr><tr><td>IGHG1v9</td><td>CH2</td><td>L7 (243), P83 (292), L85.2<br>(300), I88 (305)</td><td>CH3</td><td>L83 (396)</td><td>ADCC<br>enhancement</td><td></td><td></td></tr><tr><td>IGHG1v10</td><td>CH2</td><td>Y1.3 (234), Q1.2 (235), W1.1<br>(236), M3 (239),<br>D30 (268), E34 (270), A85.4<br>(298)</td><td></td><td></td><td>ADCC<br>enhancement</td><td></td><td></td></tr><tr><td>IGHG1v11</td><td>CH2</td><td>E34 (270), D109 (326), M115<br>(330), E119 (334)</td><td></td><td></td><td>ADCC<br>enhancement</td><td></td><td></td></tr><tr><td>IGHG1v12</td><td>CH2</td><td>A1.1 (236), D3 (239), L115<br>(330), E117 (332)</td><td></td><td></td><td>ADCC<br>enhancement</td><td></td><td></td></tr><tr><td>IGHG1v13</td><td>CH2</td><td>A1.1 (236), D3 (239), E117<br>(332)</td><td></td><td></td><td>ADCP<br>enhancement</td><td></td><td></td></tr></tbody></table>
<table><caption>Table 15. *Cont.*</caption><thead><tr><th rowspan="2">Species and<br>IMGT Gene<br>Name</th><th rowspan="2">IMGT<br>Engineered<br>Variant<br>Nomenclature</th><th colspan="4">IGHG Gene Variant Description</th><th colspan="2">Property Modifications</th></tr><tr><th>CH2</th><th>AA and IMGT Position in<br>CH2 of IGHG Gene<br>Variant</th><th>CH3</th><th>AA and IMGT<br>Position in<br>CH3 of IGHG<br>Gene Variant</th><th>ADCC<br>Enhancement or<br>Reduction, ADCP<br>Enhancement, B<br>Cell Inhibition</th><th>CDC<br>Enhancement<br>or Reduction</th><th>Half-IG Exchange<br>Reduction, Half-Life<br>Increase,<br>Knobs-into-Holes</th></tr></thead><tbody><tr><td></td><td>IGHG1v14</td><td>CH2</td><td>A1.3 (234), A1.2 (235)</td><td></td><td></td><td>ADCC reduction</td><td>CDC reduction</td><td></td></tr><tr><td></td><td>IGHG1v15</td><td>CH2</td><td>S118 (333)</td><td></td><td></td><td></td><td>CDC<br>enhancement</td><td></td></tr><tr><td></td><td>IGHG1v16</td><td>CH2</td><td>W109 (326), S118 (333)</td><td></td><td></td><td></td><td>CDC<br>enhancement</td><td></td></tr><tr><td></td><td>IGHG1v17</td><td>CH2</td><td>E29 (267),<br>F30 (268), T107 (324)</td><td></td><td></td><td></td><td>CDC<br>enhancement</td><td></td></tr><tr><td></td><td>IGHG1v18</td><td></td><td></td><td>CH3</td><td>R1 (345), G109<br>(430), Y120 (440)</td><td></td><td>CDC<br>enhancement</td><td>Favors hexamerisation</td></tr><tr><td></td><td>IGHG1v19</td><td>CH2</td><td>A34 (270)</td><td></td><td></td><td></td><td>CDC reduction</td><td></td></tr><tr><td></td><td>IGHG1v20</td><td>CH2</td><td>A105 (322)</td><td></td><td></td><td></td><td>CDC reduction</td><td></td></tr><tr><td></td><td>IGHG1v21</td><td>CH2</td><td>Y15.1 (252), T16 (254), E18<br>(256)</td><td></td><td></td><td></td><td></td><td>Half-life increase</td></tr><tr><td></td><td>IGHG1v22</td><td>CH2</td><td>Y15.1 (252), T16 (254),<br>E18 (256)</td><td>CH3</td><td>K113 (433), F114<br>(434), H116 (436)</td><td></td><td>CDC reduction</td><td>Half-life increase</td></tr><tr><td></td><td>IGHG1v23</td><td>CH2</td><td>E1.2 (235)</td><td></td><td></td><td>ADCC reduction</td><td>CDC reduction</td><td></td></tr><tr><td></td><td>IGHG1v24</td><td></td><td></td><td>CH3</td><td>L107 (428), S114<br>(434)</td><td></td><td></td><td>Half-life increase</td></tr><tr><td></td><td>IGHG1v25</td><td>CH2</td><td>E29 (267), F113 (328)</td><td></td><td></td><td>B cell inhibition</td><td></td><td></td></tr><tr><td></td><td>IGHG1v26</td><td></td><td></td><td>CH3</td><td>Y22 (366),</td><td></td><td></td><td>Knob in<br>knobs-into-holes<br>interaction</td></tr><tr><td></td><td>IGHG1v27</td><td>CH2</td><td>C3 (239)</td><td></td><td></td><td></td><td></td><td>Site-specific drug<br>attachment</td></tr><tr><td></td><td>IGHG1v28</td><td>CH2</td><td>insC3A (239~240)</td><td></td><td></td><td></td><td></td><td>Site-specific drug<br>attachment</td></tr><tr><td></td><td>IGHG1v29</td><td>CH2</td><td>A84.4 (297)</td><td></td><td></td><td></td><td></td><td>No N-glycosylation site</td></tr><tr><td></td><td>IGHG1v30</td><td>CH2</td><td>G84.4 (297)</td><td></td><td></td><td></td><td></td><td>No N-glycosylation site</td></tr></tbody></table>
<table><caption>Table 15. *Cont.*</caption><thead><tr><th rowspan="2">Species and<br>IMGT Gene<br>Name</th><th rowspan="2">IMGT<br>Engineered<br>Variant<br>Nomenclature</th><th colspan="3">IGHG Gene Variant Description</th><th colspan="2">Property Modifications</th></tr><tr><th>CH2</th><th>AA and IMGT Position in<br>CH2 of IGHG Gene<br>Variant</th><th>CH3</th><th>AA and IMGT<br>Position in<br>CH3 of IGHG<br>Gene Variant</th><th>ADCC<br>Enhancement or<br>Reduction, ADCP<br>Enhancement, B<br>Cell Inhibition</th><th>CDC<br>Enhancement<br>or Reduction</th><th>Half-IG Exchange<br>Reduction, Half-Life<br>Increase,<br>Knobs-into-Holes</th></tr></thead><tbody><tr><td rowspan="10">Homo sapiens<br>IGHG2</td><td>IGHG1v31</td><td></td><td></td><td>CH3</td><td>T86 (407)</td><td></td><td></td><td>Hole in<br>knobs-into-holes<br>interaction</td></tr><tr><td>IGHG1v32</td><td></td><td></td><td>CH3</td><td>W22 (366)</td><td></td><td></td><td>Knob in<br>knobs-into-holes<br>interaction</td></tr><tr><td>IGHG1v33</td><td></td><td></td><td>CH3</td><td>S22 (366), A24<br>(368), V86 (407)</td><td></td><td></td><td>Hole in<br>knobs-into-holes<br>interaction</td></tr><tr><td>IGHG1v34</td><td></td><td></td><td>CH3</td><td>G109 (430)</td><td></td><td></td><td>Favors hexamerisation</td></tr><tr><td>IGHG1v35</td><td>CH2</td><td>E29 (267)</td><td></td><td></td><td></td><td>CDC<br>enhancement</td><td></td></tr><tr><td>IGHG1v36</td><td>CH2</td><td>Q84.4 (297)</td><td></td><td></td><td></td><td></td><td>No N-glycosylation site</td></tr><tr><td>IGHG1v37</td><td>h</td><td>S5 (220)</td><td></td><td></td><td></td><td></td><td>No disulfide bridge<br>inter H-L</td></tr><tr><td>IGHG1v38</td><td>CH2</td><td>S108 (325), F113 (328)</td><td></td><td></td><td>Abrogation of<br>FcyRIII binding</td><td>Abrogation of<br>C1q binding</td><td></td></tr><tr><td>IGHG2v1</td><td>CH2</td><td>L1.3 (234), L1.2 (235), G1.1<br>(236),<br>G1 (237)</td><td></td><td></td><td>ADCC<br>enhancement</td><td></td><td></td></tr><tr><td>IGHG2v2</td><td>CH2</td><td>Q30 (268), L92 (309), S115<br>(330), S116 (S331)</td><td></td><td></td><td>ADCC reduction</td><td>CDC reduction</td><td></td></tr><tr><td>IGHG2v3</td><td>CH2</td><td>A1.2 (235), A1 (237), S2<br>(238), A30 (268), L92 (309),<br>S115 (330), S116 (331)</td><td></td><td></td><td>ADCC reduction</td><td>CDC reduction</td><td></td></tr><tr><td>IGHG2v4</td><td>CH2</td><td>Q14 (250)</td><td></td><td></td><td></td><td></td><td>Half-life increase</td></tr><tr><td>IGHG2v5</td><td></td><td></td><td>CH3</td><td>L107 (428)</td><td></td><td></td><td>Half-life increase</td></tr><tr><td>IGHG2v6</td><td></td><td></td><td>CH3</td><td>L107 (428)</td><td></td><td></td><td>Half-life increase</td></tr><tr><td>Homo sapiens<br>IGHG3</td><td>IGHG3v1</td><td></td><td></td><td>CH3</td><td>H115 (435)</td><td></td><td></td><td>Half-life increase</td></tr></tbody></table>
<table><caption>Table 15. *Cont.*</caption><thead><tr><th rowspan="2">Species and<br>IMGT Gene<br>Name</th><th rowspan="2">IMGT<br>Engineered<br>Variant<br>Nomenclature</th><th colspan="4">IGHG Gene Variant Description</th><th colspan="2">Property Modifications</th></tr><tr><th>CH2</th><th>AA and IMGT Position in<br>CH2 of IGHG Gene<br>Variant</th><th>CH3</th><th>AA and IMGT<br>Position in<br>CH3 of IGHG<br>Gene Variant</th><th>ADCC<br>Enhancement or<br>Reduction, ADCP<br>Enhancement, B<br>Cell Inhibition</th><th>CDC<br>Enhancement<br>or Reduction</th><th>Half-IG Exchange<br>Reduction, Half-Life<br>Increase,<br>Knobs-into-Holes</th></tr></thead><tbody><tr><td rowspan="7">Homo sapiens<br>IGHG4</td><td>IGHG4v1</td><td>CH2</td><td>L1.3 (234)</td><td></td><td></td><td>ADCC<br>enhancement</td><td></td><td></td></tr><tr><td>IGHG4v2</td><td>CH2</td><td>P116 (331)</td><td></td><td></td><td></td><td>CDC<br>enhancement</td><td></td></tr><tr><td>IGHG4v3</td><td>CH2</td><td>E1.2 (235)</td><td></td><td></td><td>ADCC reduction</td><td>CDC reduction</td><td></td></tr><tr><td>IGHG4v4</td><td>CH2</td><td>A1.3 (234), A1.2 (235)</td><td></td><td></td><td>ADCC reduction</td><td>CDC reduction</td><td></td></tr><tr><td>IGHG4v5</td><td>h</td><td>P10 (228)</td><td></td><td></td><td></td><td></td><td>Half-IG exchange<br>reduction</td></tr><tr><td>IGHG4v6</td><td></td><td></td><td>CH3</td><td>K88 (409)</td><td></td><td></td><td>Half-IG exchange<br>reduction</td></tr><tr><td>IGHG4v21</td><td>CH2</td><td>Y15.1 (252), T16 (254), E18<br>(256)</td><td></td><td></td><td></td><td></td><td>Half-life increase</td></tr><tr><td>IGHG4v36</td><td>CH2</td><td>Q84.4 (297)</td><td></td><td></td><td></td><td></td><td>No N-glycosylation site</td></tr></tbody></table>

(With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org).
Examples of Fc engineered variants from Table 15 [311], found frequently in therapeutic antibodies, include for ADCC and CDC reduction of IgG1, the variant G1v4: CH2 A114 (329), for ADCC and CDC reduction of IgG2, the variant G2v3: CH2 A1.2 (235), A1 (237), S2 (238), A30 (268), L92 (309), S115 (330), S116 (331), and for ADCC and CDC reduction of IgG4, the variant G4v4: CH2 A1.3 (234), A1.2 (235). Half-life increase of IgG1 is obtained with the variant G1v21: CH2 Y15.1 (252), T16 (254), E18 (256). IGHG4 half-IG exchange reduction is obtained with the variant G4v5: h P10 (228). An absence of H-gamma N-glycosylation is obtained by one of the variants affecting the CH2 N84.4, for example, G4v36: CH2 Q84.4 (297).

## 7. Conclusions

IMGT® bridging genes, structures and functions provides a unique frame for three research axes: deciphering the IG and TR locus, genes and alleles in genomes of vertebrates from fish to humans, identifying clonality and exploring high-throughput repertoires with IMGT/HighV-QUEST and exploiting data from IMGT/mAb-DB, IMGT/2Dstructure-DB and IMGT/3Dstructure-DB towards targeted and customized therapeutic antibodies. Regarding the first axis, IMGT® genomic annotated data are classically displayed in IMGT Repertoire Web Resources (Locus description, Locus representation, Gene tables, Alignments of alleles). So far the number of higher vertebrate species present in the IMGT Web Resources reaches forty. The curated IG and TR genes and alleles are entered in the IMGT/GENE-DB database and the corresponding IMGT® reference directories and used for coherent gene and sequence annotations of IG and TR loci of newly sequenced genomes. Thus the annotation of the IG and TR loci [78,322-327] are key to the study and comparison of the expressed adaptive immune repertoires, in normal or pathological situations. The IMGT standardized IG and TR genes and alleles in different species [328-362] offer a unique opportunity for comparison of immune responses and of potential applications in veterinary and human medicine.

IMGT/V-QUEST is the reference tool for the clonality sequence analysis in leukemia and lymphoma [291-294,363-366], which has been extended to veterinary species owing to the availability and IMGT® biocuration of the IG and TR loci [346,349-351], and the IMGT reference directories. Exploring high-throughput repertoires with IMGT/HighV-QUEST provides standardized NGS analysis of IG and TR repertoires in experimental engineered (combinatorial libraries) or in physiological conditions (vaccination, immunodeficiency, autoimmune diseases, cancers and infectious diseases). IMGT/HighV-QUEST is particularly well adapted for the analysis of complete V domains of the IG and TR repertoires from B and T subsets, in many experiments and from many individuals (humans or other vertebrate species). It allows the analysis of the content of scFv combinatorial phage display libraries which are classically screened for identification of novel therapeutic antibody specificities [367-371].

Given the importance of the interactions in the antibody specificity and affinity on the one hand and in the antibody pharmacokinetics/pharmacodynamics and half-life on the other hand, the IMGT® integrated and standardized approach provides the genetic knowledge for allowing antibody informatics to answer the needs of targeted and customized therapy in the context of personalized medicine. The INN definition for the -mab integrates the format, target(s), IMGT gene and allele nomenclature, the CDR-IMGT lengths delimitation, the post-translational modifications and the engineered AA changes [60,86,87].

The extension of the IMGT unique numbering to the IgSF [372-376] and to the MhSF [377-379] proteins other than IG or TR has opened new perspectives for the standardized description of the polymorphism of the antigens (epitopes belonging to V, C or G domains) and of the Fc receptors (FCGR of the IgSF, FCGRT of the MhSF) and for the characterization of their interactions (antibody/antigen, FcR/antibody). The F domain (for Fibronectin type III domain), the S domain (for Scavenger, of the Scavenger receptor superfamily SrSF) and the A domain (for Apple domain) have been standardized with an IMGT unique numbering. Mass spectrometry has shown promising results in the analysis of the IGHG3 polymorphism and that anti-malarial variable domains [380-382]. Using the IMGT unique numbering per domain is the bridge between the biological and computational spheres.
**Author Contributions:** Conceptualization, methodology, validation, investigation, resources, data curation, writing, review and editing, visualization, project administration, ontology, funding acquisition, M.-P.L. and G.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** IMGT® was funded in part by the BIOMED1 (BIOCT930038), Biotechnology BIOTECH2 (BIO4CT960037), 5th PCRDT Quality of Life and Management of Living Resources (QLG2-2000-01287), and 6th PCRDT Information Science and Technology (ImmunoGrid, FP6 IST-028069) programmes of the European Union (EU). IMGT® received financial support from the GIS IBiSA, the Agence Nationale de la Recherche (ANR) Labex MabImprove (ANR-10-LABX-53-01), the Région Occitanie Languedoc-Roussillon (Grand Plateau Technique pour la Recherche (GPTR), BioCampus Montpellier. IMGT® is currently supported by the Centre National de la Recherche Scientifique (CNRS), the Ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation (MESRI) and the University of Montpellier.

**Acknowledgments:** We thank Safa Aouinti for the IMGT/StatClonotype development, Karima Cherouali and Anjana Kushwaha for the biocuration of the therapeutic monoclonal antibodies in the IMGT/mAb-DB and IMGT/2Dstructure-DB, respectively, François Ehrenmann and Souphatta Sasorith for help with the 3D structure figures. We are grateful to all members of the IMGT® team for their expertise and constant motivation during these 30 years. We thank Cold Spring Harbor Protocol Press for the pdf of the IMGT Booklet available in IMGT references. IMGT® is a registered trademark of CNRS. IMGT® is member of the International Medical Informatics Association (IMIA) and a member of the Global Alliance for Genomics and Health (GA4GH). This work was granted access to the High Performance Computing (HPC) resources of Meso@LR and of Centre Informatique National de l'Enseignement Supérieur (CINES) and to Très Grand Centre de Calcul (TGCC) of the Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA) under the allocation 036029 (2010-2020) made by GENCI (Grand Equipement National de Calcul Intensif).

**Conflicts of Interest:** The authors declare no conflict of interest.

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