A sequence logo for the CDR H3 regions of 203,175 IGHV3-53/3-66 antibodies from Observed Antibody Space database 91 that have a CDR H3 length of 9 aa is shown for reference (repertoire). b Sequence logos for the CDR H3 regions of IGHV3-53/3-66 antibodies that pair with IGKV1-9 or IGKV3-20. The two most common combinations are IGKV1-9 pairing with 9 aa CDR H3 and IGKV3-20 pairing with 9 aa CDR H3, denoted as clonotype 1 and clonotype 2, respectively. As the COVID-19 pandemic continues, knowledge of public antibodies against SARS-CoV-2 can inform on therapeutic development as well as vaccine assessment.Ī The number of IGHV3-53/3-66 RBD antibodies that use the same light chain with the same CDR H3 are tabulated.
We also identify Y58F as a signature SHM among IGHV3-53/3-66 RBD antibodies that have a CDR H3 length of less than 15 amino acids. Structural and biochemical analyses show that these sequence motifs on CDR H3 are associated with light chain pairing preference. Nevertheless, IGHV3-53/3-66 RBD antibodies have varying lengths of CDR H3 with diverse sequences, which seem to deviate from the canonical definition of a public clonotype.īy categorizing IGHV3-53/3-66 RBD antibodies based on CDR H3 length and light chain usage, we now report two public clonotypes of IGHV3-53/3-66 RBD antibodies, both of which have a CDR H3 length of 9 amino acids (Kabat numbering) but with distinct sequence motifs.
IGHV3-53/3-66 antibodies carry germline-encoded features that are critical for RBD binding-an NY motif in CDR H1 and an SGGS motif in CDR H2 33, 49, 56. Antibodies to SARS-CoV-2 RBD frequently use IGHV3-53 and IGHV3-66 25, 33, 49, 56, which only differ by one amino acid (i.e. Over the past decade, public clonotypes to human immunodeficiency virus 50, malaria 54, influenza 51, and dengue virus 55 have been discovered. These antibodies can be classified as public clonotypes if they share the same IGHV gene with similar CDR H3 sequences 50, 51, 52, 53, 54. Notwithstanding this antibody diversity, some RBD antibodies with strikingly similar sequences have been found in multiple convalescent SARS-CoV-2 patients 34, 48, 49. V(D)J recombination and SHM, therefore, ensure a diverse repertoire of antibodies is available for an immune response to the enormous number and variety of potential antigens. To further improve the affinity of antibodies to an antigen, affinity maturation occurs in vivo via somatic hypermutation (SHM) 46, 47. The light chain genes also encode kappa and lambda chains that are denoted as IGKV and IGKJ, as well as IGLV and IGLJ, respectively. A similar process occurs in assembly of the coding region for the light chain except that the D gene is absent. Two complementarity-determining regions on the heavy chain (CDRs H1 and H2) are encoded by the V gene while the third (CDR H3) is encoded by the V(D)J junction.
In humans, genes encoding for the V, D, and J regions are denoted as IGHV, IGHD and IGHJ, respectively. Three genes, one from each of the variable (V), diversity (D), and joining (J) loci, are combined to form the coding region for the heavy chain. In the past year, many RBD antibodies have been isolated and characterized from convalescent SARS-CoV-2 patients 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42.Īntibody diversity is generated through V(D)J recombination 43, 44, 45. In humans, most neutralizing antibodies to SARS-CoV-2 target the immunodominant RBD on the S protein 18, 19, and can abrogate virus attachment and entry into host cells 20, 21. Most notable are the mRNA vaccines from Pfizer-BioNTech and Moderna, which have been issued emergency use authorization by the Food and Drug Administration for distribution in the United States 10, 11, 12, the adenovirus-vectored DNA vaccine from Johnson & Johnson 13, 14, and the Oxford-AstraZeneca chimpanzee adenovirus-vectored DNA vaccine in the United Kingdom 15, 16, 17. Several vaccines are currently in various stages of clinical trials 8, 9. To mitigate the devastating social and economic consequences of the pandemic, vaccines and post-exposure prophylaxes including antibody cocktails that exploit reactivity to the S protein are being developed at an unprecedented rate. The virion is decorated with the spike (S) glycoprotein, which contains a receptor-binding domain (RBD) that mediates virus entry by binding to angiotensin-converting enzyme-2 (ACE-2) receptor on the surface of host cells 1, 5, 6, 7. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the etiological agent of coronavirus disease 2019 (COVID-19) 1, 2, which primarily results in respiratory distress, cardiac failure, and renal injury in the most severe cases 3, 4.
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