When I think of antibodies, I usually think of the standard human Y-shaped IgG. It is easy to forget that the world of antibodies is extremely diverse, both in the constant domain, with many different isotypes (i.e. IgA, IgD, IgE, and IgM), and in the variable domain (i.e. with or without a light chain and CDR lengths). This is before we even start looking at engineered antibodies, like the ones illustrated in a previous blog post by Alissa. 

Of the many different antibodies, in this blog post, I want to highlight some of the exotic naturally occurring antibodies which might not have gotten much attention yet, but which each have interesting features.

The standard antibody (i.e. humans, mouse)

This is the standard antibody which we will compare with. A protein complex of two paired heavy and light chains forming the well-known Y shape. At the tips, a binding site that consists mainly of the three CDR’s on each chain. Nice and simple. 

Interesting facts:

1. CDR-H3 length: 9-40 residues
2. VH length (excluding CDR3 and J region): ~96 residues (from IMGT)
3. Can be numbered with ANARCI: Of course! 
4. Fun fact: Couldn’t be more standard

Sharks (Chondrichthyes fishes, i.e. sharks and rays)

Chondrichthyes fishes have what is regarded as the most distantly related antibodies to mammals. While sharks do have heavy and light chain pairing isotypes, i.e. IgM and IgW, they also have an additional unique isotype, the IgG new antigen receptor (IgNAR). Like camelid antibodies, IgNAR is a heavy chain homodimer with two unpaired VH domains. However, IgNAR has some noticeable differences, such as having five C domains in its secreted form and a variable domain that is the smallest naturally occurring antibody-like molecule. A reason for this size is the missing CDR2 from most IgNAR V domains. This is however compensated by its CDR-H3 length, which can be up to 40 residues long [1,2,3].

Interesting facts:

1. CDR-H3 length: 9-40 residues and median ~20 [1,2]
2. VH length (excluding CDR3 and J region): ~84 residues (from IMGT)
3. Can be numbered with ANARCI: No – possibly because of its distant relationship 
4. Fun fact: Most IgNAR V domains lack a CDR2

Cow

Cow antibodies follow the same design as human antibodies. Their IgG has a nice Y shape, consisting of two paired heavy and light chains, with the heavy chains having three constant domains. However, cows have some funky CDR-H3 loops. Their CDR-H3s have a trimodal length distribution, with the third group consisting of ultralong CDR-H3. These CDRs can be up to ~70 residues long and are packed with mutation hotspots. Instead of just being a loop, the ultralong CDR-H3 has a structure, forming an elongated stalk with a knob on top. It is argued that the distinct shape of the CDR allows it to bind certain epitopes which human antibodies will never be able to [4,5].

Interesting facts:

1. CDR-H3 length: 48-67 residues (only the ultralong CDRH3’s) [4] 
2. VH length (excluding CDR3 and J region): ~95 residues (from IMGT)
3. Can be numbered with ANARCI: Yes! 
4. Fun fact: Research is being done for using the knob alone as a binder, which would result in the smallest antibody-like molecules (smaller than the V domain of IgNAR) [5]

Chicken (includes birds, reptiles, amphibians and lungfish)

For last, we will look at an antibody from everyone’s favorite dinosaur, the mighty chicken. The main chicken antibody is IgY (also called egg yolk antibodies), which is a homolog of the human IgG. It has many structural differences, such as an extra constant domain, however, a really interesting difference is that chicken’s heavy and light chains are each only derived from a single V gene. The diversity obtained from V(D)J recombination is therefore limited compared to other species. This diversity is then restored partly by gene hyperconversion, a process where blocks of DNA are transferred from pseudo-V genes to the recombined V gene. [6, 7]

Figure of IgY from: Pereira, E.P.V., et al., 2019. Egg yolk antibodies (IgY) and their applications in human and veterinary health: A review.

Interesting facts:

1. CDR-H3 length: 8-32 residues 
2. VH length (excluding CDR3 and J region): ~87 residues (from IMGT)
3. Can be numbered with ANARCI: Yes! 
4. Fun fact: Extra diversity happens through gene hyperconversion.

References

1. Fernández-Quintero, M.L., et al., 2021. Shark Antibody Variable Domains Rigidify Upon Affinity Maturation – Understanding the Potential of Shark Immunoglobulins as Therapeutics.
2. Feng, M., et al., 2018. Construction and next-generation sequencing analysis of a large phage-displayed VNAR single-domain antibody library from six naïve nurse sharks.
3. Barelle, C., et al., 2009. Shark Novel Antigen Receptors – The Next Generation of Biologic Therapeutics?
4. Dong, J., et al., 2019. Structural Diversity of Ultralong CDRH3s in Seven Bovine Antibody Heavy Chains.
5. Macpherson, A., et al., 2020. Isolation of antigen-specific, disulphide-rich knob domain peptides from bovine antibodies.
6. Lee, L., et al., 2021. Immunoglobulin Y for Potential Diagnostic and Therapeutic Applications in Infectious Diseases.
7. Pereira, E.P.V., et al., 2019. Egg yolk antibodies (IgY) and their applications in human and veterinary health: A review.