I'm wondering if there is some threshold in size or a specific structural property that determines if a small protein or large peptide would cause an immune reaction.

Context: there are a number of drugs being developed based on antibody mimetics (small protein scaffolds with stable folding). These tend to have a size around 50-60 aminoacids (6-7 kD). These tend to be much easier to design than human / humanized antibodies. However, it is not uncommon for these to cause anaphylaxis, especially if administered repeatedly. It may be good to somehow design a version of a small antibody mimetic which itself does not cause an immune reaction.

Are peptides around 10-20 aminoacids typically immunogenic? What about slightly larger ones up to 30 aminoacids? Does it matter if they have a stable secondary or tertiary structure?


1 Answer 1


Edited to delete off-topic section:

Most (all?) proteins are ultimately immunogenic. You can't really design your way around immunogenicity, which is a good thing, because otherwise we'd all be dead from viruses.

Obviously not all proteins are equally immunogenic, but basically all protein therapeutics are immunogenic at some rate. One thing that seems positively associated with immunogenicity in that review is quaternary structure, but it's quantitative not qualitative.

Some of the commonly used synthetic antigens used in biochemistry such as HA C-terminus (24 residue) or FLAG (8 residue) are quite small.

More generally, this study finds that even 3-5 residue peptides can be sufficient to raise immune responses. So likely any polypeptide is potentially immunogenic.

Such small peptides are unlikely to have meaningful secondary/tertiary structure. My guess is that that you would have to have a pretty structurally strange protein to avoid any potential immune response. However if you had an insoluble or somehow sequestered protein you might be able to avoid it, but I'm not an expert so I can't say how.

  • $\begingroup$ Thank you, fascinating info. I'm looking in the opposite direction, for ways to have peptides not be immunogenic / less immunogenic - so the exact opposite of adding a carrier protein. Basically the idea is to have engineered small protein as a drug; if the drug itself causes an immune response that's a problem. For example Ecallantide is a ~6kDa protein drug based on Kunitz domain scaffold; it causes anaphylaxis in about 4% of people who take it. $\endgroup$
    – Alex I
    Commented Apr 29, 2020 at 21:00
  • $\begingroup$ yeah, i realized that halfway through writing it and had to go back and rewrite it with the knowledge that that was your motivation. basically, as i said above, it's hard to make proteins not immunogenic. $\endgroup$ Commented Apr 29, 2020 at 21:06
  • $\begingroup$ see also wikipedia on immunogenicity: en.wikipedia.org/wiki/Immunogenicity. basically, (nearly) all peptides are immunogenic. $\endgroup$ Commented Apr 29, 2020 at 21:27
  • $\begingroup$ @AlexI deleted irrelevant hapten section and added some more refs. $\endgroup$ Commented Apr 30, 2020 at 2:37
  • $\begingroup$ "Such small peptides are unlikely to have meaningful secondary/tertiary structure" - That should be mentioned in any basic textbook (hapten chapter)! $\endgroup$ Commented Nov 5, 2021 at 10:35

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