Yes — this is a genuine, actively studied phenomenon called immunogenicity, where the immune system recognises a peptide (or an impurity within it) as foreign and mounts an antibody response against it. Research indicates that at least two doses are typically required to prime and then boost this immune response, though immunogenic reactions have been documented after single doses of some peptide drugs.
The practical consequence is usually a gradual loss of efficacy over time from anti-drug antibodies (ADAs) binding and neutralising the peptide before it can act — a decline that's easy to mistake for simple tolerance or tachyphylaxis rather than an immune response. Compounds intended for long-term, chronic use carry the greatest immunogenic risk simply because of repeated immune exposure.
How immunogenic a given peptide is depends heavily on its specific structure — chemical modifications like PEGylation or D-amino acid substitution (used to extend half-life or resist degradation) can either increase or decrease immunogenic risk depending on how they alter the molecule's recognisability to the immune system.
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