The humoral immune response is essential for the survival of mammals. However, we still lack a systematic understanding of the specific serologic antibody repertoire in response to an antigen. We developed a proteomic strategy to survey, at an unprecedented scale, the landscapes of antigen-engaged, serum-circulating repertoires of camelid heavy-chain antibodies (hcAbs). The sensitivity and robustness of this technology were validated using three antigens spanning orders of magnitude in immune response; thousands of divergent, high-affinity hcAb families were confidently identified and quantified. Using high-throughput structural modeling, cross-linking mass spectrometry, mutagenesis, and deep learning, we mapped and analyzed the epitopes of > 100,000 antigen-antibody complexes. Our results revealed a surprising diversity of high-affinity hcAbs for specific antigen binding on a variety of dominant epitopes. hcAbs perfect both shape and charge complementarity to target challenging antigens specifically; they can rapidly evolve to recognize a conserved, promiscuous cellular protein interaction interface, unraveling the convergent force that drives protein-protein interactions. ### Competing Interest Statement The University of Pittsburgh has filed a provisional patent in connection to the manuscript.
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