Abstract The highly pathogenic avian influenza H5N1 virus clade 2.3.4.4b has been spreading globally since 2022 , causing mortality and morbidity in domestic and wild birds, as well as in mammals , which underscores its potential to cause a pandemic . Here, we generate a panel of anti-hemagglutinin (HA) human monoclonal antibodies (mAbs) against the H5 protein of clade 2.3.4.4b. To develop human chimeric antibodies , H2L2 Harbor Mice®, which express human immunoglobulin germline genes, were immunized with H5 and N1 recombinant proteins from A/mallard/New York/22-008760-007- original/2022 H5N1 virus. Through hybridoma technology, sixteen fully human mAbs are generated, most of which show cross-reactivity against H5 proteins from different clade 2.3.4.4 virus variants . Fourteen out of the sixteen mAbs neutralize the virus in vitro . The mAbs with the strongest hemagglutination inhibition activity also demonstrate greater neutralizing capacity and show increased protective effects ...