Although albumin is not inherently immunogenic, 29 fusion with other peptides may affect the immunogenicity of the resulting molecules

Although albumin is not inherently immunogenic, 29 fusion with other peptides may affect the immunogenicity of the resulting molecules. potential to protect against high viral challenging doses. Although the albumin-antibody fusion immunoadhesin provided strong and prolonged protection of the immunized animals against SIV challenge, the albumin-CD4 fusion altered the specificity and decreased the overall protection effectiveness of the immunoadhesin in comparison to the antibody-based molecules. Albumin-based immunoadhesins increase longevity of the immune protection; however, they present challenges likely linked to the induction of anti-immunoadhesin antibodies. Keywords: HIV, SIV, immunoprophylaxis, broad cross-protection, Immunodhesins, adeno-associated virus, albumin, CD4 immunoadhesins Graphical Abstract Open in a separate window Approaches toward immune control of SIV require molecules that neutralize a wide array of SIV field isolates. Johnson, Douglas, Schnepp, Spitsin, and colleagues evaluated antibody-like molecules (immunoadhesins) that were delivered by a recombinant adeno-associated virus in the SIV rhesus macaque model. Albumin and CD4-based immunoadhesins protected animals against viral challenge. Introduction Approaches toward a human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) vaccine require the induction of antibodies that neutralize a wide array of HIV/SIV field isolates.1,2 Such antibodies are rare; nevertheless, over the past few years, several HIV antibodies have been identified with a broad range of viral neutralization and high antibody potency.3, 4, 5, 6 Newer antibodies were isolated by high-throughput screening of sera from HIV-1-infected individuals, categorized as elite neutralizers, based on their neutralization breadth and potency.7,8 Extensive sequence analysis of these potent, broadly neutralizing antibodies revealed that high levels of somatic mutations were required to generate mature antibodies.9 Furthermore, the maturation process may involve repeated rounds of antibody selection through HIV- antigen interaction. Taken together, these observations indicate that the induction of potent, broadly neutralizing antibodies using traditional vaccine strategies (e.g., subunit proteins or viral vectors) remains a major challenge. Passive immunization using neutralizing monoclonal antibodies has protected rhesus macaques from SIV/HIV (SHIV) challenge infections.10, 11, 12 Injection of antibodies every few weeks is not practical or cost effective compared MK2-IN-1 hydrochloride to a large-scale prophylactic vaccine approach. Another option is to isolate the representative antibody gene and use gene-transfer technology to endow a target host with the gene. In this system, the antibody gene directs endogenous expression of the antibody molecule, and the host produces circulating antibodies.13 The HIV/SIV antibody gene is packaged into a recombinant adeno-associated virus (rAAV) vector, which is delivered by direct intramuscular injection. Thereafter, antibody molecules are endogenously synthesized in myofibers and passively distributed to the MK2-IN-1 hydrochloride circulatory system. 8 This approach has been used in many nonhuman primate and murine models14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and ongoing studies in the field of HIV/SIV. In contrast to antibodies, immunoadhesins are engineered molecules containing antigen-binding domains, as well parts designed to improve overall performance, such as to increase half-life and to decrease immunogenicity.24 In a proof-of-concept study by Johnson et?al., rhesus macaques were injected Agt with rAAV vectors expressing monkey antibody and cluster of differentiation 4 (CD4)-based fusion proteins (immunoadhesins) that neutralized SIV.24 Monkeys were protected from infection following challenge with virulent SIV, and neutralizing antibodies were detected in monkey sera for over 4 years following a single intramuscular injection.24 In human studies, utilization of rAAV-based technology in order to express HIV neutralizing antibodies in a native, full-length format was well tolerated, and although it yielded very low levels of circulating antibodies,25 it suggests that the immunoadhesin format may be a viable therapeutic approach. We have built on the work to improve efficacy and longevity of immunoadhesin constructs. Albumin is the MK2-IN-1 hydrochloride molecule of choice for a fusion partner, due to its long half-life, safety profile, and low potential for immunogenicity. It is the most abundant protein in plasma and is ubiquitous at mucosal surfaces.26,27 Albumin has a half-life of approximately 20?days in serum,28 lacks enzymatic function, and has a low potential for immunogenic reactions.29 Albumin fusion constructs increase the half-life of smaller partners, such as single-chain antibodies. Albumin-fusion products have been tested in humans, including albumin-interferon fusion, albumin-coagulation factor IX fusion, and albiglutide (albumin-GLP-1 peptide for the treatment of.