University of Pittsburgh researchers have identified, humanized, and affinity enhanced a llama nanobody capable of targeting the human immunodeficiency virus-1 (HIV-1). The llama nanobody J3, can mimic CD4, the primary entry receptor used by HIV during infection and as such can neutralize HIV-1. For the first time, humanization and affinity maturation of J3 has occurred. This novel nanobody has a low risk of immunogenicity in humans and can neutralize a broad spectrum of HIV-1 variants and may provide a novel long-term treatment approach for HIV-1.
The camelid nanobody J3 has been humanized. Following affinity maturation, these novel humanized antibodies (4E2) have demonstrated exceptional HIV-1 binding and neutralization potency and could be promising therapeutics to achieve viral suppression for HIV-infected people.
Description
Globally, around 40 million people live with HIV, the virus that can lead to acquired immunodeficiency syndrome (AIDS). Despite advancements in treatments since the 1980s, HIV continues to be a major global public health issue. Currently, HIV can be managed with antiretroviral therapy (ART) to decrease the viral load. However, there is no cure for HIV and treatment failure and resistance along with side effects from ART use can occur. There remains a clinical need to develop treatments that are effective against multiple variants of HIV-1 (i.e., to prevent viral escape) and broad neutralizing antibodies (bnAbs) are promising therapeutic agents in virology. Affinity maturation of HuJ3 (humanized J3) has led to neutralization of many variants of HIV-1, exhibiting exceptional breath. This neutralization along with the specificity of bnAbs could result in less adverse events and treatment and eradication of HIV-1 infections.
Applications
• HIV
Advantages
Previous research found bnAbs, targeting different HIV-1 envelope glycoproteins (gp160) sites, can lead to HIV-1 viral suppression in animal and early human clinical trials, but viral escape was observed impacting on efficacy. Most HIV strains enter cells through the CD4 receptor. The camelid nanobody, J3, mimics CD4 with a highly similar epitope on the envelope glycoprotein. J3 can broadly neutralize >95% of HIV-1 isolates, overcoming the challenge of viral escape. However, camelid nanobodies pose a threat of immunogenicity in humans. This challenge has been overcome for the first time through humanization and affinity maturation of J3. The resulting affinity-enhanced clone, 4E2, could be a promising anti-HIV therapy.
Invention Readiness
The camelid nanobody J3 was humanized by substitution of the VH framework region residues with their closest human VH germline counterparts. Following affinity maturation, a clone, 4E2, was identified which exhibited exceptional in vitro HIV binding and neutralization potency and breath. Work is now required to explore the use of this novel humanized J3 in various anti-HIV modalities including bispecific CAR T cells.
IP Status
Patent Pending
