mp6b01021_si_001.pdf (47.75 kB)
An Anti-Programmed Death‑1 Antibody (αPD-1) Fusion Protein That Self-Assembles into a Multivalent and Functional αPD‑1 Nanoparticle
journal contribution
posted on 2017-03-25, 00:00 authored by Peng Zhao, Djordje Atanackovic, Shuyun Dong, Hideo Yagita, Xiao He, Mingnan ChenCancer
immune checkpoint therapy has achieved remarkable clinical successes
in various cancers. However, current immune checkpoint inhibitors
block the checkpoint of not only the immune cells that are important
to cancer therapy but also the immune cells that are irrelevant to
the therapy. Such an indiscriminate blockade limits the efficacy and
causes the autoimmune toxicity of the therapy. It might be beneficial
to use a carrier to target immune checkpoint inhibitors to cancer-reactive
immune cells. Here, we explore a method to load the inhibitors into
carriers. We used the anti-programmed death-1 antibody (αPD-1)
as a model immune checkpoint inhibitor. First, we generated a recombinant
single-chain variable fragment (scFv) of αPD-1. Then, we designed
and generated a fusion protein consisting of the scFv and an amphiphilic
immune-tolerant elastin-like polypeptide (iTEP). Because of the amphiphilic
iTEP, the fusion was able to self-assemble into a nanoparticle (NP).
The NP was proved to block the PD-1 immune checkpoint in vitro and in vivo. Particularly, the NP exacerbated diabetes
development in nonobese diabetic mice as effectively as natural, intact
αPD-1. In summary, we successfully expressed αPD-1 as
a recombinant protein and linked αPD-1 to a NP, which lays a
foundation to develop a delivery system to target αPD-1 to a
subpopulation of immune cells.