J Immunother Cancer Shanghai Institute of Materia Medica, found that PD-L1/TLR7 dual-targeted nanobody conjugate drugs can reshape the tumor immune microenvironment

Tumor immunotherapy represented by immune checkpoint inhibitors has changed the pattern of cancer treatment, PD-1/PD-L1 blockade therapy has made breakthroughs in the treatment of a variety of tumors, but it has problems such as low response rate and drug resistance recurrence, and it is found that new PD treatment strategies to improve efficacy are urgent problems
to be solved.
Toll-like receptor (TLR) is an important target of innate immunity, and its agonists can effectively turn cold tumors into heat and solve the problem of low response rate of
single immune checkpoint inhibitors.
Antibody miniaturization is one of the research directions in the field of genetic engineering, nanobodies, that is, heavy-chain single-domain antibodies, are the variable region of natural heavy-chain antibodies missing light chains in animals such as camel sharks, and are the smallest
known naturally occurring binding antigens.
Compared with monoclonal antibodies, nanobodies have superior tumor targeting and stability, which can achieve targeted drug delivery to achieve precision therapy
.

Recently, Gong Likun's research group, Li Jia's research group and Jin Guangyi's research group of Shanghai Institute of Materia Medica, Chinese Academy of Sciences have cooperated to develop PD-L1/TLR7 dual-targeted nanobody conjugate (NDC), which can exert strong anti-tumor effects by reshaping the tumor immune microenvironment and show the prospect of
clinical development.
The research paper was published online in the Journal for Immunotherapy of Cancer
on October 17, 2022.

The research team used bacteriophage display technology to obtain the blocking anti-PD-L1 nanoantibody Nb16, which can significantly inhibit tumor growth and show stronger tumor penetration than monoclonal antibody.
In addition, the TLR7 agonist SZU-101 activates innate immune cells and induces upregulation
of PD-L1 expression on antigen-presenting cells (APCs) and tumor cells 。 Further, the research team evaluated the in vivo anti-tumor effect of PD-L1/TLR7 dual-targeted NDC, and found that it had more significant anti-tumor activity than the combination group.
It can reshape the tumor immune microenvironment and promote the expression of PD-L1 by APCs, including macrophages, which not only has a significant anti-tumor effect on "hot" tumors with high expression of PD-L1, but also can be used for anti-tumor therapy of "cold" tumors with low PD-L1 expression, in addition, it shows anti-tumor effects in early tumor and advanced tumor models, and can partially achieve tumor regression; Moreover, in the tumor reloading model of tumor regression mice, the mice did not grow tumors for 40 days, indicating that NDC induced effective anti-tumor immune memory
.
In terms of mechanism research, the research team found that the efficacy of PD-L1/TLR7 dual-targeted NDC mainly depends on NK cells and CD8+ T cells, and the expression of PD-L1 in tumor tissues can be dynamically regulated with the drug delivery process, which is conducive to the further tumor targeted delivery of NDCs, and its anti-tumor effect mainly depends on the expression
of the host PD-L1 axis 。 Classical antibodies and their ADCs are difficult to penetrate solid tumors due to their large size; Nanobody-conjugated small molecule agonists solve the problem of classical antibody ADCs well and open up a new direction field of ADCs; This study provides a solid theoretical basis and experimental basis
for the development of new nanobody conjugate drugs.

Antitumor effect in vivo of NDC

The first authors of the research paper are Wei Xiaolu, a postdoctoral fellow at Shanghai Institute of Materia Medica, and Long Yiru
, a doctoral candidate.
Researcher Gong Likun and Professor Li Jia of Shanghai Institute of Materia Medica, and Professor Jin Guangyi of Shenzhen University are the corresponding authors
of this paper.
The research work has been funded
by the Major New Drug Creation Science and Technology Major Project and the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences.

Original link: https://pubmed.
ncbi.
nlm.
nih.
gov/36253000/

PD-L1/TLR7 dual-targeted nanoantibody conjugates reshape the tumor immune microenvironment

(Contributing department: Gong Likun Research Group)