Blockbuster—Rhesus Monkeys Produce Similar Immune Responses to Humans Against HC

Posted by Jerry Carter on April 1st, 2021

Researchers such as Mansun Law of The Scripps Research Institute discovered that rhesus monkeys can produce a convergent antibody response to HCV envelope glycoprotein.

The paper entitled "Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins was published online in the journal Immunity.

According to the researchers, the broadly neutralizing antibody (bnAb) encoded by the IGHV1-69 gene targeting the human hepatitis C virus (HCV) envelope glycoprotein E2 is also the main target for the development of HCV vaccines. Most bnAbs isolated from HCV-infected patients bind to a conservative antigen surface called E2 neutralization surface (E2 NF), which overlaps with the CD81 receptor binding site.

E2 NF is an excellent target for HCV vaccine design. It consists of three overlapping neutralization sites, which are antigenic sites AS412, AS434, and antigenic region 3 (AR3). Virus escape studies have shown that bnAbs targeting AR3 have a high drug resistance barrier.

AR3-specific bnAb response has been reported in multiple individuals and is preferentially encoded by IGHV1-69. This is a human immunoglobulin (Ig) heavy chain variable gene (IGHV or VH), often used to fight against other viruses, such as influenza A virus and HIV-1.

These results indicate that this antibody can be produced in the general population. In addition, some studies have shown that the bnAbs encoded by IGHV1-69 are related to the natural clearance of HCV patients and can protect animals from HCV infection. Therefore, the vaccine-induced antibody response can effectively activate IGHV1-69 germline genes and has a protective effect.

In HCV Env-immunized rhesus monkeys, the orthologous gene VH1.36 of IGHV1-69 preferentially produces bnAbs. The researchers revealed the genetic, structural, and functional properties of the bnAbs encoded by VH1.36. Global B cell bank analysis confirmed the expansion of VH1.36 derived B cells in immunized animals. Most E2-specific, VH1.36-encoded antibodies cross-neutralize HCV.

The crystal structures of two RM bnAbs with E2 indicate that RM bnAb and human bnAb have similar molecular characteristics, but have different binding modes, and thus bind to the conserved E2 epitope. The longitudinal analysis of the response to the RM antibody library during the immunization process showed that the lineage of the bnAb encoded by VH1.36 developed rapidly, and somatic hypermutation was limited.

These findings reveal that the germline-encoded bnAb response has functional convergence to HCV Env and affects human vaccination.

In this study, the function of the rhesus monkey as a disease model plays a pivotal role.

Candidates need to undergo preclinical studies, including drug absorption, distribution, metabolism, excretion, efficacy, and toxicity studies before they become new drugs to prove their effectiveness and safety. Most preclinical studies use one rodent and one non-rodent animal (including dogs, rabbits, miniature pigs, and monkeys) to complete animal in vivo evaluation experiments on the efficacy, metabolism, and toxicology.

Not all experimental animals can produce corresponding biological responses to specific biomacromolecule drug candidates represented by monoclonal antibody (mAb) and cytokine. For example, the animals selected in the preclinical research of mAb drug candidates must be those species that can express the target epitopes of the candidate drug and can show a biological response similar to that of humans.

In addition, the biomacromolecule drug itself has strong antigenicity that is likely to cause an immune response in the experimental animal to generate anti-drug antibodies, which cannot effectively complete the preclinical research. Therefore, the preclinical research of such drugs has higher requirements on the disease models, and it is necessary to select experimental animals with similar molecular targets and signal transduction pathways to humans.

Currently, almost all the most cutting-edge and advanced treatments for major diseases such as AIDS and tumors are biomacromolecule drugs. The demands on non-human primate disease models and related products are showing an ascending trend.