HCMV antibody discovery for next-generation antiviral therapies

What is HCMV?

Human cytomegalovirus, or HCMV, is a ubiquitous beta-herpesvirus that poses a major challenge in clinical medicine. After the initial infection, it persists in the body for life and employs numerous strategies to evade the immune system. Its genome, the largest among known human viruses, encodes a set of glycoproteins that confer broad cellular tropism.

HCMV displays several surface glycoproteins complexes to infect cells. The gH/gL/gO trimer binds PDGFRα and allows it to infect fibroblasts. The gH/gL/UL128/UL130/UL131A pentamer binds neuropilin 2 and is required to infect epithelial cells, endothelial cells, and various leukocytes, especially myeloid cells. The gB trimer catalyses the fusion between the infected cells and the virus.

HCMV reactivation in immunocompromised patients, such as recipients of solid organ transplants or hematopoietic stem cell transplants, can lead to severe complications (pneumonia, hepatitis, retinitis, etc.). Congenital HCMV infection during the neonatal period is also a major cause of non-genetic sensorineural hearing loss and neurodevelopmental disorders.

Why target HCMV with antibodies?

The therapeutic paradigm for HCMV is gradually shifting from small-molecule systemic antivirals toward more specific biological approaches. As a result, HCMV antibody discovery is emerging as a key focus for the development of monoclonal antibodies that neutralize the viral cycle at the entry stage.

By binding with high affinity to viral envelope glycoprotein complexes, anti-HCMV monoclonal antibodies rely on direct neutralization and on effector functions mediated by the Fc fragment. This strategy neutralizes free virions and, potentially, limits cell-to-cell spread. Antibodies therefore offer a promising approach in situations where conventional antivirals are limited by their toxicity.

Approved indications and therapeutic applications of anti-HCMV antibodies

Anti-HCMV antibodies are primarily studied in the context of prophylactic applications and the prevention of complications associated with viral reactivation. They are of particular interest in recipients of solid organ transplants and hematopoietic stem cell transplants. HCMV can cause life-threatening organ damage in these populations.

These approaches are also generating interest in preventing vertical transmission during pregnancy and the complications of congenital infection. The goal is to:

• reduce viremia;
• prevent symptomatic disease;
• complement the action of existing antiviral drugs.

Anti-HCMV antibodies therefore have a preventive function and could be used in combination with other therapies.

Challenges of HCMV antibody discovery

HCMV antibody discovery is a complex field due to the biological characteristics of the virus.

• Ability to evade immune recognition: The HCMV virus is capable of spreading between neighboring cells in a “masked” manner, thereby avoiding detection by circulating antibodies.
• Mechanism of HCMV entry into host cells: Viral entry involves several glycoprotein complexes located on the envelope, making it difficult to identify a single target.

HCMV's ability to internalize antibody-antigen complexes has also contributed to the failure of certain clinical candidates.

These limitations explain why it makes sense today to turn to approaches such as:

• antibody cocktails, based on the administration of two or more monoclonal antibodies targeting distinct epitopes on different glycoproteins;
• bispecific antibodies, engineering techniques that enable interaction with two different glycoproteins and the potential for synergistic neutralization;
• formats optimized for half-life and Fc functions.

👉 Explore our pipeline to discover emerging opportunities and assess the competitive landscape.

Overview of HCMV antibodies: first generation to next generation

The first generations of anti-HCMV antibodies targeted molecules such as the gB glycoprotein or the gH-containing complexes with the aim of directly blocking viral entry. These methods laid the groundwork for HCMV antibody discovery, but they also revealed the limitations of a single-target strategy.

Next-generation approaches aim to target multiple epitopes and induce multiple mechanisms of action. Beyond neutralizing free virions, the goal is to:

• cover different cell types;
• prevent the development of resistance;
• optimize the duration of action;
• achieve a more comprehensive immune response than neutralization alone.

Approved HCMV antibodies

Several programs have led to a better understanding of how to design an effective anti-HCMV antibody, even though the clinical results have been disappointing.

MSL-109, for example, was a human IgG1 monoclonal antibody directed against a conformational epitope of the gH glycoprotein. Insufficient in vivo efficacy and a non-genetic escape mechanism involving the internalization of the antibody-antigen complex led to the discontinuation of its clinical development.

The RG7667 cocktail, composed of two antibodies targeting the gB glycoprotein and the viral envelope gH/gL/UL128/UL130/UL131A pentameric complex, demonstrated significant pharmacological activity. In its Phase II trial in high-risk kidney transplant recipients, it did not meet its primary efficacy endpoint. However, it significantly delayed the onset of viremia and reduced the incidence of CMV disease.

CSJ148, another combination of two antibodies, also demonstrated greater in vitro potency than hyperimmune immunoglobulins. Its development was halted after Phase II. Similarly, development of TCN-202, an anti-gB antibody, was halted. This is because existing antivirals, such as valganciclovir and letermovir, already set a high standard for efficacy. A monoclonal antibody must provide a significantly greater clinical benefit to justify continued development.

These results show that anti-HCMV antibodies must meet a particularly high clinical standard.

Emerging approaches in HCMV antibody engineering

Current engineering strategies aim to overcome the limitations of the initial candidates.

Antibody cocktails are an important approach, as they allow for targeting distinct epitopes on different glycoproteins and increase the genetic barrier to resistance.

Bispecific antibodies represent another promising avenue. They combine two binding activities into a single molecule, potentially leading to synergistic neutralization.

Fc region engineering also offers an interesting prospect. The YTE mutation, for example, increases affinity for the FcRn receptor and prolongs the serum half-life.

Other approaches, such as ADCs, TCR-like antibodies or CAR-NK cells, also open new avenues for targeting infected cells with greater precision and functional diversity. The goal is to broaden coverage, enhance neutralization, and circumvent resistance.

Why choose MAbSilico for HCMV antibody discovery?

The challenge is to quickly identify differentiated candidates. MAbSilico provides added value through artificial intelligence, structural modeling, and experimental data to guide HCMV antibody discovery.

This approach allows us to anticipate issues related to developability, intellectual property, and biological differentiation from the very earliest stages. For anti-HCMV projects, this enables a rational development strategy that is strategically positioned relative to existing benchmarks.