Harnessing peptide conjugates strategies for cancer immunotherapy and infectious disease

Could you tell me a bit about what you’re currently working on?

HB: I am the Chief Scientific Officer at Centauri Therapeutics, where I oversee the scientific development of our immune therapy Alphamer^® platform and progression of its lead program. The platform leverages natural anti-sugar antibodies that are inherently present in the human body. These antibodies are polyclonal, exhibit high titers, and are profusely distributed throughout all tissues.

Centauri’s technology is based on a conjugation platform, incorporating a binding moiety at one end, which targets the intended site, and a conjugated sugar at the other. This sugar facilitates the recruitment of anti-sugar antibodies, thereby activating Fc immune functions such as complement-mediated killing and phagocytosis. Between the binding moiety and the effector sugar, proprietary linkers are strategically designed to optimize balance based on the conjugation context.

Could you explain the key differences in conjugation when working with peptides compared to larger molecules and are there any specific advantages?

HB: The binding moiety of the platform varies depending on the application. In our lead program, it is a cyclic peptide, however, depending on the target, monoclonal antibodies (mAbs) and antigen-binding fragments (Fabs) can also be utilized. Considerable attention is given to linker design as its purpose differs between large biologics and smaller peptides. For larger biologics, such as mAbs and Fabs, the linker’s primary role is to maximize the number of rhamnose sugars that can be attached, thereby increasing the drug-to-antibody ratio (DARs). In this context, the linker ensures optimal rhamnose display while maintaining surface exposure to anti-rhamnose antibodies.

In contrast, when conjugating smaller molecules such as peptides, the linker must maintain the physicochemical balance of the entire molecule. Peptides often possess specific charges and some degree of lipophilicity, whereas the effector sugar is more polar. Consequently, linkers are designed to preserve binding affinity and overall molecular stability. Unlike larger biologics, where linker chemistry is more standardized, peptide conjugation requires greater customization due to its influence on molecular properties.

The primary advantage of our technology for peptide conjugation lies in the nature of the rhamnose effector moiety. Unlike traditional bioconjugations that involve cytotoxic payloads, rhamnose is a stable, non-toxic, and polar molecule, making it significantly easier to handle chemically at scale. Rhamnose conjugate manufacturing is relatively straightforward compared to the cytotoxic payloads of traditional ADCs, which require stringent production conditions and higher costs.

What regulatory and/or commercial challenges have emerged in peptide conjugation research and development following advancements in ADC regulatory approvals?

HB: The regulatory landscape is constantly evolving. While agencies have well-defined guidelines for ADCs and synthetic peptides—which can be viewed as small molecules—peptide conjugates occupy a regulatory gray area, borrowing requirements from both ADC biologics and small-molecule drug classifications. Early engagement with regulatory bodies is essential to clarify how peptide conjugates will be evaluated.

Regulatory agencies often assume that linkers are designed for payload release, which directly impacts toxicological assessment. For our platform, however, linkers are non-cleavable and stable, meaning the molecule behaves as a single entity rather than a payload-releasing conjugate. In such cases, regulatory expectations shift toward metabolite analysis and small-molecule pharmacokinetics rather than traditional ADC assessments.

How does your immune stimulatory platform differ from traditionally linked chemistry found in other conjugates, such as ADCs, and what are the key advantages?

HB: One of the fundamental differences of the platform is its stable, non-cleavable linker design. Unlike ADCs, where linkers are engineered to release cytotoxic payloads inside target cells, our approach maintains molecular integrity. This stability enables our platform to align with established small-molecule regulatory guidelines, focusing on metabolic and clearance studies rather than fragmented component analysis.

Another major difference is the retention of our effector molecule at the cell surface. Our targeting moieties function solely as high-affinity binders. We prioritize stable conjugation that ensures the effector sugar remains exposed on the cell surface. In contrast, ADC linkers are typically designed to conceal their toxic payloads within antibodies and release is triggered at the cell surface or even within the cell. The stable nature of our linkers allows for a fundamentally different immune activation strategy, leveraging surface-bound effector molecules rather than intracellular payload release.

Further, what are the key challenges associated with developing an immune stimulatory peptide conduit?

HB: Developing an immune-stimulatory platform introduces specific challenges, particularly with respect to immune safety risks. Any drug designed to enhance immune responses requires a rigorous and extensive immunotoxicity assessment. Key considerations include the selection of appropriate nonclinical species and the development of tailored immunotoxicity assays. Unlike conventional immunotherapies that modulate T cell activity, our mechanism operates earlier upstream than the T cells, engaging complement pathways and neutrophils. As a result, standard immunotoxicity assays require modification and advice from regulatory agencies to accurately evaluate immune safety in relevant assays for our platform’s mode of action.

Additionally, regulatory requirements mandate the evaluation of anti-drug antibodies (ADAs), even for small peptides. ADA assessments extend beyond the peptide itself to include linker components, necessitating comprehensive immunogenicity studies despite the molecule’s relatively small size.

What challenges exist in peptide conjugate R&D for infectious diseases compared to an oncology setting?

HB: Infectious disease research presents significant challenges, particularly due to the complexity of bacterial cell surfaces. Unlike human cells, bacteria have complex and highly variable membranes, often featuring two layers packed with components such as peptidoglycan, lipid A, and dense layers of lipopolysaccharides. These unique structural features make bacterial surfaces difficult to target effectively.

Additionally, bacteria are highly adept at immune evasion as their rapid replication enables them to quickly evolve resistance mechanisms. Many bacterial species deploy immune evasion strategies, such as inhibiting complement activation and releasing decoy membranes to misdirect neutrophils, making them formidable adversaries in drug development. However, we believe that our immunostimulatory mechanism will tip the balance back in favor of the host.

By contrast, tumor cells present a more stable and predictable landscape for targeting. The oncology field benefits from well-characterized tumor-associated antigens and the availability of high-affinity binders like monoclonal antibodies. Many of these targets have been clinically validated, making them more accessible for drug development. However, tumors pose a different set of challenges, particularly in terms of penetration. Tumors often exist in immune-suppressed environments, which lack immune surveillance and are difficult to treat.

As mentioned, one of the key advantages of our mechanism is its ability to work upstream of T cells, potentially converting cold tumors into ‘hot’ tumors by activating complement pathways and releasing pro-inflammatory chemokines. This process recruits neutrophils and macrophages, leading to tumor cell destruction and subsequent antigen release, which can enhance T-cell responses.

From a drug development perspective, the field is shifting from traditional mAbs toward smaller formats such as Fabs, single-domain antibodies (VHHs), and peptides. This transition introduces new pharmacokinetic considerations, particularly regarding conjugation strategies. In smaller biologics such as Fabs and VHHs, cysteine engineering is commonly used for conjugation, but it can sometimes destabilize these molecules. A key area for advancement lies in developing new conjugation methods that preserve stability while enabling effective payload delivery.

Peptide conjugation, by contrast, is more straightforward as peptides can be synthetically designed with built-in conjugation sites. However, for smaller biologics, optimizing conjugation strategies remains a critical challenge. As the field continues to evolve, innovations in conjugation chemistry will be essential to fully harness the potential of smaller biologics in both oncology and infectious disease applications.

Looking towards the future, what are your key goals for the next year or two?

HB: Our primary goal is advancing our lead molecule. A recent press release announced the selection of our clinical candidate, which is progressing through nonclinical development. Our goal is to achieve first-in-human trials by the end of this year. This milestone will not only validate our platform but also address a critical unmet need in broad-spectrum gram-negative bacterial pneumonia.

Beyond our lead program, we are focused on pipeline expansion. As a novel platform, our technology offers extensive therapeutic potential. Selecting the next indications for development presents both an opportunity and a challenge, given the diverse applications of our mechanism. Identifying the optimal pathways for future exploration remains a key strategic initiative.

Biography

Helen Bright is an esteemed immunologist with 30 years of experience in infectious diseases within the biopharmaceutical industry. As CSO, she leads the research and development for Centauri’s Alphamer immunotherapy platform, guiding the company’s pipeline programs which focus on indications within the anti-infectives space.

Prior to this, Bright held senior scientific and operational leadership positions at AstraZeneca, Pfizer, and GSK. Bright holds a PhD in Virology and Immunology from Newcastle University and is a Fellow of the Royal Society of Medicine.

Affiliation

Helen Bright PhD, Chief Scientific Officer, Centauri Therapeutics Ltd, Alderley Park, Nether Alderley, Cheshire, UK

Authorship & Conflict of Interest

Contributions: The named author takes responsibility for the integrity of the work as a whole, and has given his approval for this version to be published.

Acknowledgements: None.

Disclosure and potential conflicts of interest: The author is an employee of Centauri Therapuetics Ltd and a director at Bright Pharma Consulting Ltd.

Funding declaration: The author received no financial support for the research, authorship and/or publication of this article.

Article & Copyright Information

Copyright: Published by Bioconjugation Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2025 Helen Bright. Published by Bioconjugation Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited.

Revised manuscript received: Apr 4, 2025.

Publication date: Apr 25, 2025.