Researchers engineer monoclonal antibodies to selectively bind disease-associated proteins, enabling targeted prevention, detection, and treatment across multiple therapeutic areas. Unlike small-molecule drugs, which often interact with multiple biological pathways, these antibodies achieve higher target specificity through their unique antigen-recognition domains with lower off-target effects. Advances in antibody engineering, such as humanization and affinity maturation, expand therapeutic applications to previously intractable diseases.
Jacob Lalezari, PhD
Chief Executive Officer
CytoDyn
In this Innovation Spotlight, Jacob Lalezari from CytoDyn discusses how next-generation monoclonal antibodies have the potential to improve clinical outcomes of difficult-to-treat diseases. He explains the mechanism of action of leronlimab, a humanized monoclonal antibody that functions as a CCR5 antagonist and highlights its promise for treating solid tumors, specifically metastatic triple-negative breast cancer (TNBC) and advanced colorectal cancer (CRC).
What is next-generation monoclonal antibody therapy, and what benefits has it provided to cancer patients?
Monoclonal antibodies have been a mainstay of cancer therapy for decades, but the field has evolved well beyond the early days of single-target binding. Next-generation antibody therapies are designed to be more versatile, capable of delivering drugs directly to tumors, engaging multiple immune pathways, as with leronlimab, or persisting longer in circulation to sustain therapeutic effects. In oncology, we’re moving away from the idea that one mechanism alone is enough. The next wave of antibodies is about influencing biology in a more integrated way, how tumors interact with the immune system, how they spread, and how they resist treatment. Clinically, this shift has led to more precise therapies and, in some cases, improved outcomes, particularly when antibodies are combined with other agents. CytoDyn’s work with leronlimab aligns with this broader trend, focusing not on direct tumor killing but on altering the biological conditions that allow cancer to progress.
What is CCR5, and why is it considered a promising cancer target?
CCR5, or C-C chemokine receptor type 5, is best known for its role in immune cell trafficking and inflammation. Over time, researchers have recognized that the same receptor is also involved in cancer progression, particularly in metastasis and immune suppression. CCR5 is expressed on several immune cell types that tumors co-opt for their own benefit, including regulatory T cells and tumor-associated macrophages. These cells can dampen anti-tumor immune responses and create a microenvironment that supports tumor growth and spread. CCR5 functions almost like a GPS system for certain immune cells. If you disrupt that signaling, you may be able to interfere with how tumors recruit help from the immune system and how they establish metastatic niches.
Why do many patients with metastatic TNBC and advanced CRC fail to respond to traditional treatments, and how does CCR5 factor into poor outcomes?
TNBC and advanced CRC remain among the most difficult cancers to treat. TNBC lacks hormone receptors or HER2 (Human Epidermal Growth Factor Receptor 2) amplification, limiting targeted therapy options, while many CRC tumors, particularly microsatellite-stable disease, do not respond well to checkpoint inhibitors. In both cases, the tumor microenvironment plays a major role. These cancers often develop environments that suppress immune activity, promote resistance, and facilitate spread to distant organs. CCR5 has emerged as one factor contributing to these dynamics. By guiding immune cells that favor tumor survival and metastasis, CCR5 signaling may reinforce the very conditions that make these cancers so difficult to treat.
Scientists develop monoclonal antibody therapeutics to precisely target diseased cells by engineering antibodies that recognize specific surface proteins and trigger responses, such as blocking harmful pathways or marking cells for immune destruction.
©iStock, iLexx
What is leronlimab’s mechanism of action in solid tumors?
Leronlimab is a humanized monoclonal antibody that binds to CCR5 and prevents it from transmitting signals. Rather than acting as a cytotoxic agent, leronlimab is intended to modulate biology upstream and downstream of the CCR5 receptor, influencing both metastatic processes and immune behavior. Leronlimab isn’t designed to poison tumor cells. It’s designed to change the rules of the environment that the tumor depends on. This has led CytoDyn to explore leronlimab primarily as a combination therapy, particularly in combination with immune checkpoint inhibitors.
What have you learned so far from clinical studies of leronlimab in cancer?
Across multiple programs, leronlimab demonstrates a consistent, generally well-tolerated safety profile, which enables its evaluation in oncology, infectious diseases, and metabolic conditions.
In oncology, CytoDyn reported retrospective and follow-up analyses in metastatic TNBC, indicating immune-related changes, including increased Programmed Death-Ligand 1 (PD-L1) expression on circulating tumor cells and macrophage-like cells. These analyses also reported more prolonged survival in patients who received leronlimab in combination with, or following, checkpoint inhibitors, along with favorable tolerability. For example, the pooled analysis reported no dose-limiting toxicities. These findings generated hypotheses rather than confirmed them. Small sample sizes and selection effects limited interpretation. As the company has stated, the appropriate next step is prospective evaluation, which will be the focus of subsequent trials in metastatic TNBC.
CytoDyn publicly reported FDA discussions supporting a Phase 2 approach in CCR5-positive, microsatellite-stable, metastatic CRC, combining leronlimab with standard agents. The goal is to move from biologically intriguing observations to clinically testable hypotheses in a CRC subgroup that historically responded poorly to immunotherapy alone.
What’s on the horizon for leronlimab, and what should people know about CytoDyn?
Right now, CytoDyn is focusing on testing the biological hypotheses that emerged from earlier clinical and translational observations. Our current work with leronlimab is focused on solid tumor oncology and on understanding how CCR5 blockade may influence tumor–immune interactions in patients.
An ongoing Phase 2 study in metastatic colorectal cancer is collecting both clinical outcome data and biomarker information to better understand how the tumor microenvironment changes during treatment. A Phase 2 trial in metastatic triple-negative breast cancer is also planned, designed to evaluate leronlimab in combination-based regimens while closely tracking immune markers that may help explain which patients benefit and why.
Together, these studies are designed to link patient outcomes with measurable biological effects in a prospective setting. Strengthening that translational connection should help clarify leronlimab’s role and inform how it may ultimately be used alongside other cancer therapies.
