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Leronlimab’s Mechanism of Action for Immuno-oncology
Read More on CCR5

Upon malignant transformation, pathological expression of CCR5 occurs in many types of cancer.

In addition, oncogene transformation induced CCR5 expression, and the subpopulation of cells that expressed functional CCR5 also displayed increased invasiveness.1 CCR5 expression induced by transformation imbues the cell with dramatic alteration in motility, gene expression, and homing behavior to metastatic sites.2 CCR5 augments the pro-inflammatory pro-metastatic immune phenotype and enhances DNA repair, providing aberrant cell survival and resistance to DNA damaging agents.2

It is believed that CCR5 may play an integral role in tumor progression in a variety of cancers. CCR5 is overexpressed in breast cancer, prostate cancer, colorectal carcinoma, melanoma, head and neck cancer, gastric cancer, esophageal cancer, pancreatic cancer, and other tumors.1Increased CCR5 expression is an indicator of disease status in several cancers.

Leronlimab’s Potential

  • Research has shown multiple key properties of the CCR5’s role in cancer:
    • The CCR5 receptor on cancer cells potentially plays a role in the migration and invasion of cells into the bloodstream, which may lead to metastasis of breast, prostate, and colon cancer.
    • Blocking the CCR5 receptor on Tregs also turns on anti-tumor fighting properties restoring immune function.
    • Blockage of the CCR5/CCL5 interaction had a synergistic effect with chemotherapy and controlled cancer progression.
      • Chemotherapy traditionally increased expression of CCR5, so blocking CCR5 is expected to reduce the levels of invasion and metastasis.
    • Animal studies revealed a significant decrease in angiogenesis following administration of leronlimab.
    • The CCR5 receptor has been shown to play an integral role in macrophage repolarization due to macrophage plasticity.

1Velasco-Velázquez M, Jiao X, De La Fuente M, Pestell TG, Ertel A, Lisanti MP, Pestell RG. CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res. 2012 Aug 1;72(15):3839-50. doi: 10.1158/0008-5472.CAN-11-3917. Epub 2012 May 25. PMID: 22637726.

2Jiao X, Nawab O, Patel T, Kossenkov AV, Halama N, Jaeger D, Pestell RG. Recent Advances Targeting CCR5 for Cancer and Its Role in Immuno-Oncology. Cancer Res. 2019 Oct 1;79(19):4801-4807. doi: 10.1158/0008-5472.CAN-19-1167. Epub 2019 Jul 10. PMID: 31292161; PMCID: PMC6810651

INFLAMMATION / HIV

With the advent of effective antiretroviral therapy, premature cardiovascular disease and other effects of immune activation and systemic inflammation have become the major cause of morbidity and mortality for people living with HIV. C-Reactive Protein (CRP) has been shown to be an important prognostic marker of inflammation in people with HIV. Elevated levels of CRP correlate with immunodeficiency disease progression,1,2 cardiovascular disease, and overall survival.

Leronlimab’s Potential

  • Promising data on clinical activity of leronlimab relevant to immune activation is available from a clinical study in
    • The pathology of MASH is driven by liver inflammation and damage caused by a buildup of fat in the liver. 
    • Thus, individuals with chronic immune activation as measured by elevation of CRP may benefit from leronlimab through reduction of their chronic inflammatory process.
    • The following summarizes the results of the changes observed in the markers of inflammation from the overall population of the MASH trial and from subjects who entered the study with an elevated CRP at baseline (> 5 mg/L):
Overall population The data showed a reduction from baseline in mean CRP for the 700 mg group of ‑0.58 mg/ml and an increase of +1.0 mg/L for the 350 mg group vs an increase of +2.48 mg/L for the placebo group
Subjects with C-Reactive Protein > 5.0 mg/L at baseline The data showed a reduction of -1.65 mg/L of CRP from the 700 mg dose while those on a 350 mg dose showed an increase of +0.7 mg/L and those on placebo showed a +0.93 mg/L increase

1 Lau, B., Sharrett, A. R., Kingsley, L. A., Post, W., Palella, F. J., Visscher, B., & Gange, S. J. (2006). C-reactive protein is a marker for human immunodeficiency virus disease progression. Archives of internal medicine, 166(1), 64–70. https://doi.org/10.1001/archinte.166.1.64

2 Feldman, J. G., Goldwasser, P., Holman, S., DeHovitz, J., & Minkoff, H. (2003). C-reactive protein is an independent predictor of mortality in women with HIV-1 infection. Journal of acquired immune deficiency syndromes (1999), 32(2), 210–214. https://doi.org/10.1097/00126334-200302010-00014

HIV

Thirty-seven million people are currently living with HIV. While daily oral antiretroviral therapy limits HIV replication, its use is a lifelong requirement and increases the likelihood for the development of drug-resistant variants1. The World Health Organization emphasized the need for new ART strategies in their Global Action Plan on HIV Drug Resistance2.

Leronlimab’s Potential

  • Recent in-vitro research suggests leronlimab maintained full activity in the presence of extensive resistance to the four main antiviral classes3.
  • Leronlimab and maraviroc have been reported to have synergistic activity, further corroborating the different mechanisms of the two drugs despite the same CCR5 target3
  • Leronlimab belongs to a class of HIV therapies known as viral entry inhibitors that block HIV from entering and infecting healthy cells.
    • Highly Active Antiretroviral Therapy (HAART), the current standard of care for HIV, waits until the virus enters the cell and begins replicating before it attacks the virus.
    • In illustrating the importance of CCR5 in HIV, individuals that lack CCR5 expression due to a natural genetic mutation are naturally resistant to HIV infection1.
    • Today, six people have been cured of HIV who were given transplanted cells either completely or partially deficient in the CCR5 receptor.
  • CytoDyn is currently evaluating the potential role of leronlimab in achieving an HIV cure.

1Chang XL, Reed JS, Webb GM, Wu HL, Le J, Bateman KB, et al. (2022) Suppression of human and simian immunodeficiency virus replication with the CCR5-specific antibody Leronlimab in two species. PLoS Pathog 18(3): e1010396.https://doi.org/10.1371/journal.ppat.1010396

2Global action plan on HIV drug resistance 2017–2021. Geneva: World Health Organization. 2017.

3Stefano Rusconi, Francesco Saladini, Maria Concetta Bellocchi, Laura Galli, Roberta Gagliardini, Lidia Gazzola, Daniela Francisci, Francesca Vichi, Emanuele Focà, Maurizio Zazzi, Maria M. Santoro, Arianna Gabrieli, Antonella Castagna, Leronlimab (PRO 140) in vitro activity against 4-class drug resistant HIV-1 from heavily treatment experienced subjects, Pharmacological Research,Volume 176,2022,106064,ISSN 1043-6618, https://doi.org/10.1016/j.phrs.2022.106064.

MASH

Prolonged inflammation and liver damage related to steatosis can cause fibrosis of the liver. Metabolic dysfunction-associated steatohepatitis (MASH) patients with fibrosis have a higher risk of progression to cirrhosis, end-stage liver disease, and hepatocellular carcinoma.1,2 

Leronlimab’s Potential

  • Current potential therapeutic options are focused on the reduction of steatosis and fibrosis.
    • In an exploratory study of MASH, leronlimab 350mg was shown to decrease both steatosis and fibrosis.
    • The CCR5 receptor exists in the liver on the surface of hepatocytes and stellate cells. Stellate cells are the cells that produce scar tissue in the liver, which can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. It is critical to have therapeutic options to resolve MASH before it progresses to later life-threatening stages. There are multiple comorbidities associated with MASH including a higher cardiovascular mortality rate.

1European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol, 2016;64(6):1388-1402.

2Rinella ME, Sanyal AJ. Management of NAFLD: a stage-based approach. Nature. 2016;13:196-205.

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