Novel drug liberates tumour vessels to aid cancer drug delivery

A therapeutic antibody developed by scientists at UCL has been shown to unblock and normalise blood vessels inside cancerous tumours, enabling the more effective delivery of targeted cancer treatments.

The findings in mice, published in the journal MED, are the first to demonstrate that inhibiting the activity of LRG1, a protein produced in many tumorous tissues, liberates disorganised angiogenesis (blood vessel formation) - a leading cause of morbidity in numerous diseases including cancer.

Researchers say the novel drug offers the potential to achieve a far better outcome in patients who respond poorly to current standard of care for cancers, including those of the breast, colon, bladder, prostate, and lung.

Furthermore, researchers also found the antibody significantly enhanced the ability of immunotherapies to reduce solid tumours, including cancers resistant to immune checkpoint inhibitors* and CAR T-cell** therapy, something that clinicians and scientists have struggled to overcome.

Explaining the study, co-lead author, Professor John Greenwood (UCL Institute of Ophthalmology) said: “Cancers need a blood supply to grow, but when new vessels form inside a tumour they are typically abnormal, resulting in compromised oxygen delivery that may render the tumour more aggressive.

"This impaired blood supply also limits the delivery of therapies reducing their effectiveness and contributing to treatment resistance. We asked whether blocking the activity of a novel molecule that damages blood vessels, namely LRG1, would allow vessels to grow more normally thus reducing tumour expansion and, most importantly, enhancing the delivery and efficacy of other drugs."

For the study, a UCL-developed LRG1-blocking antibody was administered to tumour-bearing mice in the presence and absence of various cancer therapeutics, simulating similar treatment courses as found in humans.

In the models of cancer examined, the antibody, when used alone (monotherapy), significantly improved blood flow and oxygenation and reduced tumour growth rates. When combined with chemotherapy, or new immunotherapies which have shown less utility in solid tumours, such as carcinomas and glioblastomas, there was an increase in immune cell infiltration and tumour cell killing activity inside the tumour compared to monotherapy.

Co-lead author Professor Stephen Moss (UCL Institute of Ophthalmology) said: "Although counterintuitive, finding a way to normalise cancerous tumour blood vessels has become a clinical objective, but identifying an effective therapeutic tool has proven elusive.

"Our results provide direct evidence that blocking the LRG1 protein, which is produced at high levels in tumours, normalises the vasculature and enhances the current sub-optimal effectiveness of immunotherapies, including checkpoint inhibition and CAR-T cell therapy, in solid cancers.

"This opens up the potential to achieve a far better result in many cancer patients who respond poorly to current standard of care."

Discovering the role of LRG1 in eye disease

In 2008, the same research team based at the UCL Institute of Ophthalmology discovered LRG1 was a potent stimulator of abnormal angiogenesis in the human eye, and contributes to vascular problems associated with conditions such as diabetic retinopathy and wet age-related macular degeneration (AMD). This discovery was published in the journal Nature in 2013 and led to the development of a therapeutic antibody targeting LRG1 for the treatment of eye diseases, which was successfully trialled in mice.

For this latest study, the researchers used the same therapeutic antibody to see if it would block LRG1 and normalise angiogenesis in cancerous tumours and whether this improves the effectiveness of various current sub-optimal cancer treatments.

Next steps

The research team have developed a human version of the LRG1-blocking antibody, named Magacizumab, that is ready to progress to clinical trials in patients with cancer and eye disease.

With support from UCL Business and the UCL Technology Fund, a spin-out company called PanAngium Therapeutics, has been created to accelerate future clinical developments of the drug.

This research was supported by funding from Wellcome, the Medical Research Council and the British Heart Foundation.

Marie N O'Connor, David M Kallenberg, Rene Jackstadt, Angharad H Watson, Markella Alatsatianos, Julia Ohme, Carlotta Camilli, Camilla Pilotti, Athina Dritsoula, Chantelle E Bowers, Laura Dowsett, Jestin George, Xiaomeng Wang, Ann Ager, Owen J Sansom, Stephen E Moss, John Greenwood.
LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency.
bioRxiv 2020.10.12.334359; doi: 10.1101/2020.10.12.334359

*Checkpoint inhibitors are a type of immunotherapy that stops cancer cells from ‘switching off’ the body’s immune response. While effective in some, not all patients respond to treatment.
**In CAR T therapy, immune cells (T-cells) are genetically engineered to contain a molecule called a chimeric antigen receptor (CAR) on their surface which can specifically recognise cancerous cells. While effective in some, not all patients respond to treatment.

Most Popular Now

Pfizer to provide U.S. government with 10 million …

Pfizer Inc. (NYSE: PFE) today announced an agreement with the U.S. government to supply 10 million treatment courses of its investigational COVID-19 oral antiviral candid...

GSK and Vir Biotechnology announce United States g…

GlaxoSmithKline plc (LSE/NYSE: GSK) and Vir Biotechnology, Inc. (Nasdaq: VIR) announced US government contracts totalling approximately $1 billion[1] (USD) to purchase so...

Primary endpoint met in COMET-TAIL Phase III trial…

GlaxoSmithKline plc (LSE/NYSE: GSK) and Vir Biotechnology, Inc. (Vir) (Nasdaq: VIR) announced headline data from the randomised, multi-centre, open-label COMET-TAIL Phase...

Two billion doses of AstraZeneca’s COVID-19 vaccin…

AstraZeneca and its partners have released for supply two billion doses of their COVID-19 vaccine to more than 170 countries across every continent on the planet in the l...

Merck and Ridgeback's molnupiravir, an oral COVID-…

Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Ridgeback Biotherapeutics announced that the United Kingdom Medicines and Healthcare products Re...

Johnson & Johnson COVID-19 vaccine named one o…

The editors of Time announced that the Johnson & Johnson COVID-19 vaccine has been selected as one of Time's Best Inventions of 2021. The vaccine, for which Johnson & ...

New target for COVID-19 vaccines identified

Next generation vaccines for COVID-19 should aim to induce an immune response against 'replication proteins', essential for the very earliest stages of the viral cycle, c...

Repurposing a familiar drug for COVID-19

For the past year and a half, the COVID-19 pandemic has continued to engulf the globe, fueled in part by novel variants and the uneven distribution of vaccines. Every day...

Safety concerns raised for neuroblastoma candidate…

St. Jude Children's Research Hospital scientists looking for drugs to improve survival of children with high-risk neuroblastoma found a promising candidate in CX-5461. Th...

Pfizer and BioNTech receive expanded U.S. FDA emer…

Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) announced that the U.S. Food and Drug Administration (FDA) has expanded the emergency use authorization (EUA) of a ...

'Dancing molecules' successfully repair severe spi…

Northwestern University researchers have developed a new injectable therapy that harnesses “dancing molecules” to reverse paralysis and repair tissue after severe spinal ...

A target for potential cancer drugs may, in fact, …

In recent years, much scientific effort and funding has focused on developing drugs that target an enzyme with the unwieldy name of Src homology 2-containing protein tyro...