Novel drug liberates tumor vessels to aid cancer drug delivery

Date:
November 3, 2021
Source:
University College London
Summary:
A therapeutic antibody has been shown to unblock and normalize
blood vessels inside cancerous tumors, enabling the more effective
delivery of targeted cancer treatments.



FULL STORY ==========================================================================
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.


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The findings in mice, published in the journalMED, 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.



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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.



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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.

* 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.

========================================================================== Story Source: Materials provided by University_College_London. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Marie N. O'Connor, David M. Kallenberg, Carlotta Camilli, Camilla
Pilotti, Athina Dritsoula, Rene Jackstadt, Chantelle E. Bowers, H.

Angharad Watson, Markella Alatsatianos, Julia Ohme, Laura Dowsett,
Jestin George, Jack W.D. Blackburn, Xiaomeng Wang, Mahak Singhal,
Hellmut G.

Augustin, Ann Ager, Owen J. Sansom, Stephen E. Moss,
John Greenwood. LRG1 destabilizes tumor vessels and
restricts immunotherapeutic potency. Med, 2021; DOI:
10.1016/j.medj.2021.10.002 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211103115448.htm

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