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12-14-2014, 02:22 PM
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#1
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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THIS MAY BE BIG: new monoclonalantibody-peptide conjugate crosses blood-brainbarrier
in mice
Let's get the clinical trial started soon!
ANG4043, a Novel Brain-Penetrant Peptide-mAb Conjugate, Is Efficacious against HER2-Positive Intracranial Tumors in Mice.
Regina A1, Demeule M1, Tripathy S1, Lord-Dufour S1, Currie JC1, Iddir M2, Annabi B2, Castaigne JP1, Lachowicz JE3.
Author information
Abstract
Anti-HER2 monoclonal antibodies (mAb) have been shown to reduce tumor size and increase survival in patients with breast cancer, but they are ineffective against brain metastases due to poor brain penetration. In previous studies, we identified a peptide, known as Angiopep-2 (An2), which crosses the blood-brain barrier (BBB) efficiently via receptor-mediated transcytosis, and, when conjugated, endows small molecules and peptides with this property. Extending this strategy to higher molecular weight biologics, we now demonstrate that a conjugate between An2 and an anti-HER2 mAb results in a new chemical entity, ANG4043, which retains in vitro binding affinity for the HER2 receptor and antiproliferative potency against HER2-positive BT-474 breast ductal carcinoma cells. Unlike the native mAb, ANG4043 binds LRP1 clusters and is taken up by LRP1-expressing cells. Measuring brain exposure after intracarotid delivery, we demonstrate that the new An2-mAb conjugate penetrates the BBB with a rate of brain entry (Kin) of 1.6 × 10-3 mL/g/s. Finally, in mice with intracranially implanted BT-474 xenografts, systemically administered ANG4043 increases survival. Overall, this study demonstrates that the incorporation of An2 to the anti-HER2 mAb confers properties of increased uptake in brain endothelial cells as well as BBB permeability. These characteristics of ANG4043 result in higher exposure levels in BT-474 brain tumors and prolonged survival following systemic treatment. Moreover, the data further validate the An2-drug conjugation strategy as a way to create brain-penetrant biologics for neuro-oncology and other CNS indications. Mol Cancer Ther; 1-12. ©2014 AACR.
©2014 American Association for Cancer Research.
PMID: 25492620 [PubMed - as supplied by publisher]
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12-14-2014, 03:14 PM
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#2
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Senior Member
Join Date: Jun 2014
Posts: 162
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Re: THIS MAY BE BIG: new monoclonalantibody-peptide conjugate crosses blood-brainbar
Oh MY that is good news !!!!
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12-14-2014, 04:21 PM
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#3
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Senior Member
Join Date: Nov 2014
Posts: 83
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Re: THIS MAY BE BIG: new monoclonalantibody-peptide conjugate crosses blood-brainbar
Thank you for this! Hoping the trials begin soon.
__________________
June 2013 DX Stage 3 Idc, rt breast, er/pr-, her2+++
PET/CT/Brain MRI clear
ACTHP until Dec 2013
BMX Dec 2013
28 Rads Feb 2014
Exchange surgery June 2014
Herceptin end Sept 2014
Headaches start Oct 2014
CT body clear Nov 2014
Brain MRI 4 lesions Nov 2014
SRS via LINAC in Dec 2014
Rt side infection, hospitalized, lost right implant on Jan 1, 2015
Jan 14 2015 MRI brain lesions shrinking
Jan 27 2015 Re-start herceptin every 3 weeks
Feb 2015 CT/PET Body clear
Re-start Lymphedema treatment April 2015
Breast MRI clear April 2015
Brain MRI April 2015 - shows everything stable, nothing new (whew)
CT scan June 2015 - clear
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12-15-2014, 11:26 AM
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#4
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Senior Member
Join Date: May 2006
Location: Haarlem, the Netherlands
Posts: 835
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Re: THIS MAY BE BIG: new monoclonalantibody-peptide conjugate crosses blood-brainbar
If this pans out, it is a major breakthrough and yet another nail in Her2positive BC's coffin. Let's see how it works out in trials. May they start soon!
Jacqueline
__________________
Diagnosed age 44, January 2004, 0.7 cm IDC & DCIS. Stage 1, grade 3, ER/PR pos. HER2 pos. clear margins, no nodes. SNB. 35 rads. On Zoladex and Armidex since Dec. 2004. Stopped Zoladex/Arimidex sept 2009 Still taking mistletoe shots (CAM therapy) Doing fine.
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12-18-2014, 12:59 AM
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#5
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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Re: THIS MAY BE BIG: new monoclonalantibody-peptide conjugate crosses blood-brainbar
bringing this up so ROLEPAUL can see it if he missed it
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12-18-2014, 01:18 PM
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#6
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Member
Join Date: Mar 2013
Location: Toronto, Canada
Posts: 23
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Re: THIS MAY BE BIG: new monoclonalantibody-peptide conjugate crosses blood-brainbar
We need something like this badly...
Lani, you are such a treasure for bringing them up! No mater where we look for info we can't find it all, and you bring it all here! We love you :-)
__________________
2011/03 - dx IDC (15 weeks pregnant), Rx mastectomy, 1.5 cm, stage 1B, grade 3, ER-/PR-/HER2+, 1/20
2011/04 - started 3xFEC while pregnant (2 sessions)
2011/06 - daughter born healthy @36 weeks
2011/08 - 3xTaxotere & Herceptin, followed by 1 year of Herceptin, no rads
2013/09 - mets to liver, bones & lungs, started weekly Taxotere + Herceptin
2013/10 - stopped Taxotere after 4 weeks due to severe side effects, stay on weekly Herceptin, pleurodesis to right lung (previously 2 x thoracentesis)
2014/01 - Dec CT scan shows good liver response but progression to bones, Pamidronate plus Herceptin only
2014/01 - brain & spine MRI (symptomatic) shows very large number of mets in the brain, do urgent WBR (20Gy/5 fractions)
2014/02 - Herceptin, Perjeta, Abraxane, XGeva
2014/08 - stopped Abraxane, stayed on Herceptin, Perjeta, XGeva
2014/12 - brain mets progression, second round of WBR (25Gy/10 fractions), lungs stable, light activity in liver
2015/02 - progression in lungs (lymphangitic carcinomatosis), stop Herceptin / Perjeta, start TDM1
2015/07 - stable on the extra cranial disease (lungs, abdomen)
2015/07- brain MRI show tumors went to the leptomeningeal area and also new one started to grow deep brain, still on TDM1, not sure of next step ....
2015/08 - looking for help to get IT Herceptin in Canada
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12-19-2014, 04:15 PM
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#7
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Senior Member
Join Date: Jan 2012
Location: Boulder Colorado as of January 2013
Posts: 391
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Re: THIS MAY BE BIG: new monoclonalantibody-peptide conjugate crosses blood-brainbar
Funny. I saw this and saw the results on the MRI scans with Nina's brain lesions. Are the researcher's missing something with conjugated antibodies and water/lipid solubility thinking. If the MAb is water soluble and the BBB prevents the MAb penetrating to help by forming a fat film, conjugating the non-water soluble cancer drug may work because it allows the MAb to to get through the BBB, not because it makes the conjugate more deadly to the cancer cell. Maybe the concept is to conjugate a fat like substance, which is cheap versus the cancer drugs. Another thing to ask a MAb guru.
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