Development of a human immuno-oncology therapeutic agent targeting HER2: targeted delivery of granzyme B

Journal of Experimental & Clinical Cancer Research : CR
Lawrence H CheungMichael G Rosenblum

Abstract

Immunotherapeutic approaches designed to augment T and B cell mediated killing of tumor cells has met with clinical success in recent years suggesting tremendous potential for treatment in a broad spectrum of tumor types. After complex recognition of target cells by T and B cells, delivery of the serine protease granzyme B (GrB) to tumor cells comprises the cytotoxic insult resulting in a well-characterized, multimodal apoptotic cascade. We designed a recombinant fusion construct, GrB-Fc-4D5, composed of a humanized anti-HER2 scFv fused to active GrB for recognition of tumor cells and internal delivery of GrB, simulating T and B cell therapy. We assessed the construct's antigen-binding specificity and GrB enzymatic activity, as well as in vitro cytotoxicity and internalization into target and control cells. We also assessed pharmacokinetic and toxicology parameters in vivo. GrB-Fc-4D5 was highly cytotoxic to Her2 positive cells such as SKBR3, MCF7 and MDA-MB-231 with IC50 values of 56, 99 and 27 nM, respectively, and against a panel of HER2+ cell lines regardless of endogenous expression levels of the PI-9 inhibitor. Contemporaneous studies with Kadcyla demonstrated similar levels of in vitro activity against virtually all cell...Continue Reading

References

May 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·P CarterH M Shepard
Jul 1, 1996·Current Biology : CB·A M ChinnaiyanV M Dixit
Dec 4, 2003·Acta Haematologica·Felipe AndradeAntony Rosen
Mar 21, 2006·Molecular Cancer Therapeutics·Hugo CaldasRachel A Altura
Apr 14, 2006·Neoplasia : an International Journal for Oncology Research·Yuying LiuMichael G Rosenblum
Nov 23, 2006·The Journal of Cell Biology·Dion KaisermanPhillip I Bird
Sep 16, 2008·Molecular Cancer Therapeutics·Bettina StahnkeStefan Barth
Sep 2, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jagath R JunutulaMark X Sliwkowski
Oct 19, 2010·Critical Reviews in Oncology/hematology·Anna EmdeUNKNOWN Association of Radiotherapy and Oncology of the Mediterranean arEa (AROME)
Feb 18, 2011·Cancer Chemotherapy and Pharmacology·Isao KanataniStephen B Howell
Oct 2, 2012·The New England Journal of Medicine·Sunil VermaUNKNOWN EMILIA Study Group
Jul 17, 2013·Molecular Cancer Therapeutics·Khalid A MohamedaliMichael G Rosenblum
Jan 1, 2012·American Society of Clinical Oncology Educational Book·Howard A Burris
Jun 3, 2014·Breast Cancer Research : BCR·Mark BarokJorma Isola
Jun 27, 2014·Journal of Medicinal Chemistry·John M Lambert, Ravi V J Chari
Sep 24, 2014·Proceedings of the National Academy of Sciences of the United States of America·Mingyang LuEshel Ben-Jacob
Oct 15, 2014·Antimicrobial Agents and Chemotherapy·Stephanie KapelskiRolf Fendel
Nov 7, 2014·Frontiers in Oncology·Ahmed A Mostafa, Don G Morris
Jan 18, 2015·Molecular Immunology·Connie P M DuongPhillip K Darcy
Jan 27, 2015·Annual Review of Immunology·Seng-Ryong WooThomas F Gajewski
May 20, 2015·Current Drug Targets·Hanna A KnausIvana Gojo
Jul 17, 2015·Bioscience Reports·Christina Peters, Stuart Brown
Aug 13, 2015·Immunobiology·Jens Pahl, Adelheid Cerwenka
Nov 27, 2015·Science Translational Medicine·Philipp MüllerAlfred Zippelius
Dec 15, 2015·Expert Opinion on Drug Delivery·Sagun ParakhAndrew M Scott
Dec 26, 2015·The Lancet Oncology·Ahmed ElsadaE Jane Adam
Jan 23, 2016·Pharmacotherapy·Taleen V JerjianCindy L O'Bryant
Jan 30, 2016·Oncotarget·Debora de Melo GagliatoGabriel N Hortobagyi
Apr 22, 2016·Respirology : Official Journal of the Asian Pacific Society of Respirology·Antonius StevenBruce W Robinson
May 18, 2016·Journal for Immunotherapy of Cancer·David B PageBernard A Fox

❮ Previous
Next ❯

Citations

Sep 23, 2020·Journal for Immunotherapy of Cancer·Ana Alvarez de CienfuegosMichael G Rosenblum
Dec 29, 2020·Drug Discovery Today·Rakesh Kumar Dhritlahre, Ankit Saneja
Sep 8, 2021·Cancer Cell International·Reza MahmoudiMohammad Rahmati

❮ Previous
Next ❯

Datasets Mentioned

BETA
MDA-MB-468

Methods Mentioned

BETA
transfection
ion exchange chromatography
ELISA
PCR
confocal microscopy
glycosylation
enzymatic cleavage

Software Mentioned

PKSolver

Related Concepts

Related Feeds

B cells: Gene Expression

B lymphocytes are white blood cells that play a role in the adaptive immune system by secreting antibodies. Here is the latest research on gene expression in B cells.

Cancer Vaccines

Cancer vaccines are vaccines that either treat existing cancer or prevent development of a cancer.

Related Papers

Acta Haematologica
F AndradeAntony Rosen
The Journal of Immunology : Official Journal of the American Association of Immunologists
Magdalena HagnJ A Trapani
International Journal of Cancer. Journal International Du Cancer
Donatella D'EliseoFrancesca Velotti
© 2021 Meta ULC. All rights reserved