Discovery and Optimization of HKT288, a Cadherin-6-Targeting ADC for the Treatment of Ovarian and Renal Cancers

Cancer Discovery
Carl U BialuchaEmma Lees

Abstract

Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody-drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models-a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation.Significance: We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorp...Continue Reading

References

Jan 1, 1994·The Journal of Cell Biology·C R MackayU Günthert
Aug 30, 2005·Molecular & Cellular Proteomics : MCP·Mathias UhlénFredrik Pontén
Oct 26, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Bernard M TijinkGuus A M S van Dongen
Dec 13, 2006·Genes & Development·Jennifer M Halbleib, W James Nelson
Oct 23, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Lucie BaudinoShozo Izui
Dec 6, 2008·Traffic·Emmanuella Delva, Andrew P Kowalczyk
May 28, 2011·Cell Death and Differentiation·C Royer, X Lu
Jul 12, 2011·The Lancet Oncology·Susanna L Cooke, James D Brenton
Apr 18, 2012·Nature Reviews. Clinical Oncology·John J TentlerS Gail Eckhardt
May 23, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Barbara ProAndrei Shustov
Aug 10, 2012·The AAPS Journal·Hans K Erickson, John M Lambert
Oct 2, 2012·The New England Journal of Medicine·Sunil VermaUNKNOWN EMILIA Study Group
Oct 10, 2012·Annual Review of Medicine·Eric L Sievers, Peter D Senter
May 30, 2013·Nature Genetics·UNKNOWN GTEx Consortium
Jun 5, 2013·Cancer Research·Despina Siolas, Gregory J Hannon
Jul 11, 2013·Nature Communications·Silvia DomckeNikolaus Schultz
Sep 27, 2013·PloS One·Valentina SancisiAlessia Ciarrocchi
Sep 28, 2013·Nature Genetics·UNKNOWN Cancer Genome Atlas Research NetworkJoshua M Stuart
May 6, 2014·Trends in Cell Biology·Marcos SotomayorDavid P Corey
Sep 4, 2014·Cancer Discovery·Manuel HidalgoAlberto Villanueva
Jan 24, 2015·Science·Mathias UhlénFredrik Pontén
Sep 10, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Junzo HamanishiIkuo Konishi
Sep 26, 2015·The New England Journal of Medicine·Robert J MotzerUNKNOWN CheckMate 025 Investigators
Nov 6, 2015·Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics·Joshua Seth EatonChristopher J Murphy
Nov 22, 2015·Pharmacological Reviews·Paul Polakis
Nov 27, 2015·Science Translational Medicine·Philipp MüllerAlfred Zippelius
Apr 29, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Markus WallesSanela Bilic
Jun 4, 2016·Oncotarget·Tiziana de CristofaroMariastella Zannini
Oct 30, 2016·Traffic·Chantel M CadwellAndrew P Kowalczyk
Oct 14, 2016·Annals of Oncology : Official Journal of the European Society for Medical Oncology·A W Tolcher

❮ Previous
Next ❯

Citations

May 10, 2019·Frontiers in Pharmacology·Haichao TangYing Jin
Jul 22, 2019·International Journal of Molecular Sciences·J Ignacio Casal, Rubén A Bartolomé
Feb 7, 2018·Molecular & Cellular Oncology·Scott David CollinsHui Gao
Mar 3, 2018·Journal of Clinical Medicine·Juliet A Williams
Aug 21, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Vivek SubbiahGregory Ravizzini
Feb 5, 2021·Research and Practice in Thrombosis and Haemostasis·Emma G BouckMarvin T Nieman

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.