Melissa Call-Projects

Melissa Call-Projects

Researcher: 
Associate Professor Melissa Call

Projects

Last modified: 
Fri, 28/01/2022 - 11:19am

Tuning CAR T-cell potency with de novo designed receptor transmembrane domains

With collaborator Sarel Fleishman (Weizmann Institute of Science, Israel), we have developed and validated a panel of de novo designed transmembrane domains (TMDs) that form stable and specific dimeric, trimeric and tetrameric structures in cell membranes. We used these to enforce the corresponding oligomeric states in second-generation chimeric antigen receptors (CARs) against the solid tumour antigen HER2 and showed that both tumour control and cytokine production scaled in direct proportion to the designed oligomeric structure of the TMD (see eLife 2022).

Ongoing work in this program is focused on (1) expanding our panel of available TMD sequences and structures, (2) testing the clinical relevance of these new tools for optimising the safety/efficacy profiles of cellular immunotherapies in specific cancer contexts and (3) developing even more sophisticated applications for these sequences in the CAR T-cell space.

Project resources: · 'Goldilocks' treatment window could lead to cancer therapy without harmful side-effects

Team members:

Matthew Call, Laboratory Head, BS Trinity PhD Harvard

Samyuktha Ramesh, Postdoctoral Fellow, BTech Anna Univ Chennai PhD Melbourne

Ashleigh Davey, Senior Postdoctoral Fellow, BBiotech(Hons) Monash PhD Melbourne

Jasmine Rou, Honours Student, BSc Melbourne

Julie Nguyen, Research Assistant, BSc(Hons) Monash

Margareta Go, Research Assistant, BMedSci Univ Applied Sciences Utrecht

Lincoln Smith, Research Assistant, BBiotech(Hons) PhD Newcastle

Understanding the mechanism of type I cytokine receptor activation

Homodimeric type I cytokine receptors for growth hormone, erythropoietin and thrombopoietin (GHR, EpoR, TpoR) control processes essential to human health such as tissue growth, regeneration and blood cell production. Impaired activation and/or signalling of these receptors can lead to various pathological conditions, including blood pathologies, cancers, developmental and metabolic disorders.

GHR, EpoR, TpoR transmit signals by forming specific structures in their transmembrane domains (TM), though the identities of active and inactive orientations are not well understood. Our laboratory utilizes deep mutational scanning method coupled to next-generation sequencing to evaluate how mutating a large number of residues in receptors’ TM affects their function.

Project resources: Genetic cause of blood disease found

Team members:

Matthew Call, Laboratory Head, BS Trinity PhD Harvard

Samyuktha Ramesh, Postdoctoral Fellow, BTech Anna Univ Chennai PhD Melbourne

Harry McLeod, Honours Student, BSc Melbourne

Margareta Go, Research Assistant, BMedSci Univ Applied Sciences Utrecht

Predicting escape mutations of SARS-CoV-2 to emerging therapies

Inhibition of SARS-CoV-2 proteases is a proven strategy for the treatment of COVID-19.  We are constructing and screening expression libraries of the SARS-CoV-2 proteases to identify mutations that will allow SARS-CoV-2 to evade inhibition by therapeutics that are already in the clinic as well as those under development.  The results of these screens will guide drug-discovery efforts and hasten the development of second-generation therapeutics to target variants that will emerge in the future.

Team members:

Matthew Call, Laboratory Head, BS Trinity PhD Harvard

Xinyu Wu, Postgraduate Student, BSc(Hons) Tsinghua

Margareta Go, Research Assistant, BMedSci Univ Applied Sciences Utrecht