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Target Overview
EGFR (epidermal growth factor receptor) and c-MET (hepatocyte growth factor receptor) are proteins expressed simultaneously on the surface of many cancer cells, unlike normal tissues. Overexpression or mutation of these receptors is correlated with the development, progression, and metastasis of cancer as well as poor prognosis.1,2 EGFR and c-MET share overlapping biology, with a functional cross-talk between the receptors that translates into clinically relevant phenotypes. In EGFR-mutated NSCLC, c-MET gene amplification has been identified as the most common mechanism of resistance to third-generation EGFR inhibitors, such as osimertinib.3-5
Compound Overview
[ 225Ac]-FPI-2068 is targeted alpha therapy and is part of a theranostic pair with [ 111In]-FPI2107 which will be used with SPECT imaging for patient selection and evaluation of dosimetry. The antibody is a bispecific human IgG1 monoclonal antibody that can bind to EGFR and c-MET simultaneously on the surface of cells. Attached to the antibody via a bifunctional chelator is actinium-225 which is an alpha-emitting radioisotope. After binding to the tumor cells, [ 225Ac]-FPI-2068 gets internalized and radioactive decay of actinium-225 (and subsequent daughter isotopes) leads to significant DNA and cellular damage and apoptotic cell death. Internalization of [225Ac]-FPI-2068 is not required for efficacy although internalization will increase the likelihood of DNA damage.
Mechanism of Action
Targeted alpha therapies utilize highly specific vectors such as monoclonal antibodies, peptides or small molecules to deliver alpha radiation directly to tumor cells. Alpha decay leads to the release of high-energy alpha particles which have a short path length leading to significant tumor cell damage whilst sparing adjacent healthy tissue. Actinium-225 ultimately decays to bismuth-209 with the emission of 4 alpha particles.
References
1. Benedettini E, Sholl LM, Peyton M, et al. Am J Pathol. 2010;177(1):415-423. 2. Engelman JA, Zejnullahu K, Mitsudomi T, et al. Science. 2007;316(5827):1039-1043. 3. Leonetti A, Sharma S, Minari R, et al. Br J Cancer. 2019;121(9):725-737. 4. Passaro A, Jänne PA, Mok T, Peters S. Nat Cancer. 2021;2(4):377-391. 5. Zhang Z, Yang S, Wang Q. Biomark Res. 2019;7:27.
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Abbreviations
cMET
Tyrosine-protein kinase MET
CRC
colorectal cancer
EGFR
epidermal growth factor receptor
HNSCC
head and neck squamous cell carcinoma
NSCLC
non-small cell lung cancer
PDAC
pancreatic ductal adenocarcinoma
Target Overview
EGFR (epidermal growth factor receptor) and c-MET (hepatocyte growth factor receptor) are proteins expressed simultaneously on the surface of many cancer cells, unlike normal tissues. Overexpression or mutation of these receptors is correlated with the development, progression, and metastasis of cancer as well as poor prognosis.1,2 EGFR and c-MET share overlapping biology, with a functional cross-talk between the receptors that translates into clinically relevant phenotypes. In EGFR-mutated NSCLC, c-MET gene amplification has been identified as the most common mechanism of resistance to third-generation EGFR inhibitors, such as osimertinib.3-5
Compound Overview
[ 225Ac]-FPI-2068 is targeted alpha therapy and is part of a theranostic pair with [ 111In]-FPI2107 which will be used with SPECT imaging for patient selection and evaluation of dosimetry. The antibody is a bispecific human IgG1 monoclonal antibody that can bind to EGFR and c-MET simultaneously on the surface of cells. Attached to the antibody via a bifunctional chelator is actinium-225 which is an alpha-emitting radioisotope. After binding to the tumor cells, [ 225Ac]-FPI-2068 gets internalized and radioactive decay of actinium-225 (and subsequent daughter isotopes) leads to significant DNA and cellular damage and apoptotic cell death. Internalization of [225Ac]-FPI-2068 is not required for efficacy although internalization will increase the likelihood of DNA damage.
Mechanism of Action
Targeted alpha therapies utilize highly specific vectors such as monoclonal antibodies, peptides or small molecules to deliver alpha radiation directly to tumor cells. Alpha decay leads to the release of high-energy alpha particles which have a short path length leading to significant tumor cell damage whilst sparing adjacent healthy tissue. Actinium-225 ultimately decays to bismuth-209 with the emission of 4 alpha particles.
References
1. Benedettini E, Sholl LM, Peyton M, et al. Am J Pathol. 2010;177(1):415-423. 2. Engelman JA, Zejnullahu K, Mitsudomi T, et al. Science. 2007;316(5827):1039-1043. 3. Leonetti A, Sharma S, Minari R, et al. Br J Cancer. 2019;121(9):725-737. 4. Passaro A, Jänne PA, Mok T, Peters S. Nat Cancer. 2021;2(4):377-391. 5. Zhang Z, Yang S, Wang Q. Biomark Res. 2019;7:27.
Clinical trial information
Select trial for more information
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Abbreviations
cMET
Tyrosine-protein kinase MET
CRC
colorectal cancer
EGFR
epidermal growth factor receptor
HNSCC
head and neck squamous cell carcinoma
NSCLC
non-small cell lung cancer
PDAC
pancreatic ductal adenocarcinoma