determining-binding-affinity-kd-radiolabeled-antibodies-to

Determining Binding Affinity (K<sub>D</sub>) of Radiolabeled Antibodies to Immobilized Antigens

Determining binding affinity (KD) is an important aspect of the characterization of radiolabeled antibodies (rAb). Typically, binding affinity is ...

Yale University

Amivantamab is a novel bispecific antibody that simultaneously targets the epidermal growth factor receptor (EGFR) and the hepatocyte growth factor receptor (HGFR/c-MET) that are overexpressed in several types of cancer including triple-negative breast cancer (TNBC). Targeting both receptors simultaneously can overcome resistance to mono-targeted therapy. The purpose of this study is to develop Zr-labeled amivantamab as a potential companion diagnostic imaging agent to amivantamab therapy using various preclinical models of TNBC for evaluation.

Development of [Zr]ZrDFO-amivantamab bispecific to EGFR and c-MET for PET imaging of triple-negative breast cancer.

Breast cancer is the most common cancer in women worldwide. The heterogeneity of breast cancer and drug resistance to therapies make the diagnosis and treatment difficult. Molecular imaging methods with positron emission tomography (PET) and single-photon emission tomography (SPECT) provide useful tools to diagnose, predict, and monitor the response of therapy, contributing to precision medicine for breast cancer patients. Recently, many efforts have been made to find new targets for breast cancer therapy to overcome resistance to standard of care treatments, giving rise to new therapeutic agents to offer more options for patients with breast cancer. The combination of diagnostic and therapeutic strategies forms the foundation of theranostics. Some of these theranostic agents exhibit high potential to be translated to clinic. In this review, we highlight the most recent advances in theranostics of the different molecular subtypes of breast cancer in preclinical studies.

Preclinical Advances in Theranostics for the Different Molecular Subtypes of Breast Cancer.

There is a need for prognostic markers to select patients most likely to benefit from antibody-drug conjugate (ADC) therapy. We quantified the relationship between pretreatment PET imaging of glycoprotein nonmetastatic melanoma B (gpNMB) with 89Zr-labeled anti-gpNMB antibody ([89Zr]ZrDFO-CR011) and response to ADC therapy (CDX-011) in triple-negative breast cancer. First, we compared different PET imaging metrics and found that standardized uptake values (SUV) and tumor-to-heart SUV ratios were sufficient to delineate differences in radiotracer uptake in the tumor of four different cell- and patient-derived tumor models and achieved high standardized effect sizes. These tumor models with varying levels of gpNMB expression were imaged with [89Zr]ZrDFO-CR011 followed by treatment with a single bolus injection of CDX-011. The percent change in tumor volume relative to baseline (% CTV) was then correlated with SUVmean of [89Zr]ZrDFO-CR011 uptake in the tumor. All gpNMB-positive tumor models responded to CDX-011 over 6 weeks of treatment, except one patient-derived tumor regrew after 4 weeks of treatment. As expected, the gpNMB-negative tumor increased in volume by 130 ± 59% at endpoint. The magnitude of pretreatment SUV had the strongest inverse correlation with the % CTV at 2-4 weeks after treatment with CDX-011 (Spearman ρ = -0.8). However, pretreatment PET imaging with [89Zr]ZrDFO-CR011 did not inform on which tumor types will regrow over time. Other methods will be needed to predict resistance to treatment.

Article	Year
Development of [Zr]ZrDFO-amivantamab bispecific to EGFR and c-MET for PET imaging of triple-negative breast cancer. European journal of nuclear medicine and molecular imaging\| PubMed ID: 32770372	2021
Preclinical Advances in Theranostics for the Different Molecular Subtypes of Breast Cancer. Frontiers in pharmacology\| PubMed ID: 33986665	2021
[89Zr]ZrDFO-CR011 PET Correlates with Response to Glycoprotein Nonmetastatic Melanoma B-targeted Therapy in Triple-negative Breast Cancer. Molecular cancer therapeutics\| PubMed ID: 35027482	2022

Alessandra Cavaliere

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