Related Experiment Video
Updated: Dec 9, 2025
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Potent Activity of an Anti-ICAM1 Antibody-Drug Conjugate against Multiple Myeloma
Daniel W Sherbenou1,2, Yang Su3, Christopher R Behrens3
1Department of Medicine, University of California at San Francisco, California.
Purpose:
New therapies have changed the outlook for patients with multiple myeloma, but novel agents are needed for patients who are refractory or relapsed on currently approved drug classes. Novel targets other than CD38 and BCMA are needed for new immunotherapy development, as resistance to daratumumab and emerging anti-BCMA approaches appears inevitable. One potential target of interest in myeloma is ICAM1. Naked anti-ICAM1 antibodies were active in preclinical models of myeloma and safe in patients, but showed limited clinical efficacy. Here, we sought to achieve improved targeting of multiple myeloma with an anti-ICAM1 antibody-drug conjugate (ADC).
Experimental Design:
Our anti-ICAM1 human mAb was conjugated to an auristatin derivative, and tested against multiple myeloma cell lines in vitro, orthotopic xenografts in vivo, and patient samples ex vivo. The expression of ICAM1 was also measured by quantitative flow cytometry in patients spanning from diagnosis to the daratumumab-refractory state.
Results:
The anti-ICAM1 ADC displayed potent anti-myeloma cytotoxicity in vitro and in vivo. In addition, we have verified that ICAM1 is highly expressed on myeloma cells and shown that its expression is further accentuated by the presence of bone marrow microenvironmental factors. In primary samples, ICAM1 is differentially overexpressed on multiple myeloma cells compared with normal cells, including daratumumab-refractory patients with decreased CD38. In addition, ICAM1-ADC showed selective cytotoxicity in multiple myeloma primary samples.
Conclusions:
We propose that anti-ICAM1 ADC should be further studied for toxicity, and if safe, tested for clinical efficacy in patients with relapsed or refractory multiple myeloma.
Insights
A novel antibody-drug conjugate targeting ICAM1 shows potent anti-myeloma activity in preclinical models. This new therapy offers potential for patients with relapsed or refractory multiple myeloma who have limited treatment options.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Novel therapeutic targets are crucial for multiple myeloma, especially for patients refractory to existing treatments like daratumumab and emerging anti-BCMA therapies.
- Intercellular Adhesion Molecule 1 (ICAM1) presents a potential target, with previous naked anti-ICAM1 antibodies showing safety but limited efficacy.
Purpose of the Study:
- To develop an improved anti-ICAM1 antibody-drug conjugate (ADC) for enhanced targeting of multiple myeloma.
- To evaluate the efficacy and expression of ICAM1 in multiple myeloma models and patient samples.
Main Methods:
- An anti-ICAM1 human monoclonal antibody was conjugated to an auristatin derivative to create the ADC.
- The anti-ICAM1 ADC was tested in vitro against multiple myeloma cell lines, in vivo using orthotopic xenografts, and ex vivo on patient samples.
- ICAM1 expression was quantified using flow cytometry in patients at various disease stages, including those refractory to daratumumab.
Main Results:
- The anti-ICAM1 ADC demonstrated potent in vitro and in vivo anti-myeloma cytotoxicity.
- ICAM1 was found to be highly expressed on myeloma cells, with expression further increased by bone marrow microenvironmental factors.
- ICAM1 was differentially overexpressed on multiple myeloma cells compared to normal cells, even in daratumumab-refractory patients, and the ICAM1-ADC showed selective cytotoxicity in primary samples.
Conclusions:
- Anti-ICAM1 ADC warrants further investigation for toxicity and potential clinical efficacy in relapsed or refractory multiple myeloma.
- ICAM1 represents a promising target for novel immunotherapy development in multiple myeloma.
More Related Videos
15:04Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation
Published on: January 19, 2019
13:59High-Content Screening Assay for the Identification of Antibody-Dependent Cellular Cytotoxicity Modifying Compounds
Published on: August 18, 2023
