Abstract
To identify antibodies suitable for multiple myeloma (MM) immunotherapy, a cellular screening approach was developed using plasma cell lines JK-6L and INA-6 and human synthetic single-chain fragment variable (scFv) phage libraries. Isolated phage antibodies were screened for myeloma cell surface reactivity. Due to its binding characteristics, phage PIII-15 was selected to generate the scFv-Fc fusion protein TP15-Fc with an Fc domain optimized for FcγRIIIa binding. Various MM cell lines and patient-derived CD138-positive malignant plasma cells, but not granulocytes, B or T lymphocytes from healthy donors were recognized by TP15-Fc. Human intercellular adhesion molecule-1 (ICAM-1/CD54) was identified as target antigen by using transfected Chinese hamster ovary (CHO) cells. Of note, no cross-reactivity of TP15-Fc with mouse ICAM-1 transfected cells was detected. TP15-Fc was capable to induce antibody-dependent cell-mediated cytotoxicity (ADCC) against different human plasma cell lines and patients’ myeloma cells with peripheral blood mononuclear cells (PBMC) and purified NK cells. Importantly, TP15-Fc showed potent in vivo efficacy and completely prevented growth of human INA-6.Tu1 plasma cells in a xenograft SCID/beige mouse model. Thus, the novel ADCC-optimized TP15-Fc exerts potent anti-myeloma activity and has promising characteristics to be further evaluated for MM immunotherapy.
Highlights
MM is a malignant plasma cell disorder that accounts for approx. 10-15% of the hematologic malignancies in the US and Europe [1, 2]
Called ‘novel drugs’ like proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) in combination with stem cell transplantation have led to an increased overall survival [2, 3], but still most of the patients, especially patients ineligible for transplantation, older than 65 years and/or relapsed/refractory to PIs and IMiDs, succumb to their disease and new treatment approaches are needed
Since the FcγRIIIa V158F and the FcγRIIa H131R polymorphisms were correlated with the ability of IgG1 monoclonal antibody (mAb) to efficiently recruit immune effector cells, i.e. NK cells for antibody-dependent cell-mediated cytotoxicity (ADCC) and macrophages for antibody-dependent cellular phagocytosis (ADCP), and have an impact on their clinical efficacy, strategies have been developed to improve effector cell recruitment [12, 13]
Summary
MM is a malignant plasma cell disorder that accounts for approx. 10-15% of the hematologic malignancies in the US and Europe [1, 2]. Therapeutic mAbs are well established for the treatment of hematologic malignancies and solid tumors www.impactjournals.com/oncotarget [10, 11] To date, they are predominantly of human IgG1 isotype. Since the FcγRIIIa V158F and the FcγRIIa H131R polymorphisms were correlated with the ability of IgG1 mAbs to efficiently recruit immune effector cells, i.e. NK cells for ADCC and macrophages for ADCP, and have an impact on their clinical efficacy, strategies have been developed to improve effector cell recruitment [12, 13] Such attempts include amino acid exchanges (proteinengineering) and modifications in the glycosylation pattern (glyco-engineering) [14,15,16]. As shown for Xmab5592, a humanized IgG1 directed against HM1.24/CD317, Fc-engineered mAbs can have potent anti-myeloma activity and be synergistically active in combination with lenalidomide in vivo [27]
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