Generation and characterization of a therapeutic human antibody to melanoma antigen TYRP1
Dipa Patel1, Paul Balderes, Armin Lahiji
1ImClone Systems Incorporated, 180 Varick Street, New York, NY 10014, USA.
Abstract:
TYRP1 (tyrosinase-related protein 1) is a melanoma antigen expressed in melanosomes and on the surface of melanoma cells. Previous studies have shown that mouse antibodies to TYRP1 localized to melanomas in vivo and inhibited tumor growth and metastasis. Here, we describe the characterization of a novel fully human anti-TYRP1 MAb (20D7) generated by immunizing HuMAb mice (Medarex). 20D7 recognized recombinant and native human TYRP1 by Western blotting and ELISA, and native TYRP1 in melanoma cells as determined by flow cytometry analysis. 20D7 cross-reacted with mouse TYRP1. The binding affinity to human TYRP1 for the human MAb was in the low nM range as determined by surface plasmon resonance kinetics. 20D7 can bind to human and mouse Fc receptor and induce a strong ADCC response against human melanoma cells in vitro. The antitumor activity of 20D7 was tested in human melanoma xenografts and mouse metastatic melanoma models in athymic nude mice. Growth of s.c. human melanoma tumors and metastatic nodules of murine B16 tumor were significantly suppressed by 20D7 compared to human IgG control. These results suggest that human anti-TYRP1 MAb may be a potent therapeutic for the treatment of malignant melanoma.
Insights
A new fully human antibody, 20D7, targets tyrosinase-related protein 1 (TYRP1) on melanoma cells. This antibody demonstrated significant suppression of human melanoma tumor growth and metastasis in preclinical models, suggesting therapeutic potential.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Tyrosinase-related protein 1 (TYRP1) is a melanoma-specific antigen found in melanosomes and on melanoma cell surfaces.
- Previous mouse antibody studies showed TYRP1 targeting inhibited melanoma growth and metastasis.
- A novel fully human monoclonal antibody (MAb), 20D7, targeting TYRP1 was developed.
Purpose of the Study:
- To characterize the novel fully human anti-TYRP1 MAb (20D7).
- To evaluate the in vitro and in vivo antitumor activity of 20D7 against malignant melanoma.
Main Methods:
- Characterization of 20D7 binding to human and mouse TYRP1 using Western blotting, ELISA, and flow cytometry.
- Affinity determination by surface plasmon resonance kinetics.
- Assessment of antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.
- Evaluation of antitumor efficacy in human melanoma xenografts and murine B16 melanoma metastasis models.
Main Results:
- 20D7 recognized both recombinant and native human TYRP1, as well as native TYRP1 on melanoma cells.
- The antibody exhibited low nM binding affinity for human TYRP1 and cross-reacted with mouse TYRP1.
- 20D7 induced significant antibody-dependent cell-mediated cytotoxicity (ADCC) against human melanoma cells in vitro.
- Significant suppression of human melanoma tumor growth and murine B16 melanoma metastasis was observed with 20D7 treatment in vivo.
Conclusions:
- The fully human anti-TYRP1 MAb 20D7 is a well-characterized antibody with potent anti-melanoma activity.
- 20D7 demonstrates significant therapeutic potential for treating malignant melanoma through direct tumor cell targeting and immune-mediated mechanisms.
- Further clinical investigation of 20D7 as a melanoma therapy is warranted.
