Identification of novel anti-CD16a antibody clones for the development of effective natural killer cell engagers
Natural killer (NK) cells are key players in human innate immunity. Cell engager antibody formats that recruit and activate NK cells more effectively have emerged as a promising immunotherapy approach to target cancer cells through more effective antibody-dependent cell-mediated cytotoxicity (ADCC)....
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2381261 |
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| _version_ | 1832576576661749760 |
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| author | Bill Liao Christine Tumanut Lin Li Adam Corper Dilip Challa Alex Chang Hydari Begum Elinaz Farokhi Catherine Woods Xiaomin Fan |
| author_facet | Bill Liao Christine Tumanut Lin Li Adam Corper Dilip Challa Alex Chang Hydari Begum Elinaz Farokhi Catherine Woods Xiaomin Fan |
| author_sort | Bill Liao |
| collection | DOAJ |
| description | Natural killer (NK) cells are key players in human innate immunity. Cell engager antibody formats that recruit and activate NK cells more effectively have emerged as a promising immunotherapy approach to target cancer cells through more effective antibody-dependent cell-mediated cytotoxicity (ADCC). Monoclonal antibody drugs with ADCC activity have shown clinical benefit and improved outcomes for patients with certain types of cancer. CD16a, a Fc gamma III receptor, is the major component that is responsible for the ADCC activity of NK cells. Screening AvantGen’s yeast displayed human antibody libraries led to the isolation of 2 antibody clones, #1A2 and #2-2A2, that selectively recognize both isoforms (F and V) of CD16a on primary NK cells with high affinity, yet minimally (#1A2) or do not (#2-2A2) cross-react with both allelotypes of CD16b (NA1 and NA2) expressed by neutrophils. Epitope mapping studies revealed that they bind to an epitope dependent on residue Y158 of CD16a, since mutation of Y158 to the corresponding CD16b residue H158 completely abolishes binding to CD16a. When formatted as bispecific antibodies targeting CD16a and a tumor-associated antigen (TAA, e.g. CD19), they exhibit specific binding to NK cells and induce potent NK cell activation upon encountering tumor cells, resulting in effective tumor cell killing. Notably, these bispecific antibody engagers stimulate NK cell cytokine release during co-culture with target cells, resulting in target cell cytotoxicity. These anti-CD16a antibody clones are promising candidates for combination with any TAA of interest, offering the potential for novel NK cell engager-based cancer therapeutics that are minimally affected by the high concentrations of human IgG in the circulation. |
| format | Article |
| id | doaj-art-cb6b464dfe384eb4832cd56fa7dd2049 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-cb6b464dfe384eb4832cd56fa7dd20492025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2381261Identification of novel anti-CD16a antibody clones for the development of effective natural killer cell engagersBill Liao0Christine Tumanut1Lin Li2Adam Corper3Dilip Challa4Alex Chang5Hydari Begum6Elinaz Farokhi7Catherine Woods8Xiaomin Fan9AvantGen, Inc, San Diego, CA, USAAvantGen, Inc, San Diego, CA, USAAvantGen, Inc, San Diego, CA, USAAvantGen, Inc, San Diego, CA, USAAvantGen, Inc, San Diego, CA, USAAvantGen, Inc, San Diego, CA, USAAvantGen, Inc, San Diego, CA, USAAvantGen, Inc, San Diego, CA, USAAvantGen, Inc, San Diego, CA, USAAvantGen, Inc, San Diego, CA, USANatural killer (NK) cells are key players in human innate immunity. Cell engager antibody formats that recruit and activate NK cells more effectively have emerged as a promising immunotherapy approach to target cancer cells through more effective antibody-dependent cell-mediated cytotoxicity (ADCC). Monoclonal antibody drugs with ADCC activity have shown clinical benefit and improved outcomes for patients with certain types of cancer. CD16a, a Fc gamma III receptor, is the major component that is responsible for the ADCC activity of NK cells. Screening AvantGen’s yeast displayed human antibody libraries led to the isolation of 2 antibody clones, #1A2 and #2-2A2, that selectively recognize both isoforms (F and V) of CD16a on primary NK cells with high affinity, yet minimally (#1A2) or do not (#2-2A2) cross-react with both allelotypes of CD16b (NA1 and NA2) expressed by neutrophils. Epitope mapping studies revealed that they bind to an epitope dependent on residue Y158 of CD16a, since mutation of Y158 to the corresponding CD16b residue H158 completely abolishes binding to CD16a. When formatted as bispecific antibodies targeting CD16a and a tumor-associated antigen (TAA, e.g. CD19), they exhibit specific binding to NK cells and induce potent NK cell activation upon encountering tumor cells, resulting in effective tumor cell killing. Notably, these bispecific antibody engagers stimulate NK cell cytokine release during co-culture with target cells, resulting in target cell cytotoxicity. These anti-CD16a antibody clones are promising candidates for combination with any TAA of interest, offering the potential for novel NK cell engager-based cancer therapeutics that are minimally affected by the high concentrations of human IgG in the circulation.https://www.tandfonline.com/doi/10.1080/19420862.2024.2381261ADCCbispecific antibodiesCD16aengagerFc bindingimmunotherapy |
| spellingShingle | Bill Liao Christine Tumanut Lin Li Adam Corper Dilip Challa Alex Chang Hydari Begum Elinaz Farokhi Catherine Woods Xiaomin Fan Identification of novel anti-CD16a antibody clones for the development of effective natural killer cell engagers mAbs ADCC bispecific antibodies CD16a engager Fc binding immunotherapy |
| title | Identification of novel anti-CD16a antibody clones for the development of effective natural killer cell engagers |
| title_full | Identification of novel anti-CD16a antibody clones for the development of effective natural killer cell engagers |
| title_fullStr | Identification of novel anti-CD16a antibody clones for the development of effective natural killer cell engagers |
| title_full_unstemmed | Identification of novel anti-CD16a antibody clones for the development of effective natural killer cell engagers |
| title_short | Identification of novel anti-CD16a antibody clones for the development of effective natural killer cell engagers |
| title_sort | identification of novel anti cd16a antibody clones for the development of effective natural killer cell engagers |
| topic | ADCC bispecific antibodies CD16a engager Fc binding immunotherapy |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2381261 |
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