Biography

Dr. Ningyan Zhang received her Ph.D. degree from the University of Kentucky and did her postdoctoral training at the University of Wisconsin-Madison.  She started academic research laboratory in 2010 at the Brown Foundation Institute of Molecular Medicine (IMM) in the McGovern Medical School, the University of Texas Health Science Center at Houston (UTHealth).  Before joining UTHealth, she spent more than 15 years in drug discovery research in the pharmaceutical and biotechnology industry.  She currently is a professor and director for Antibody Engineering Service Center at UTHealth.  She also serves as co-director for the Antibody Core Facility funded by the Cancer Prevention and Research Institute of Texas (CPRIT).  Dr. Zhang’s key research interest is to study mechanisms of cancer immune evasion for development of improved immunotherapy.

Cancer immune evasion is being recognized as one of hallmarks of cancer. Our studies have demonstrated the prevalence of proteolytic impairment of antibody Fc effector function in the tumor microenvironment. Trastuzumab and pertuzumab (anti-HER2 antibody) with a single hinge cleavage showed a loss of immune effector function against cancer cells in vitro and reduced antitumor efficacy in vivo. Based on our findings and reports by others, we hypothesize that antibodies recognizing tumor associated antigens (TAA) in the tumor microenvironment are susceptible to proteolytic impairment through a hinge cleavage by matrix metalloproteinases (MMPs). Such proteolytic hinge cleavage of antibodies not only weakens antibody anticancer immunity but also leads to an immune suppressive tumor microenvironment. Our current research programs are centered on better understanding of tumor evasion of antibody immunity and develop therapeutic strategies to modulate anticancer immunity for improved anticancer therapies.  We employ a wide array of experimental approaches including in vitro 2D and 3D cell co-cultures, mouse tumor models, and studies with clinical samples from cancer patients to determine factors influencing proteolytic impairment and to identify mechanisms of cancer immune evasion triggered by proteolytic impairment of antibody hinge.  State of the art technologies are used in our studies such as high content fluorescence imaging, mass spectrometry, fluorescence activated cell sorting (FACS), and single cell cloning of antibodies. We have established a monoclonal antibody platform technology to discover and select novel anticancer antibodies for functional evaluation and preclinical development. The overarching goal of our research is to understand mechanisms of cancer evasion of antibody therapies and to identify key molecular targets for development of effective anticancer immunotherapies.

Professional Highlights

  • Development of platform technologies for discovery of therapeutic antibodies
  • Inventor of more than 30 patents on antibody therapeutics

Education

Postdoctoral Fellowship
University of Wisconsin-Madison
PhD - Biochemistry
University of Kentucky
MS - Biology
Hebei Agricultural University
BS - Biology
Shanxi Agricultural University

Areas of Interest

Research Interests

Our group focuses on antibody drug resistance mechanisms, biomarkers for therapeutic antibodies, antibody response to viral infection and vaccination, antibody drug discovery targeting human diseases, and therapeutic antibody drug discovery technologies and platforms. During the last ten years, our group and collaborators published over 150 publications in highly competitive journals such as Nature, Nature Communications, Cell Metabolism, Science Advances, Journal of Immunotherapy of Cancer, PNAS, Clinical Cancer Research, Cancer Research, Cancer Immunology Research, Cell Reports, eLife and others. On the translational side, we have advanced 5 first-in-class drug candidates into clinical trials for diseases ranging from acute myeloid leukemia (IO-202), breast cancer bone metastasis (ALMB-0168), solid tumor (IO-108), spinal cord injury (ALMB-0166), and COVID-19 (IGM6268). Five other drug candidates are in preclinical development including PRTH-101 which pioneers a foundational concept of blocking T-cell exclusion in the tumor microenvironment for cancer therapy.

Publications

 Selected recent publications (from >130 peer reviewed research articles)

https://www.ncbi.nlm.nih.gov/myncbi/1B_bnemrTwPAt/bibliography/public/?sortby=pubDate&sdirection=ascending

 

  1. Manuel A. Riquelme, Francisca M. Acosta, Jeffery Chavez, Sumin Gu, Wei Xiong, Ningyan Zhang, Lu-Zhe Sun, Nu Zhang, Zhiqiang An, and Jean X. Jiang (2024) Antibody-Activation of Connexin Hemichannels in Bone Osteocytes with ATP Release Suppresses Breast Cancer Bone Metastasis and Osteosarcoma. Cell Reports 43, 114377. https://doi.org/10.1016/j.celrep.2024.114377.
  2. Christopher J. LaFargue, Paola Amero, Kyunghee Noh, Lingegowda S. Mangala, Chunhua Lu, Yunfei Wen, Emine Bayraktar, Sunila Pradeep, Yihong Wan, Wonbeak Yoo, Santosh K Dasari, Vinod Vathipadiekal, Anca Chelariu-Raicu, Rajesha Roopaimoole, Zhiqiang Ku, Deng Hui, Wei Xiong, Hyun-Jin Choi, Rouba Ali-Fehmi, Michael J. Birrer, Wei Hu, Ningyan Zhang, Gabriel Lopez Berestein, Vittorio de Franciscis, Zhiqiang An, and Anil K. Sood (2023) Overcoming Adaptive Resistance to Anti-VEGF Therapy by Targeting CD5L. Nature Communications. https://doi.org/10.1038/s41467-023-36910-5.
  3. Peng Zhao, Yuanzhong Xu, LuLin Jiang, Xuejun Fan, Leike Li, Xin Li, Hisashi Arase, Yingjun Zhao, Huaxi Xu, Qingchun Tong, Ningyan Zhang*, Zhiqiang An* (2022). Engineering of a tetravalent TREM2 agonistic antibody with αTfR-mediated brain entry for the reduction amyloid pathology in 5XFAD mice. 2022. Science Translational Medicine 14, eabq0095 (2022) 7 September 2022, 10.1126/scitranslmed.abq0095.
  4. Junquan Liu, Huai-Chin Chiang, Wei Xiong, Victor Laurent, Samuel C. Griffiths, Jasmin Dülfer, Hui Deng, Xiujie Sun, Y. Whitney Yin, Wenliang Li, Laurent P. Audoly, Zhiqiang An, Thomas Schürpf, Rong Li, and Ningyan Zhang* (2023) A highly selective humanized DDR1 mAb reverses immune exclusion by disrupting collagen fiber alignment in breast cancer. Journal of ImmunoTherapy of Cancer http://dx.doi.org/10.1136/jitc-2023-006720.
  5. Xuejun Fan, Zihao Yuan, Hao-Ching Hsiao, Yueshui Zhao, Wei Xiong, Rahmawati Pare, Xin Li, Georgina Salazar, Jianmin Ding, Ahmad Almosa, Kai Sun, Songlin Zhang, Robert Jordan, Cheok Song Lee, Zhiqiang An, Ningyan Zhang* (2022) Impairment of IgG Fc Engagement of Effector Cells Contributes to an Immune Suppressive Tumor Microenvironment. Communications Biology, doi.1038/s42003-022-03931-7.
  6. Guojin Wu, Yixiang Xu, Robbie D Schultz, Heyu Chen, Jingjing Xie, Mi Deng, Xiaoye Liu, Xun Gui, Samuel John, Zhigang Lu, Ningyan Zhang, Zhiqiang An, Chengcheng Zhang (2021) LILRB3 supports development of acute myeloid leukemia and regulates NF-κB signaling by recruiting TRAF2 and cFLIP. Nature Cancer, org/10.1038/s43018-021-00262.
  7. Peng Zhao, Xuejun Fan, LuLin Jiang, Zhiqiang Ku, Leike Li, Xiaoye Liu, Mi Deng, Hisashi Arase, Jay-Jiguang Zhu, Yingjun Zhao, Chengcheng Zhang, Huaxi Xu, Ningyan Zhang*, Zhiqiang An*(2022) LILRB2-Mediated TREM2 Signaling Inhibition Suppresses Microglia Functions. Molecular Neurodegeneration 17:44, doi.org/10.1186/s13024-022-00550-y.
  8. Daniel Wrapp, Xiaohua Ye, Zhiqiang Ku, Hang Su, Harrison G. Jones, Nianshuang Wang, Akaash K. Mishra, Daniel C. Freed, Fengsheng Li, Aimin Tang, Leike Li, Dabbu Kumar Jaijyan, Hua Zhu, Dai Wang, Tong-Ming Fu, Ningyan Zhang, Zhiqiang An, Jason S. McLellan (2022) Structural basis for HCMV Pentamer recognition by antibodies and neuropilin 2, Science Advances DOI: 10.1126/sciadv.abm2546.
  9. Xiujie Sun, Bogang Wu, Huai-Chin Chiang, Hui Deng, Xiaowen Zhang, Wei Xiong, Junquan Liu, Aaron M Rozeboom, Brent T Harris, Eline Blommaert, Antonio Gomez, Roderic Espin Garcia, Yufan Zhou, Payal Mitra, Madeleine Prevost, Deyi Zhang, Debarati Banik, Claudine Isaacs, Deborah Berry, Catherine Lai, Krysta Chaldekas, Patricia S Latham, Christine A Brantner, Anastas Popratiloff, Victor X Jin, Ningyan Zhang, Yanfen Hu, Miguel Angel Pujana, Tyler J Curiel, Zhiqiang An, Rong Li (2021) Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion. Nature https://doi.org/10.1038/s41586-021-04057-2.
  10. Anjali Geethadevi, Ajay Nair, Deepak Parashar, Zhiqiang Ku, Wei Xiong, Hui Deng, Yongsheng Li, Jasmine George, Donna M. McAllister, Yunguang Sun, Ishaque P. Kadamberi, Prachi Gupta, Michael B. Dwinell, William H. Bradley, Janet S. Rader, Hallgeir Rui, Robert F. Schwabe, Ningyan Zhang, Sunila Pradeep, Zhiqiang An and Pradeep Chaluvally-Raghavan (2021) Oncostatin M Receptor-targeted antibodies suppress STAT3 signaling and inhibit ovarian cancer growth. Cancer Research DOI: 10.1158/0008-5472.CAN-21-0483.
  11. Zhiqiang Ku , Xuping Xie , Paul Hinton , Xinli Liu , Xiaohua Ye, Antonio Muruato , Dean Ng , Sujit Biswas , Jing Zou , Yang Liu , Deepal Pandya , Vineet Menachery , Sachi Rahman , Yu-An Cao , Hui Deng , Wei Xiong , Kevin Carlin , Junquan Liu , Hang Su , Elizabeth Haanes , Bruce Keyt*, Ningyan Zhang* , Stephen Carroll*, Pei-Yong Shi*, and Zhiqiang An*(2021) Nasal delivery of an IgM against SARS-CoV-2 offers potent protection and coverage of variants. Nature 595:718–723 https://doi.org/ 10.1038/s41586-021-03673-2.
  12. Zihao Yuan, Xuejun Fan, Jay-Jiguang Zhu, Tong-Ming Fu, Jiaqian Wu, Hua Xu, Ningyan Zhang, Zhiqiang An, and W. Zheng (2021) Presence of Complete Murine Viral Genome Sequences in Patient-Derived Xenografts. Nature Communications https://doi.org/10.1038/s41467-021-22200-5.
  13. Zhiqiang Ku, Xuping Xie, Edgar Davidson, Xiaohua Ye, Hang Su, Yize Li, Zihao Yuan, Ariadna Grinyo Escuer, Benjamin J. Doranz, Daniel Wrapp, Breanna Tyrell, Kyle Doolan, Paul F. Bates, Jason S. McLellan, Susan R. Weiss, Ningyan Zhang*, Pei-Yong Shi*, and Zhiqiang An* (2021) Molecular determinants and mechanism for antibody cocktail preventing SARS-CoV-2 escape. Nature Communications DOI:10.1038/s41467-020-20789-7
  14. Xun Gui, Mi Deng, Hao Song, Yuanzhi Chen, Jingjing Xie, Zunling Li, Licai He, Fangfang Huang, Yixiang Xu, Yasuaki Anami, Hai Yu, Chenyi Yu, Leike Li, Zihao Yuan, Xiaoying Xu, Qihui Wang, Yan Chai, Tao Huang, Yi Shi, Kyoji Tsuchikama, X. Charlene Liao, Ningshao Xia, George F. Gao, Ningyan Zhang*, Cheng Cheng Zhang* and Zhiqiang An*(2019) Disrupting LILRB4/APOE interaction by an efficacious humanized antibody reverses T cell suppression and blocks AML development. Cancer Immunology Research doi: 10.1158/2326-6066.CIR-19-0036.
  15. Dawei Bu, Clair Crewe, Christine M. Kusminski, Ruth Gordillo, Wei Xiong, Hui Deng, Xiao-Zheng Liu, Per Eystein Lønning, Nils Halberg, Adan Rios, Yujun Chang, Anneliese Gonzalez, Ningyan Zhang, Zhiqiang An, and Philipp E. Scherer (2019) Human Endotrophin as a Driver of Malignant Tumor Growth. Journal of Clinical Investigation Insight https://doi.org/10.1172/jci.insight.125094.
  16. Mi Deng, Xun Gui, Jaehyup Kim, Xie Li, Weina Chen, Zunling Li, Yuanzhi Chen, Heyu Chen, Weiguang Luo, Zhigang Lu, Jingjing Xie, Hywyn Churchill, Yixiang Xu, Zhan Zhou, Guojin Wu, Chenyi Yu, Samuel John, Kouyuki Hirayasu, Nam Nguyen, Hui Deng, Haidong Tang, Yizhou Zou, Benjamin Chen, Hisashi Arase, Ningshao Xia, Youxing Jiang, Robert Collins, Yang-Xin Fu, Zhiqiang An, Junke Zheng*, Ningyan Zhang*, and Cheng Cheng Zhang*(2018) Inhibitory receptor signaling in leukemia cells mediates tumor infiltration and T cell suppression. Nature 562:605–609.
  17. Ningyan Zhang*, Hui Deng, Xuejun Fan, Anneliese Gonzalez, Songlin Zhang, Randall J Brezski, Byung-Kwon Choi, Michael Rycyzyn, William R Strohl, Robert E. Jordan, and Zhiqiang An (2015) Dysfunctional antibodies in the tumor microenvironment associate with impaired anticancer immunity. Clinical Cancer Research 21(23):5380-90.

*Corresponding authors