Periodic Reporting for period 2 - SI (Structural and functional characterization of the ICOS/ICOSL immune complex)
Okres sprawozdawczy: 2020-08-01 do 2021-07-31
Publications:
1. Edurne Rujas; Hong Ciu; Taylor Sicard; Anthony Semesi; Jean-Philippe Julien. Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies. Nat. Commun.11 - 5066, 2020.
2. Edurne Rujas, Hong Cui, Jonathan Burnie, Clare Burn Aschner, Tiantian Zhao, Sara Insausti, Krithika Muthuraman, Anthony Semesi, Jasper Ophel, Jose Luis Nieva, Michael S. Seaman, Christina Guzzo, Bebhinn Treanor, Jean-Philippe Julien. Engineering pan-HIV-1 neutralization breadth and outstanding potency by multi-specific antibody avidity. PNAS, In Press. 2021.
3. Edurne Rujas*, Daniel P. Leaman, Sara Insausti, Pablo Carravilla, Miguel Garc a-Porras, Eneko Largo, Izaskun Morillo, Rub n S nchez-Eugenia, Lei Zhang, Hong Cui, Ibon Iloro, F lix Elortza, Jean-Philippe Julien, Christian Eggeling, Michael B. Zwick, Jose M. M. Caaveiro*, Jos L*. Nieva. Focal accumulation of aromaticity at the CDRH3 loop mitigates 4E10 polyreactivity without altering its HIV neutralization profile. iScience. 24 - 9, 2021.
*Corresponding author
4. Moustafa T. Mabrouk, Kevin Chiem, Edurne Rujas, Wei-Chiao Huang, Dushyant Jahagirdar, Breandan Quinn, Meera Surendran Nair, Ruth H Nissly, Victoria S. Cavener, Nina R. Boyle, Ty A. Sornberger, Suresh V. Kuchipudi, Joaquin Ortega, Jean-Philippe Julien, Luis Martinez-Sobrido, Jonathan Lovell. Lyophilized, Thermostable Spike or RBD Immunogenic Liposomes Induce Protective Immunity Against SARS-CoV-2 in Mice. Sci. Adv. 7 (49), 2021.
5. Michael G. Sugiyama, Haotian Cui, Dar’ya S. Redka, Mehran Karimzadeh, Edurne Rujas, Hassaan Maan, Sikander Hayat, Kyle Cheung, Rahul Misra, Joseph B. McPhee, Russell D. Viirre, Andrew Haller, Roberto J. Botelho, Raffi Karshafian, Sarah A. Sabatinos, Gregory D. Fairn, Seyed Ali Madani Tonekaboni, Andreas Windemuth, Jean-Philippe Julien, Vijay Shahani, Stephen S. MacKinnon, Bo Wang, Costin N. Antonescu. Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease. Sci Rep. 11(1) 23315, 2021.
6. Edurne Rujas, Iga Kucharska, Yong Zi Tan, Samir Benlekbir, Hong Cui, Tiantian Zhao, Gregory A. Wasney, Patrick Budylowski, Furkan Guvenc, Jocelyn C. Newton, Taylor Sicard, Anthony Semesi, Krithika Muthuraman, Amy Nouanesengsy, Clare Burn Aschner, Katherine Prieto, Stephanie A. Bueler, Sawsan Youssef, Sindy Liao-Chan, Jacob Glanville, Natasha Christie-Holmes, Samira Mubareka, Scott D. Gray-Owen, John L. Rubinstein, Bebhinn Treanor, Jean-Philippe Julien. Multivalency transforms SARS-CoV-2 antibodies into ultrapotent neutralizers. Nat. Commun. 12 - 3661, 2021.
The number of antibodies targeting the ICOS/ICOS-L complex entering clinical trials is rapidly increasing but no information on their mode of action at the molecular level have been reported to date. Hence, I have also solved the crystal structure of two clinically relevant antibodies named STIM003 and prezalumab in complex with ICOS and ICOS-L, respectively. The crystallographic studies revealed that these antibodies mimic the physiological interaction of ICOS and ICOS-L with remarkable similarity. Accordingly, the structural data provides insights into the mechanism of action of prezalumab suggesting that its antagonistic effect is likely due to a combination of outcompeting ICOS for binding to ICOS-L and steric hindrances that block receptor ligand clustering at the membrane surface.
A detailed analysis of the antibody binding interfaces identified eight single nucleotide variations (SNVs) in ICOS (S76P, G70R, N73Y, K78N, F114V, P116S, P116H and P117A) and two in ICOS-L (Y51C and Y65H) that could impact antibody binding and hence their therapeutic outcome.
In addition, I developed a protein-based antibody multimerization strategy to increase antibody avidity. This approach transformed antibodies targeting the RBD of SARS-CoV-2 into potent neutralizers with an average of 1000-fold higher potency than the parental IgGs. The “plug-and-play” format of this technology allows to alter specificities by easily swapping antibody sequences and hence it was also used to rapidly transform the broadly acting HIV antibodies into potent neutralizers.
In addition, the potent and broadly-active antiviral antibody-like molecules against SARS-CoV-2 and HIV will directly contribute to lasting medical countermeasures developed against COVID-19 and AIDS.