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Structure-Guided Design and Biophysical Characterization of Novel Anti-HIV Reagents


Jiang, Siduo (Stone) (2014) Structure-Guided Design and Biophysical Characterization of Novel Anti-HIV Reagents. Senior thesis (Major), California Institute of Technology. doi:10.7907/SP19-9R34.


Despite over 30 years of effort, an HIV-1 vaccine that elicits protective antibodies still does not exist. Recent clinical studies have identified that during natural infection about 20% of the population is capable of mounting a potent and protective antibody response. Closer inspection of these individuals reveal that a subset of these antibodies, recently termed potent VRC01-like (PVL), derive exclusively from a single human germline heavy chain gene. Induced clonal expansion of the B cell encoding this gene is the first step through which PVL antibodies may be elicited. Unfortunately, naturally occurring HIV gp120s fail to bind to this germline, and as a result cannot be used as the initial prime for a vaccine regimen. We have determined the crystal structure of an important germline antibody that is a promising target for vaccine design efforts, and have set out to engineer a more likely candidate using computationally-guided rational design.

In addition to prevention efforts on the side of vaccine design, recently characterized broadly neutralizing anti-HIV antibodies have excellent potential for use in gene therapy and passive immunotherapy. The separation distance between functional Fabs on an antibody is important due to the sparse distribution of envelop spikes on HIV compared to other viruses. We set out to build and characterize novel antibody architectures by incorporating structured linkers into the hinge region of an anti-HIV antibody b12. The goal was to observe whether these linkers increased the arm-span of the IgG dimer. When incorporated, flexible Gly4Ser repeats did not result in detectable extensions of the IgG antigen binding domains, by contrast to linkers including more rigid domains such as β2-microglobulin, Zn-α2-glycoprotein, and tetratricopeptide repeats (TPRs). This study adds an additional set of linkers with varying lengths and rigidities to the available linker repertoire, which may be useful for the modification and construction of antibodies and other fusion proteins.

Item Type:Thesis (Senior thesis (Major))
Subject Keywords:Antibody Engineering, Protein Design, HIV
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Chemistry and Chemical Engineering
Major Option:Biology
Awards:Arie J. Haagen-Smit Memorial Award, 2013. George W. Housner Award, 2014. Richard P. Schuster Memorial Prize, 2014.
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Bjorkman, Pamela J. (advisor)
  • Galimidi, Rachel P. (co-advisor)
  • West, Anthony P. (co-advisor)
  • Sievers, Stuart A. (co-advisor)
Thesis Committee:
  • None, None
Defense Date:6 June 2014
Non-Caltech Author Email:siduojiang (AT)
Record Number:CaltechTHESIS:06172014-114402762
Persistent URL:
Jiang, Siduo (Stone)0000-0002-2143-4030
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8523
Deposited By: Siduo Jiang
Deposited On:28 Oct 2014 19:12
Last Modified:08 Nov 2023 00:16

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