About

George Georgiou is the Dula D. Cockrell Centennial Chair Professor at the University of Texas at Austin, where he has served on the faculty since 1986. He holds appointments in the Departments of Chemical Engineering, Molecular Biosciences, and Biomedical Engineering. He received his B.S. degree in Chemical Engineering from the University of Manchester, UK, and his Ph.D. in Chemical Engineering and Molecular Biology from Cornell University in 1987. His early research focused on the biogenesis of secreted proteins in bacteria and protein engineering technologies. Starting in 2007, his research shifted to human immunology and the discovery and preclinical development of protein therapeutics. He co-invented and led the early development of four protein therapeutics, one of which has been approved, with three in clinical development. Georgiou invented methods for analyzing the human serological antibody repertoire at the molecular level, demonstrating the restricted clonality of antibody responses to infection or vaccination, and contributed significantly to antibody effector function biology and Fc engineering. He has published over 280 research papers and holds more than 170 issued and pending US patents, resulting in 28 IP suites licensed to 31 pharma and biotech companies. His entrepreneurial activities include founding and leading biotech companies, with one acquired by Maxygen and others listed on NASDAQ. His contributions have been recognized through numerous awards, including the Amgen award in Biochemical Engineering, and he has been elected to several prestigious national academies, including the US National Academy of Engineering, the National Academy of Medicine, the National Academy of Inventors, and the American Academy of Arts and Sciences.

Research topics

• Biology
• Immunology
• Genetics
• Biochemistry
• Virology
• Chemistry
• Computational biology
• Cell biology
• Cancer research
• Medicine
• Pharmacology

Selected publications

• Dual role of Fc Receptor-triggered trogocytosis mediated by human tumor-infiltrating macrophages and neutrophils in the regulation of anti-tumor antibody efficacy 3084

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description The clinical benefits of tumor-targeting antibodies (tAb) are modest in solid human tumors. The efficacy of many tAbs is dependent on Fc receptor (FcR)–expressing leukocytes that bind Fc fragments of tAb. Tumor-associated macrophages (TAM) and neutrophils (TAN) represent the majority of FcR+ effectors in solid tumors. A better understanding of the mechanisms by which TAN and TAM regulate tAb response could help improve the efficacy of tAbs. Here, we found that myeloid effectors interacting with tAb-opsonized cancer cells used antibody-dependent trogocytosis (ADT). During this process, myeloid cells “nibble off” tumor cell fragments containing tAb/targeted antigen (tAg) complexes. ADT is only tumoricidal when tumor cells express high levels of tAg and effectors are present at high effector-to-tumor ratios. If neither of these conditions are met, which is typical for solid tumors, ADT is sublethal. Sublethal ADT, mainly mediated by TAM, leads to two outcomes: (i) removal of surface tAg/tAb complexes from the tumor surface thereby facilitating tumor cell escape; and (ii) acquisition of bystander tAgs by TAM with subsequent cross-presentation and stimulation of tumor-specific T-cell responses. TAN stimulate tumor cell growth in the presence of IgG1 tAb; however, IgA tAbs trigger the tumoricidal activity and negate the stimulatory effect of TAN. Overall, this study provides mechanistic insight by which myeloid effectors mediate tumor cell killing and resistance during tAb therapy Funding Sources This work was supported by the NIH/NCI RO1 CA187392–01 and Janssen Pharmaceuticals Inc. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

  PublisherOA PDFDOI

• Abstract 4725: Engineering a novel serine-degrading enzyme for targeted cancer therapy

  Cancer Research · 2025-04-21

  article

  Abstract The non-essential amino acid L-serine (serine) is the second most consumed amino acid by cancer cells, supporting their survival and proliferation by contributing to the biosynthesis of nucleotides, lipids, and proteins. Serine-auxotrophic tumors such as luminal breast cancers have compromised serine synthesis pathways, thus rely on extracellular serine, making them vulnerable to serine depletion therapies. While dietary serine restriction, the only current method to reduce serine availability for tumors in vivo, has shown limited success in reducing tumor growth, its application is hindered by poor patient compliance and an inadequate reduction of circulating serine. To overcome these limitations, we developed an engineered human serine/threonine dehydratase (eSDH) enzyme that irreversibly depletes over 95% of circulating serine and threonine without requiring dietary changes. Preclinical studies show that eSDH treatment significantly inhibits the growth of serine-auxotrophic tumors. To enhance the therapeutic potential of eSDH and reduce off-target effects, particularly the depletion of the essential amino acid threonine, we focused on improving the specificity of eSDH for serine. Through iterative structure-based engineering, we developed a new SDH variant with over 20 times higher selectivity for serine toward threonine. Both in vitro and in vivo studies have confirmed that this novel SDH variant depletes serine while preserving threonine in cell culture media and serum. Current efforts are focused on improving the stability of the new SDH variant to extend its half-life in serum and optimize dosing for greater therapeutic efficiency. This advancement allows us to target serine-auxotrophic cancers more precisely while minimizing the impact on normal cells. The broader impact of this work lies in establishing enzymatic serine depletion as a more effective and feasible alternative to dietary restriction for cancer therapy. This approach could provide a new therapeutic strategy for treating various serine-auxotrophic tumors, offering better patient compliance and fewer side effects. Citation Format: Ladan Mashouri, Ebru Cayir, Sarita Bhetawal, Daniel J Diaz, Vipin Rawat, Jonathan Coloff, George Georgiou, Everett Stone. Engineering a novel serine-degrading enzyme for targeted cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4725.

  PublisherDOI

• Selective decoupling of IgG1 binding to viral Fc receptors restores antibody-mediated NK cell activation against HCMV

  Cell Reports · 2025-12-01 · 3 citations

  articleOpen access

  Antibodies binding cell-surface antigens to activate cellular immunity are an important mechanism of anti-viral protection, yet antibodies targeting cells infected by human cytomegalovirus (HCMV) exhibit limited efficacy. This is due to HCMV immune evasion mechanisms, including viral receptors (vFcγRs) that bind human immunoglobulin G Fc domains to inhibit host Fcγ receptor activation and impair Fc-mediated immune functions. Here, we biochemically characterize two conserved vFcγRs, gp34 and gp68, and map their Fc binding sites. We then engineer Fc variants to retain binding to host Fc receptors CD16A and FcRn but exhibit markedly reduced gp34/gp68 interactions. Antibodies targeting the gB fusogen with engineered Fc domains are not internalized by infected cells, mediate enhanced immune cell activation, and limit viral spread in HCMV-infected fibroblasts more effectively than antibodies with wild-type Fc. This work demonstrates a strategy to enhance therapeutic antibody control of HCMV infections and other herpesvirus infections with similar immune-evasion mechanisms.

  PublisherDOI

• Therapeutic administration of an engineered sphingosine-1-phosphate lyase improves T cell trafficking to tumors and enhances antitumor response 2160

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description Immunotherapy has revolutionized cancer treatment; however, only limited aspects of the tumor-immune interaction have been exploited successfully. While it is well-known that trafficking of T cells is often impaired during cancer, there are no available therapies that address this aspect of antitumor immunity. Clinically, expression levels of the sphingosine-1-phosphate producing enzyme sphingosine kinase 1 negatively correlates with survival of melanoma patients after immune checkpoint inhibitor (ICI) therapy. We therefore hypothesized that aberrant S1P signaling in tumors causes immune exclusion by impeding lymphocyte egress from the tumor draining lymph node (TDLN). We tested the efficacy of an engineered S1P-degrading enzyme (S1PL) on established murine tumors and performed immune profiling of TDLN and intratumoral T cell populations. S1PL increased both trafficking of lymphocytes out of TDLNs and T cell infiltration of tumors. Mice treated with S1PL evinced a higher proportion of S1P1+ circulating T cells relative to controls, suggesting that liberation of T cells from the TDLN occurred through the S1P/S1P1 axis. Increased lymphocyte trafficking correlated with strong inhibition of tumor growth and enhanced efficacy of ICI therapy. Administration of S1PL may be an attractive strategy for improving therapies that rely on antitumor adaptive immunity. This approach may thus be potent in settings wherein tumor-mediated immune exclusion is a dominant method of immune escape. Funding Sources Texas Biologics & CPRIT RP240454 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

  PublisherOA PDFDOI

• Dissecting the Clonal Composition and Determinants of Neutralization Potency Enhancement of Serum Dimeric and Monomeric IgA to Human Norovirus

  Research Square · 2025-12-02

  preprintOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Broadly neutralizing antibodies targeting pandemic GII.4 variants or seven GII genotypes of human norovirus

  Science Translational Medicine · 2025-03-05 · 11 citations

  articleOpen accessCorresponding

  Human norovirus causes more than 700 million illnesses annually. Extensive genetic diversity and a paucity of information on conserved neutralizing epitopes pose major obstacles to the design of broadly protective norovirus immunogens. Here, we used high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS)-driven proteomics to quantitatively characterize the circulating serum IgG repertoire before and after immunization with an experimental monovalent norovirus GII.4 VP1 capsid-encoding adenoviral vaccine. Two participants were specifically selected on the basis of the breadth of serum neutralization responses either across GII.4 variants (participant A) or across GII genotypes (participant B). In participant A, vaccination back-boosted highly abundant serum antibody clonotypes targeting epitopes conserved among rapidly evolving GII.4 variants spanning from a strain identified in 1987 to a strain identified in 2019. In participant B, we identified a recall response consisting of broadly neutralizing monoclonal antibodies with remarkable cross-GII ligand-binding blockade (blocking ≥ seven GII genotypes) and virus neutralization breadth. The cocrystal structure of one of these antibodies, VX22, in complex with the VP1 capsid protruding (P) domain revealed a highly conserved epitope (residues 479 to 484 and 509 to 513) within two lateral loops of the P1 subdomain. Antibody evolutionary trajectory analysis further revealed that VX22 had originally evolved from an early heterologous infection, likely by a GII.12 strain. Together, our study demonstrates that norovirus human monoclonal antibodies with broad GII.4 potency and cross-GII breadth can be boosted in serum after immunization with an adenoviral vector-based vaccine, findings that may guide the design of immunogens for broadly protective norovirus vaccines.

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• Selective decoupling of IgG1 binding to viral Fc receptors restores antibody-mediated NK cell activation against HCMV

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-18 · 1 citations

  preprintOpen access

  A key mechanism of antiviral antibodies is to bind cell-surface viral antigens and activate cellular immunity to clear infected cells, yet antibodies targeting human cytomegalovirus (HCMV) have exhibited limited efficacy. This appears due to HCMV's multiple immune evasion mechanisms, including viral receptors (vFcγRs) which bind human IgG Fc domains to co-operatively inhibit Fc activation of host Fcγ receptors and impair Fc-mediated effector functions. We biochemically characterized and evaluated the functions of two highly conserved vFcγRs, gp34 and gp68, and mapped their binding epitopes on the Fc domain. Based on this information, we then engineered Fc variants that retain binding to CD16A, which is essential for NK activation, and to FcRn but have markedly attenuated binding to gp34 and gp68. IgG1 antibodies targeting the gB fusogen with engineered Fc domains were not internalized by infected cells, mediated enhanced CD16A activation and limited viral spread in HCMV-infected fibroblasts more effectively than wild-type Fc. Together, this work demonstrates a strategy to enhance the efficacy of antibody therapies to clear HCMV infections. Highlights: Host and HCMV FcR compete for IgG1 binding but engage different residues.Fc-engineering abrogates viral FcR antagonism while retaining CD16A activation.Antibodies that resist vFcR capture promote superior ADCC against infected cells.Designer Fc domains complement Fabs to create enhanced disease-specific therapies.

  PublisherOA PDFDOI

• Proteomic deconvolution of the antigen-specific serum IgA repertoire reveals clonal overlap with IgG and between monomeric and dimeric IgA following mucosal norovirus vaccination 2438

  The Journal of Immunology · 2025-11-01

  articleOpen accessSenior author

  Abstract Description IgA antibodies are key to mucosal immunity; however, the identity, abundance, and oligomeric states of individual IgA clonotypes comprising the polyclonal repertoire remain poorly understood. To determine the molecular nature and protective mechanism of IgA clones elicited by mucosal vaccination, we performed serum proteomics analysis (Ig-Seq) in three subjects immunized with an oral norovirus vaccine designed for gut delivery. Serum IgA titers specific to the GII.4 norovirus vaccine strain were higher than IgG titers both on day 0 pre- and day 28 post-vaccination. Ig-Seq analysis of GII.4-specific serum IgA and IgG repertoires revealed that oral vaccination increased IgG+IgA clonal overlap by 2.4-fold, with 43 ± 17% of IgA clonotypes on day 28 also detectable in IgG. Mass separation of monomeric (mIgA) and dimeric IgA (dIgA) showed that >75% of antigen-specific IgA clonotypes co-circulate in both forms, with some clonotypes 5-times more abundant as dIgA. Monoclonal dIgAs targeting surface-exposed, immunodominant GII.4 epitopes significantly enhanced neutralization potency compared to mIgA or IgG. Conversely, dIgAs targeting partially occluded epitopes showed minimal potency gains, suggesting that epitope accessibility may impact the neutralization mechanism of dIgA and that dIgA titers to highly exposed epitopes could provide robust protection at mucosal sites. Our study provides molecular insights into oligomeric serum IgA repertoires, guiding future mucosal vaccine design. Funding Sources National Institute of Allergy and Infectious Disease R01 AI148260. Topic Categories Vaccines and Immunotherapy (VAC)

  PublisherOA PDFDOI

• Gene discovery and expression analysis of the B cell receptor repertoire in the domestic ferret model

  Vaccine · 2025-09-16 · 1 citations

  articleOpen access

  The domestic ferret is the preferred model organism for the study of influenza A infection and responses to vaccination, because its respiratory tract architecture and sialic acid receptor type and distribution are similar to those in humans. Despite this, the ferret has remained underutilized in antibody-omics research, which is increasingly critical to inform vaccine design. The molecular analysis of antibody responses is predicated on precise knowledge of the germline V(D)J segments, and is an active area of research for this species. To define a reference immunoglobulin repertoire for the ferret, we used a curated set of V(D)J genes from human and closely related carnivores to BLAST the ferret genome. Non-overlapping BLAST hits were annotated and vetted for recombination signal sequences as well as segment-specific functionality as defined by IMGT. Immunoglobulin transcript expression was analyzed for both variable and constant region genes, and we identified two functional IGHG genes in the ferret. We report a publicly available workflow for annotating immunoglobulin genes in any species, as well as a complete ferret immunoglobulin gene set. We include the genomic sequences for 409 ferret immunoglobulin genes of both the heavy and light chains. This reference data set establishes a critically important foundation for future BCR and antibody repertoire studies in this established preclinical vaccine model.

  PublisherDOI

• Repertoire, function, and structure of serological antibodies induced by the R21/Matrix-M malaria vaccine

  The Journal of Experimental Medicine · 2025-06-24 · 7 citations

  articleOpen access

  The World Health Organization (WHO) recently recommended the programmatic use of the R21/Matrix-M vaccine for Plasmodium falciparum malaria prevention in children living in malaria-endemic areas. To determine its effects on humoral immunity, we conducted a proteomic analysis of polyclonal IgG antibodies directed against the NANP tetrapeptide of the circumsporozoite protein (CSP), which comprises the vaccine's core immunogen. In 10 malaria-naïve adult volunteers, R21/Matrix-M induced polarized IgG anti-NANP repertoires, heavily skewed for IGHV3-30/3-33 genes bearing minimal somatic mutation, which remained static in composition following a controlled human malaria infection challenge. Notably, these vaccine-generated antibodies cross-reacted with another protective CSP epitope, the N-terminal junction region, despite its absence from the R21 construct. NANP-specific IGHV3-30/3-33 mAbs mined from polyclonal IgG repertoires blocked sporozoite invasion in vitro and prevented parasitemia in vivo. Overall, R21/Matrix-M elicits polarized, minimally mutated, polyclonal IgG responses that can target multiple protective CSP epitopes, offering molecular insight into the serological basis for its demonstrated efficacy against P. falciparum malaria.

  PublisherDOI

Recent grants

• NIH Grant R01CA189623

  NIH · $2.9M · 2020

• NIH Grant R01GM073089

  NIH · $1.7M · 2010

• NIH Grant R01CA139059

  NIH · $989k · 2013

• NIH Grant R01GM069872

  NIH · $936k · 2009

• Mechanisms of DNA-Specific Autoimmunity in Systemic Lupus Erythematosus

  NIH · $4.4M · 2026–2029

Frequent coauthors

• Brent L. Iverson

  The University of Texas at Austin

  112 shared

• Everett Stone

  The University of Texas at Austin

  86 shared

• Gregory C. Ippolito

  The University of Texas at Austin

  58 shared

• Andrew D. Ellington

  The University of Texas at Austin

  42 shared

• Thomas Valerius

  33 shared

• Edmund K. Moon

  32 shared

• Jiwon Lee

  Dartmouth College

  31 shared

• Neil T. Sullivan

  31 shared

Labs

• Translational Protein Therapeutics LabPI

  Not provided

Education

• Ph.D., Chemical Engineering

  Cornell University

  1987

• M.S., Chemical Engineering

  Cornell University

  1983

• B.S., Chemical Engineering

  University of Manchester Institute of Science and Technology (UMIST)

  1981

Awards & honors

• William H. Walker Award for Excellence in Contributions to C…
• Billy & Claude R. Hocott Distinguished Centennial Engineerin…
• National Academy of Inventors member (2015)
• American Academy of Arts and Sciences (AAAS) fellow (2015)
• Inventor of the Year – The University of Texas at Austin (20…