Press

Publications


Trellis collaborates with various research organizations and institutions to demonstrate the characteristics and efficacy of its monoclonal antibody candidates. Below is a selection of the company's published research:

"Respiratory Syncytial Virus (RSV): Targeting the G Protein Provides a New Approach for an Old Problem" - Journal of Virology
Published online November 8, 2017

Authors: Ralph A. Tripp, Ultan F. Power, Peter J. M. Openshaw and Lawrence M. Kauvar

Direct Link: http://jvi.asm.org/content/early/2017/11/02/JVI.01302-17

"Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) annually affecting >2 million children in the US <5 years old. In the elderly (>65 years old), RSV results in ∼175,000 hospitalizations annually in the US with worldwide incidence ∼34 million. There is no approved RSV vaccine and treatments are limited. Recently, a Phase 3 trial in the elderly using a recombinant RSV F protein vaccine failed to meet its efficacy objectives, namely prevention of moderate-to-severe RSV-associated LRTI and reduced incidence of acute respiratory disease. Moreover, a recent Phase 3 trial evaluating suptavumab (REGN2222), an antibody to RSV F protein, did not meet its primary endpoint of preventing medically attended RSV infections in pre-term infants. Despite these setbacks, numerous efforts targeting the RSV F protein with vaccines, antibodies, and small molecules continue based on the commercial success of a monoclonal antibody (mAb) against the RSV F protein (palivizumab). As the understanding of RSV biology has improved, the other major coat protein, the RSV G protein, has re-emerged as an alternative target reflecting progress in understanding its roles in infecting bronchial epithelial cells and in altering the host immune response. In mouse models, a high-affinity, strain-independent human mAb to the RSV G protein has shown potent direct antiviral activity combined with the alleviation of virus-induced immune system effects that contribute to disease pathology. This mAb, being prepared for clinical trials, provides a qualitatively new approach to managing RSV for populations not eligible for prophylaxis with palivizumab.."

"High affinity anti-TIM-3 and anti-KIR monoclonal antibodies cloned from healthy human individuals" - PLOS ONE
Published July 19, 2017

Authors: Stefan Ryser, Angeles Estellés, Edgar Tenorio, Lawrence M. Kauvar, Mikhail L. Gishizky

Direct Link: https://doi.org/10.1371/journal.pone.0181464

"We report here the cloning of native high affinity anti-TIM-3 and anti-KIR IgG monoclonal antibodies (mAbs) from peripheral blood mononuclear cells (PBMC) of healthy human donors. The cells that express these mAbs are rare, present at a frequency of less than one per 10^5 memory B-cells. Using our proprietary multiplexed screening and cloning technology CellSpot™ we assessed the presence of memory B-cells reactive to foreign and endogenous disease-associated antigens within the same individual. When comparing the frequencies of antigen-specific memory B-cells analyzed in over 20 screening campaigns, we found a strong correlation of the presence of anti-TIM-3 memory B-cells with memory B-cells expressing mAbs against three disease-associated antigens: (i) bacterial DNABII proteins that are a marker for Gram negative and Gram positive bacterial infections, (ii) hemagglutinin (HA) of influenza virus and (iii) the extracellular domain of anaplastic lymphoma kinase (ALK). One of the native anti-KIR mAbs has similar characteristics as lirilumab, an anti-KIR mAb derived from immunization of humanized transgenic mice that is in ongoing clinical trials. It is interesting to speculate that these native anti-TIM-3 and anti-KIR antibodies may function as natural regulatory antibodies, analogous to the pharmacological use in cancer treatment of engineered antibodies against the same targets. Further characterization studies are needed to define the mechanisms through which these native antibodies may function in healthy and disease conditions."

"A Human Biofilm-Disrupting Monoclonal Antibody Potentiates Antibiotic Efficacy in Rodent Models of both Staphylococcus aureus and Acinetobacter baumannii Infections" - Antimicrobial Agents and Chemotherapy
Published Online July 17, 2017

Authors: Yan Q. Xiong, Angeles Estellés, L. Li, W. Abdelhady, R. Gonzales, Arnold S. Bayer, Edgar Tenorio, Anton Leighton, Stefan Ryser and Lawrence M. Kauvar

Direct Link: http://aac.asm.org/content/early/2017/07/11/AAC.00904-17.abstract

"Many serious bacterial infections are antibiotic-refractory due to biofilm formation. A key structural component of biofilm is extracellular DNA which is stabilized by bacterial proteins, including those from the DNABII family. TRL1068 is a high affinity human monoclonal antibody against a DNABII epitope conserved across both gram-positive and gram-negative bacterial species. In the current study, the efficacy of TRL1068 for disruption of biofilm was demonstrated in vitro in the absence of antibiotics by scanning electron microscopy. In vivo efficacy of this antibody was investigated in a well-characterized catheter-induced aortic valve infective endocarditis model in rats infected with a methicillin-resistant Staphylococcus aureus (MRSA) strain with the ability to form thick biofilm, obtained from the blood of a patient with a persistent clinical infection. Animals were treated with vancomycin alone or in combination with TRL1068. MRSA burdens in cardiac vegetations, and within intracardiac catheters, kidneys, spleen and liver showed a significant reduction in the combination arm vs vancomycin alone (p<0.001). A trend towards mortality reduction was also observed (p=0.09). In parallel, in vivo efficacy of TRL1068 against a multi-drug resistant clinical Acinetobacter baumannii isolate was explored using an established skin and soft tissue catheter-related biofilm infection mouse model. Catheter segments infected with A. baumannii were implanted subcutaneously in mice; animals were treated with imipenem alone or in combination with TRL1068. The combination showed a significant reduction in catheter-adherent bacteria vs. antibiotic alone (p<0.001). TRL1068 shows excellent promise as an adjunct to standard-of-care antibiotics for a broad range of difficult-to-treat bacterial infections."

"A High-Affinity Native Human Antibody Disrupts Biofilm from Staphylococcus aureus Bacteria and Potentiates Antibiotic Efficacy in a Mouse Implant Infection Model." - Antimicrobial Agents and Chemotherapy
Published Online March 25, 2016

Authors: Angeles Estellés, Anne-Kathrin Woischnig, Keyi Liu, Robert Stephenson, Evelene Lomongsod, Da Nguyen, Jianzhong Zhang, Manfred Heidecker, Yifan Yang, Reyna J. Simon, Edgar Tenorio, Stote Ellsworth, Anton Leighton, Stefan Ryser, Nina Khanna Gremmelmaier, and Lawrence M. Kauvar

Direct Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808150/

"Many serious bacterial infections are difficult to treat due to biofilm formation, which provides physical protection and induces a sessile phenotype refractory to antibiotic treatment compared to the planktonic state. A key structural component of biofilm is extracellular DNA, which is held in place by secreted bacterial proteins from the DNABII family: integration host factor (IHF) and histone-like (HU) proteins. A native human monoclonal antibody, TRL1068, has been discovered using single B-lymphocyte screening technology. It has low-picomolar affinity against DNABII homologs from important Gram-positive and Gram-negative bacterial pathogens. The disruption of established biofilm was observed in vitro at an antibody concentration of 1.2 μg/ml over 12 h. The effect of TRL1068 in vivo was evaluated in a murine tissue cage infection model in which a biofilm is formed by infection with methicillin-resistant Staphylococcus aureus (MRSA; ATCC 43300). Treatment of the established biofilm by combination therapy of TRL1068 (15 mg/kg of body weight, intraperitoneal [i.p.] administration) with daptomycin (50 mg/kg, i.p.) significantly reduced adherent bacterial count compared to that after daptomycin treatment alone, accompanied by significant reduction in planktonic bacterial numbers. The quantification of TRL1068 in sample matrices showed substantial penetration of TRL1068 from serum into the cage interior. TRL1068 is a clinical candidate for combination treatment with standard-of-care antibiotics to overcome the drug-refractory state associated with biofilm formation, with potential utility for a broad spectrum of difficult-to-treat bacterial infections."

"Human cytomegalovirus infection interferes with the maintenance and differentiation of trophoblast progenitor cells of the human placenta." - Journal of Virology
Published Online March 4, 2015

Authors: Takako Tabata, Matthew Petitt, Martin Zydek, June Fang-Hoover, Nicholas Larocque, Mitsuru Tsuge, Matthew Gormley, Lawrence M. Kauvar and Lenore Pereira

Direct Link: http://jvi.asm.org/content/89/9/5134.long

"Human cytomegalovirus (HCMV) is a major cause of birth defects that include severe neurological deficits, hearing and vision loss, and intrauterine growth restriction. Viral infection of the placenta leads to development of avascular villi, edema, and hypoxia associated with symptomatic congenital infection. Studies of primary cytotrophoblasts (CTBs) revealed that HCMV infection impedes terminal stages of differentiation and invasion by various molecular mechanisms. We recently discovered that HCMV arrests earlier stages involving development of human trophoblast progenitor cells (TBPCs), which give rise to the mature cell types of chorionic villi-syncytiotrophoblasts on the surfaces of floating villi and invasive CTBs that remodel the uterine vasculature. Here, we show that viral proteins are present in TBPCs of the chorion in cases of symptomatic congenital infection. In vitro studies revealed that HCMV replicates in continuously self-renewing TBPC lines derived from the chorion and alters expression and subcellular localization of proteins required for cell cycle progression, pluripotency, and early differentiation. In addition, treatment with a human monoclonal antibody to HCMV glycoprotein B rescues differentiation capacity, and thus, TBPCs have potential utility for evaluation of the efficacies of novel antiviral antibodies in protecting and restoring placental development. Our results suggest that HCMV replicates in TBPCs in the chorion in vivo, interfering with the earliest steps in the growth of new villi, contributing to virus transmission and impairing compensatory development. In cases of congenital infection, reduced responsiveness of the placenta to hypoxia limits the transport of substances from maternal blood and contributes to fetal growth restriction."

"A High-Affinity Native Human Antibody Neutralizes Human Cytomegalovirus Infection of Diverse Cell Types." - Antimicrobial Agents and Chemotherapy
Published Online December 22, 2014

Authors: Lawrence M. Kauvar, Keyi Liu, Minha Park, Neal DeChene, Robert Stephenson, Edgar Tenorio, Stote L. Ellsworth, Takako Tabata, Matthew Petitt, Mitsuru Tsuge, June Fang-Hoover, Stuart P. Adler, Xiaohong Cui, Michael A. McVoy, and Lenore Pereirab

Direct Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325823/

"Human cytomegalovirus (HCMV) is the most common infection causing poor outcomes among transplant recipients. Maternal infection and transplacental transmission are major causes of permanent birth defects. Although no active vaccines to prevent HCMV infection have been approved, passive immunization with HCMV-specific immunoglobulin has shown promise in the treatment of both transplant and congenital indications. Antibodies targeting the viral glycoprotein B (gB) surface protein are known to neutralize HCMV infectivity, with high-affinity binding being a desirable trait, both to compete with low-affinity antibodies that promote the transmission of virus across the placenta and to displace nonneutralizing antibodies binding nearby epitopes. Using a miniaturized screening technology to characterize secreted IgG from single human B lymphocytes, 30 antibodies directed against gB were previously cloned. The most potent clone, TRL345, is described here. Its measured affinity was 1 pM for the highly conserved site I of the AD-2 epitope of gB. Strain-independent neutralization was confirmed for 15 primary HCMV clinical isolates. TRL345 prevented HCMV infection of placental fibroblasts, smooth muscle cells, endothelial cells, and epithelial cells, and it inhibited postinfection HCMV spread in epithelial cells. The potential utility for preventing congenital transmission is supported by the blockage of HCMV infection of placental cell types central to virus transmission to the fetus, including differentiating cytotrophoblasts, trophoblast progenitor cells, and placental fibroblasts. Further, TRL345 was effective at controlling an ex vivo infection of human placental anchoring villi. TRL345 has been utilized on a commercial scale and is a candidate for clinical evaluation."

"Multiplexed screening of natural humoral immunity identifies antibodies at fine specificity for complex and dynamic viral targets." - MAbs
Published Online January 8, 2014

Authors: Krista M McCutcheon, Julia Gray, Natalie Y Chen, Keyi Liu, Minha Park, Stote Ellsworth, Ralph A Tripp, S Mark Tompkins, Scott K Johnson, Shelly Samet, Lenore Pereira, and Lawrence M Kauvar

Direct Link: https://www.ncbi.nlm.nih.gov/pubmed/24492306

"Viral entry targets with therapeutic neutralizing potential are subject to multiple escape mechanisms, including antigenic drift, immune dominance of functionally irrelevant epitopes, and subtle variations in host cell mechanisms. A surprising finding of recent years is that potent neutralizing antibodies to viral epitopes independent of strain exist, but are poorly represented across the diverse human population. Identifying these antibodies and understanding the biology mediating the specific immune response is thus difficult. An effective strategy for meeting this challenge is to incorporate multiplexed antigen screening into a high throughput survey of the memory B cell repertoire from immune individuals. We used this approach to discover suites of cross-clade antibodies directed to conformational epitopes in the stalk region of the influenza A hemagglutinin (HA) protein and to select high-affinity anti-peptide antibodies to the glycoprotein B (gB) of human cytomegalovirus. In each case, our screens revealed a restricted VH and VL germline usage, including published and previously unidentified gene families. The in vivo evolution of paratope specificity with optimal neutralizing activity was understandable after correlating biological activities with kinetic binding and epitope recognition. Iterative feedback between antigen probe design based on structure and function information with high throughput multiplexed screening demonstrated a generally applicable strategy for efficient identification of safe, native, finely tuned antibodies with the potential for high genetic barriers to viral escape."

"Potent high-affinity antibodies for treatment and prophylaxis of respiratory syncytial virus derived from B cells of infected patients." - Journal of Immunology
Published Online October 19, 2009

Authors: Ellen J. Collarini, F. Eun-Hyung Lee, Orit Foord, Minha Park, Gizette Sperinde, Hai Wu, William D. Harriman, Stephen F. Carroll, Stote L. Ellsworth, Larry J. Anderson, Ralph A. Tripp, Edward E. Walsh, Bruce A. Keyt and Lawrence M. Kauvar

Direct Link: http://www.jimmunol.org/content/183/10/6338.long

"Native human Abs represent attractive drug candidates; however, the low frequency of B cells expressing high-quality Abs has posed a barrier to discovery. Using a novel single-cell phenotyping technology, we have overcome this barrier to discover human Abs targeting the conserved but poorly immunogenic central motif of respiratory syncytial virus (RSV) G protein. For the entire cohort of 24 subjects with recent RSV infection, B cells producing Abs meeting these stringent specificity criteria were rare, <10 per million. Several of the newly cloned Abs bind to the RSV G protein central conserved motif with very high affinity (K(d) 1-24 pM). Two of the Abs were characterized in detail and compared with palivizumab, a humanized mAb against the RSV F protein. Relative to palivizumab, the anti-G Abs showed improved viral neutralization potency in vitro and enhanced reduction of infectious virus in a prophylaxis mouse model. Furthermore, in a mouse model for postinfection treatment, both anti-G Abs were significantly more effective than palivizumab at reducing viral load. The combination of activity in mouse models for both prophylaxis and treatment makes these high-affinity human-derived Abs promising candidates for human clinical testing."

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