Our Science - GenrAb

Using B-cell Biology for State-of-the-Art Drug Discovery

During the course of antibody development, B cells accumulate mutations to produce trillions of antibody variations. This biology allows humans to defend themselves from a diverse array of pathogens, but also leads to the creation of rare, therapeutically beneficial antibodies. Until GenrAb, those antibodies were hidden in the blood of humans, unable to be discovered, isolated and studied.

Founded on the groundbreaking research of Dr. Nancy Monson (UTSW), GenrAb is able to employ sophisticated B cell genetic analyses, models and algorithms, validated in a large clinical cohort, to identify anti-neuronal antibodies (Abs) containing specific motifs (AGS+) from patients undergoing neurological stress. These fully human Abs are, by their nature, less likely to have deleterious off-target effects and reduce neurologic disability in well-established preclinical models. GenrAb has identified a target for its lead neuroprotective antibody therapy, TGM-010, which plays an important role in managing neuronal survival. It is possible that the biological impact of TGM-010 could be broadened to the treatment of other neurodegenerative diseases.

The Approach

The Challenge
Current neurodegenerative therapeutic strategies rely on immunosuppression. Although this approach reduces stress on neurons, it has not been shown to reduce the accumulation of neuronal loss, resulting in increased lifetime disability¹, while also carrying the risk of compromising patients’ immune systems.²

GenrAb’s Approach
GenrAb is identifying non-immunosuppressive therapies that can sustain neuronal health while reducing the risks for patients undergoing neuronal stress and neurodegeneration.

GenrAb’s Therapeutic Discoveries
The platform has already identified therapeutic antibody candidates, such as TGM-010, targeting a broad spectrum of neurological dysfunctions.

¹Tur C, Carbonell-Mirabent P, Cobo-Calvo Á, et al. Association of Early Progression Independent of Relapse Activity With Long-term Disability After a First Demyelinating Event in Multiple Sclerosis. JAMA Neurol.2023;80(2):151–160. doi:10.1001/jamaneurol.2022.4655

²Winkelmann, A., Loebermann, M., Reisinger, E. et al. Disease-modifying therapies and infectious risks in multiple sclerosis. Nat Rev Neurol 12, 217–233 (2016). https://doi.org/10.1038/nrneurol.2016.21

TGM-010 is the first antibody that has progressed to this stage of development, as GenrAb’s platform currently consists of >400 outstanding rhAb candidates. To further explore this pipeline, the Company recently opened a lab (@ BioLabs, Pegasus Park) where we are actively characterizing the top 100 AGS scored rhAbs to prioritize those with clear binding affinity for neurons.

RHAB CANDIDATES

The AGS technology allows GenrAb to find the needle in a stack of needles

Innovative AGS Immunogenetic models
GenrAb’s proprietary AGS modeling identifies a new class of endogenous antibodies encoded in B cell DNA taken from the CSF of human patients experiencing neurological stress.

High Potential for Neuronal Binding
These mAbs are characterized by somatic hypermutations at six codons, conferring a high likelihood for neuronal binding … >93%*

^*30 or the first 32 GenrAb pipeline mAbs bound to neurons

Advanced Cloning and Screening
AGS+ mAb candidates are cloned and screened in vitro for neuroprotection and lack of neurotoxicity and then evaluated for reduction in disability through well-established animal models of disease.

Growing Pipeline of Neuroprotective Therapies
Our technology has identified a robust pipeline of fully human mAbs with high CNS tissue and cell-binding affinity, being prioritized for further development.

Novel Disease Biology Identified
Our approach has identified a novel mechanism of disease biology, revealing that TGM-010 engages with a novel target within cellular machinery that actively manages stress response and neuronal health.

Patents

A US patent has been issued for TGM-010’s mAb composition and fragments thereof, with planned expansion of claims to include therapeutic indications. Intellectual Property has been exclusively licensed from the University of Texas Southwestern Medical Center.

VIEW PATENT

Peer-Reviewed Publications

GenrAb has contributed to peer-reviewed, high-impact journals with research revealing the proliferation of autoreactive B cells in early multiple sclerosis patients and the potential of a unique antibody gene signature to foresee the progression to clinically definite multiple sclerosis. These studies underline the predictive power and therapeutic promise of GenrAb’s antibody-based platform in identifying and countering neurological autoimmunity at its inception.

Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients.

Potential of a unique antibody gene signature to predict conversion to clinically definite multiple sclerosis.

A Distinct Class of Antibodies May Be an Indicator of Gray Matter Autoimmunity in Early and Established Relapsing Remitting Multiple Sclerosis Patients.

Rivas JR, Ireland SJ, Chkheidze R, Rounds WH, Lim J, Johnson J, Ramirez DM, Ligocki AJ, Chen D, Guzman AA, Woodhall M, Wilson PC, Meffre E, White C 3rd, Greenberg BM, Waters P, Cowell LG, Stowe AM, Monson NL. Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients. Acta Neuropathol. 2017 Jan;133(1):43-60. doi: 10.1007/s00401-016-1627-0. Epub 2016 Oct 11. PMID: 27730299; PMCID: PMC5312707.

Cameron EM, Spencer S, Lazarini J, Harp CT, Ward ES, Burgoon M, Owens GP, Racke MK, Bennett JL, Frohman EM, Monson NL. Potential of a unique antibody gene signature to predict conversion to clinically definite multiple sclerosis. J Neuroimmunol. 2009 Aug 18;213(1-2):123-30. doi: 10.1016/j.jneuroim.2009.05.014. Epub 2009 Jul 24. PMID: 19631394; PMCID: PMC2785005.

Ligocki AJ, Rivas JR, Rounds WH, Guzman AA, Li M, Spadaro M, Lahey L, Chen D, Henson PM, Graves D, Greenberg BM, Frohman EM, Ward ES, Robinson W, Meinl E, White CL 3rd, Stowe AM, Monson NL. A Distinct Class of Antibodies May Be an Indicator of Gray Matter Autoimmunity in Early and Established Relapsing Remitting Multiple Sclerosis Patients. ASN Neuro. 2015 Oct 21;7(5):1759091415609613. doi: 10.1177/1759091415609613. PMID: 26489686; PMCID: PMC4710131.

Rounds WH, Salinas EA, Wilks TB 2nd, Levin MK, Ligocki AJ, Ionete C, Pardo CA, Vernino S, Greenberg BM, Bigwood DW, Eastman EM, Cowell LG, Monson NL. MSPrecise: A molecular diagnostic test for multiple sclerosis using next generation sequencing. Gene. 2015 Nov 10;572(2):191-7. doi: 10.1016/j.gene.2015.07.011. Epub 2015 Jul 11. PMID: 26172868; PMCID: PMC4702260.