Seth Lederman

Biography

Lederman earned his bachelor's degree in Chemistry from Princeton University where he graduated cum laude in 1979. He completed his M.D. from Columbia University in 1983 and continued his training at the Columbia Presbyterian Medical Center until 1986. Lederman became instructor at Columbia in 1985, Assistant Professor in 1988 and Associate Professor with tenure in 1996. From October 30, 2015 until November 1, 2016 he took a leave of absence and left Columbia in April 2017. In addition to his research, he served as attending physician in the Edward Daniels Faulkner Arthritis Clinic at Columbia Presbyterian Hospital from 1988-1996 and served as Associate Attending physician at Columbia Presbyterian Hospital until 2000 (now New York Presbyterian Hospital).

As Assistant Professor at Columbia, Dr. Lederman discovered the CD40-Ligand (CD154) and elucidated the molecular basis of T cell helper function. Lederman also collaborated with Professor David Baltimore in identifying and functionally characterizing the CD40 signaling molecule, TRAF-3. Dr. Lederman’s “early work on HIV contributed to the understanding of how the V3 loop of HIV gp120 was involved in fusion with CD4 cell membranes, an early and essential event in viral entry and infection”.

Lederman founded Targent Pharmaceuticals, which sold levoleucovorin to Spectrum Pharmaceuticals, who market it as Fusilev. Lederman co-founded and served as a managing partner of Konanda Pharma Partners and Konanda Pharma Fund I, LP, and its wholly owned operating companies, Validus and Fontus Pharmaceuticals Inc. Validus acquired Fontus and markets Equetro (carbamazepine – Extended Release), Marplan (isocarboxazid) and Rocaltrol (calcitriol).

Lederman founded Tonix Pharmaceuticals which is developing TNX-102 SL for post-traumatic stress disorder (PTSD). FDA awarded TNX -102 SL “Breakthrough Therapy” (breakthrough therapy) designation for PTSD because its effects in military-related PTSD have the potential to be improvements over existing therapies

Discovery of CD40-ligand (CD154): the Molecular Basis of T Helper Function

As Assistant Professor at Columbia, Dr. Lederman discovered the CD40-Ligand (CD154) and elucidated the molecular basis of T cell helper function. Dr. Lederman’s work on the CD40-Ligand (CD154) led to the development of therapeutic candidates for autoimmune diseases and organ transplant rejection in collaboration with Biogen and UCB/CellTech. Dartmouth University challenged the CD40-Ligand patents, but the challenge (called an interference) was rejected on all claims. UCB is currently in Phase 2 trials with dapirolizumab pegol (a pegylated anti-CD40L Fab'). Transcriptional changes in Dapirolizumab pegol treated Systemic Lupus Erythematosus (SLE) patients were recently reported.

Targent Pharmaceuticals and Levoleucovorin

Lederman founded Targent Pharmaceuticals, which sold levoleucovorin to Spectrum Pharmaceuticals, who market it as Fusilev. Fusilev is approved for the treatment of advanced colorectal cancer and for methotrexate rescue.

Tonix Pharmaceuticals: Drug Discovery and Development for Central Nervous System Conditions including Posttraumatic Stress Disorder (PTSD)

As of April 2017, Tonix had approximately fifteen employees. Lederman is a co-founder and current CEO;. and Bradley Saenger, CPA and Gregory Sullivan, MD hold positions of CFO and CMO, respectively. Founded in 2007 and based in New York City, the company specializes in developing next generation medicines for central nervous system disorders. Among the current projects of the company is the development of TNX-102 SL (cyclobenzaprine HCl, 5.6 mg tablets for sublingual administration) for the treatment of post-traumatic stress disorder (PTSD). TNX-102 SL 5.6 mg was evaluated a Phase 2 study (the AtEase Trial) for military PTSD and showed significant effects.

The results of the Phase 2b trial of TNX-102 SL in military-related PTSD, referred to as AtEase, have been reported at medical conferences in 2016.

On December 19, 2016, FDA awarded TNX -102 SL breakthrough therapy designation for PTSD because its effects in military-related PTSD have the potential to be improvements over existing therapies

TNX-102 SL is believed to improve sleep quality in PTSD. Before focusing on PTSD, Tonix Pharmaceuticals developed TNX-102 SL for fibromyalgia, including a Phase 2a study that included sleep EEGs. Whereas fibromyalgia is associated with a sleep disturbance confined to nonREM sleep, PTSD is associated with impaired nonREM and REM sleep.

TNX-301 (disulfiram 250 mg/selegiline 4 mg tablets), for the treatment of alcohol abuse and addiction is in preclinical development.

TNX-701 (tianeptine tablets), for PTSD is in preclinical development. TNX-601 is a novel oral formulation of tianeptine. Currently there is no tianeptine-containing product approved in the U.S., but tianeptine sodium (amorphous) has been marketed in Europe, Asia, and Latin America for the treatment of depression since 1987. Tonix has discovered a novel salt and polymorph which may provide improved stability, consistency, and manufacturability relative to the known forms of tianeptine. Like cyclobenzaprine, tianeptine shares structural similarities with classic tricyclic antidepressants, but it has unique pharmacological and neurochemical properties. Tianeptine modulates the glutamatergic system indirectly and reverses the inhibitory neuroplasticity observed during periods of stress and steroid use. It is a weak mu-opioid receptor (MOR) agonist, but does not have significant affinity for known neurotransmitter receptors. Tianeptine has an established safety profile based on its decades of use in many European, Asian, and Latin American countries. TNX-601 is being developed as a first line monotherapy for PTSD for daytime dosing.

The company was listed on the NASDAQ exchange in 2013 under the symbol TNXP. In addition to corporate headquarters in New York City, the company has facilities in La Jolla, CA; Montreal, Quebec, Canada and Dublin, Ireland.

Tonix Pharmaceuticals and Biodefense

TNX-801 is a new potential vaccine for smallpox. TNX-801 is a synthetic form of horsepox, which is an otherwise extinct virus. Evolutionary analysis of modern vaccines indicates that the vaccine isolated and used by Dr. Edward Jenner to vaccinate against smallpox was either horsepox or something quite similar. The synthesis of horsepox was a collaboration with Professor David Evans and Dr. Ryan Noyce at the University of Alberta in Edmonton, Alberta, Canada. TNX-801 or horsepox is the first poxvirus, or poxviridae, to be synthesized and provides a platform for developing new vaccines against infectious disease and cancer.

International Biotechnology Policy and Cooperation

In September 2015, Dr. Lederman represented U.S. Biotechnology at a Summit with China's President Xi Jinping. The Summit was organized by the United States Chamber of Commerce and was held September 17–18, 2015 in Beijing. The delegation of U.S. CEOs, former U.S. cabinet officials and leading academic experts was the 7th meeting of the U.S.-China CEO and Former Senior Officials' Dialogue. The Dialogue was co-chaired by the United States Chamber of Commerce and the China Center for International Economic Exchanges (CCIEE), led by former Vice Premier Zeng Peiyan.

Fellowships and grants

1. 1985-1990 National Institutes of Health, Physician Scientist
2. 1988-1993 Co-investigator (with Dr. Leonard Chess) "Biologic and Functional Consequences of CD4- gp120 Interactions": Project #1 of PO-1 AI26886, "Pathogenesis of AIDS: Molecular and Cellular Mechanisms", Dr. Leonard Chess, P.I.
3. 1992-1994 Arthritis Investigator, Arthritis Foundation (National)
4. 1992-1995 "Differentiation and Function of Human Helper T cells", RO-1 (rank 8.1 percentile), P.I., Seth Lederman.
5. 1992-1995 "Differentiation and Function of Human Helper T cells", American Cancer Society (Declined).
6. 1993 Columbia Presbyterian Medical Center, Clinical Research Development Grant, "Preclinical Studies of the mAb 5c8", P.I., Seth Lederman.
7. 1993-1996 "Preclinical Studies of the mAb 5c8", P.I. with Dr. Leonard Chess, Biogen, Inc.
8. 1993-1994 Howard Hughes Medical Student Fellowship and Continuing Scholar Award for Sarah M. Fortune.
9. 1994-1995 Howard Hughes Medical Student Fellowship for Aarif Y. Khakoo
10. 1996-1999 "Molecular Analysis of Helper T cells Function", American Cancer Society (rank, top 10%. (Declined).
11. 1996-2001 "Differentiation and Function of Human Helper T cells", RO-1 (rank 7.3 percentile), P.I., Seth Lederman, Competitive renewal.

Selected publications

1. Lederman S; Gulick R; Chess L (August 1989). "Dextran sulfate and heparin interact with CD4 molecules to inhibit the binding of coat protein (gp120) of HIV". J. Immunol. 143 (4): 1149–54. PMID 2545782. 
2. Reddy MM; Goetz RR; Gorman JM; Grieco MH; Chess L; Lederman S (1991). "Human immunodeficiency virus type-1 infection of homosexual men is accompanied by a decrease in circulating B cells". J. Acquir. Immune Defic. Syndr. 4 (4): 428–34. PMID 1706770. 
3. Lederman S, DeMartino JA, Daugherty BL, et al. (November 1991). "A single amino acid substitution in a common African allele of the CD4 molecule ablates binding of the monoclonal antibody, OKT4". Mol. Immunol. 28 (11): 1171–81. PMID 1961196. doi:10.1016/0161-5890(91)90003-3. 
4. Yellin MJ; Lee JJ; Chess L; Lederman S (November 1991). "A human CD4- T cell leukemia subclone with contact-dependent helper function". J. Immunol. 147 (10): 3389–95. PMID 1834738. 
5. Lederman S; Yellin MJ; Krichevsky A; Belko J; Lee JJ; Chess L (April 1992). "Identification of a novel surface protein on activated CD4+ T cells that induces contact-dependent B cell differentiation (help)". J. Exp. Med. 175 (4): 1091–101. PMC 2119166 . PMID 1348081. doi:10.1084/jem.175.4.1091. 
6. Lederman S; Bergmann JE; Cleary AM; Yellin MJ; Fusco PJ; Chess L (September 1992). "Sulfated polyester interactions with the CD4 molecule and with the third variable loop domain (v3) of gp120 are chemically distinct". AIDS Res. Hum. Retroviruses. 8 (9): 1599–610. PMID 1457206. doi:10.1089/aid.1992.8.1599. 
7. Lederman S; Yellin MJ; Inghirami G; Lee JJ; Knowles DM; Chess L (December 1992). "Molecular interactions mediating T-B lymphocyte collaboration in human lymphoid follicles. Roles of T cell-B-cell-activating molecule (5c8 antigen) and CD40 in contact-dependent help". J. Immunol. 149 (12): 3817–26. PMID 1281189. 
8. Stein CA; Cleary AM; Yakubov L; Lederman S (1993). "Phosphorothioate oligodeoxynucleotides bind to the third variable loop domain (v3) of human immunodeficiency virus type 1 gp120". Antisense Res. Dev. 3 (1): 19–31. PMID 8495104. 
9. Ramesh N, Fuleihan R, Ramesh V, et al. (July 1993). "Deletions in the ligand for CD40 in X-linked immunoglobulin deficiency with normal or elevated IgM (HIGMX-1)". Int. Immunol. 5 (7): 769–73. PMID 8103673. doi:10.1093/intimm/5.7.769. 
10. Yellin MJ, Sinning J, Covey LR, et al. (July 1994). "T lymphocyte T cell-B cell-activating molecule/CD40-L molecules induce normal B cells or chronic lymphocytic leukemia B cells to express CD80 (B7/BB-1) and enhance their costimulatory activity". J. Immunol. 153 (2): 666–74. PMID 7517421. 
11. Yellin MJ, Sippel K, Inghirami G, et al. (January 1994). "CD40 molecules induce down-modulation and endocytosis of T cell surface T cell-B cell activating molecule/CD40-L. Potential role in regulating helper effector function". J. Immunol. 152 (2): 598–608. PMID 7506727. 
12. Lederman S, Yellin MJ, Cleary AM, et al. (March 1994). "T-BAM/CD40-L on helper T lymphocytes augments lymphokine-induced B cell Ig isotype switch recombination and rescues B cells from programmed cell death". J. Immunol. 152 (5): 2163–71. PMID 7907632. 
13. Covey LR, Cleary AM, Yellin MJ, et al. (April 1994). "Isolation of cDNAs encoding T-BAM, a surface glycoprotein on CD4+ T cells mediating contact-dependent helper function for B cells: identity with the CD40-ligand". Mol. Immunol. 31 (6): 471–84. PMID 7514269. doi:10.1016/0161-5890(94)90066-3. 
14. Cheng G; Cleary AM; Ye ZS; Hong DI; Lederman S; Baltimore D (March 1995). "Involvement of CRAF1, a relative of TRAF, in CD40 signaling". Science. 267 (5203): 1494–8. PMID 7533327. doi:10.1126/science.7533327. 
15. Cleary AM; Fortune SM; Yellin MJ; Chess L; Lederman S (October 1995). "Opposing roles of CD95 (Fas/APO-1) and CD40 in the death and rescue of human low density tonsillar B cells". J. Immunol. 155 (7): 3329–37. PMID 7561026. 
16. Karpusas M, Hsu YM, Wang JH, et al. (October 1995). "2 A crystal structure of an extracellular fragment of human CD40 ligand". Structure. 3 (10): 1031–9. PMID 8589998. doi:10.1016/S0969-2126(01)00239-8. 
17. Lederman S, Sullivan G, Benimetskaya L, et al. (1996). "Polydeoxyguanine motifs in a 12-mer phosphorothioate oligodeoxynucleotide augment binding to the v3 loop of HIV-1 gp120 and potency of HIV-1 inhibition independency of G-tetrad formation". Antisense Nucleic Acid Drug Dev. 6 (4): 281–9. PMID 9012864. doi:10.1089/oli.1.1996.6.281. 
18. Sullivan GM; Canfield SM; Lederman S; Xiao E; Ferin M; Wardlaw SL (1997). "Intracerebroventricular injection of interleukin-1 suppresses peripheral lymphocyte function in the primate". Neuroimmunomodulation. 4 (1): 12–8. PMID 9326740. 
19. Liu QY; Rubin MA; Omene C; Lederman S; Stein CA (July 1998). "Fas ligand is constitutively secreted by prostate cancer cells in vitro". Clin. Cancer Res. 4 (7): 1803–11. PMID 9676859. 
20. van Eyndhoven WG, Frank D, Kalachikov S, et al. (December 1998). "A single gene for human TRAF-3 at chromosome 14q32.3 encodes a variety of mRNA species by alternative polyadenylation, mRNA splicing and transcription initiation". Mol. Immunol. 35 (18): 1189–206. PMID 10199393. doi:10.1016/S0161-5890(98)00099-6. 
21. van Eyndhoven WG; Gamper CJ; Cho E; Mackus WJ; Lederman S (July 1999). "TRAF-3 mRNA splice-deletion variants encode isoforms that induce NF-kappaB activation". Mol. Immunol. 36 (10): 647–58. PMID 10509816. doi:10.1016/S0161-5890(99)00079-6. 
22. Gamper C; van Eyndhoven WG; Schweiger E; Mossbacher M; Koo B; Lederman S (2000). "TRAF-3 interacts with p62 nucleoporin, a component of the nuclear pore central plug that binds classical NLS-containing import complexes". Mol. Immunol. 37 (1-2): 73–84. PMID 10781837. doi:10.1016/S0161-5890(00)00015-8. 
23. Gamper C; Omene CO; van Eyndhoven WG; Glassman GD; Lederman S (October 2001). "Expression and function of TRAF-3 splice-variant isoforms in human lymphoma cell lines". Hum. Immunol. 62 (10): 1167–77. PMID 11600226. doi:10.1016/S0198-8859(01)00284-1. 
24. van der Kolk, L E (2002). "CD20-induced B cell death can bypass mitochondria and caspase activation". Leukemia. 16 (9): 1735–1744. PMID 12200688. doi:10.1038/sj.leu.2402559. 
25. Moldofsky H; Harris HW; Archambault WT; Kwong T; Lederman S (December 2011). "Effects of bedtime very low dose cyclobenzaprine on symptoms and sleep physiology in patients with fibromyalgia syndrome: a double-blind randomized placebo-controlled study" (PDF). J. Rheumatol. 38 (12): 2653–63. PMID 21885490. doi:10.3899/jrheum.110194. 

Review Articles

1. Lederman S; Yellin MJ; Covey LR; Cleary AM; Callard R; Chess L (June 1993). "Non-antigen signals for B-cell growth and differentiation to antibody secretion". Curr. Opin. Immunol. 5 (3): 439–44. PMID 7688518. doi:10.1016/0952-7915(93)90066-2. 
2. Lederman S; Yellin MJ; Cleary AM; Fortune SM; Chess L (1994). "The understanding of contact-dependent T-cell helper function in molecular, cellular and physiological detail". Res. Immunol. 145 (3): 215–21; discussion 244–9. PMID 7527578. doi:10.1016/s0923-2494(94)80187-8. 
3. Lederman S, Cleary AM, Yellin MJ, et al. (January 1996). "The central role of the CD40-ligand and CD40 pathway in T-lymphocyte-mediated differentiation of B lymphocytes". Curr. Opin. Hematol. 3 (1): 77–86. PMID 9372055. doi:10.1097/00062752-199603010-00012. 
4. Lederman S; Suciu-Foca N (July 1999). "Antigen presenting cells integrate opposing signals from CD4+ and CD8+ regulatory T lymphocytes to arbitrate the outcomes of immune responses". Hum. Immunol. 60 (7): 533–61. PMID 10426271. doi:10.1016/s0198-8859(99)00045-2. 
5. Lederman S (2001). "The role of CD154 (CD40-ligand) in costimulation". Transplant. Proc. 33 (1-2): 202–6. PMID 11266780. doi:10.1016/s0041-1345(00)01975-8. 

Patents

1. U.S. Patent #5,474,771 (Issued December 12, 1995) “Murine monoclonal antibody (5c8) recognizes a human glycoprotein on the surface of T lymphocytes, Compositions containing same,” Lederman, S., L. Chess and M.J. Yellin.
2. U.S. Patent #5,756,710 (Issued May 26, 1998) “Phosphorothioate oligonucleotides that bind to the V3-loop and uses thereof.” Stein, C.A., S. Lederman and G. Sullivan.
3. U.S. Patent #5,933,816 (Issued November 30, 1999) “Methods to inhibit humoral immune responses, immunoglobulin production, and B cell activation with 5c8-specific antibodies”, Lederman, S., L. Chess and M.J. Yellin.
4. U.S. Patent #6,331,433 B1 (Issued December 18, 2001) “Human T cell leukemia cell line designated D1.1”, Lederman, S., L. Chess and M.J. Yellin.
5. U.S. Patent #6,331,615 B1 (Issued December 18, 2001) “Nucleic acid molecule encoding heavy or light chain of an antibody which specifically recognizes a protein specifically recognized by monoclonal antibody 5c8 (anti-CD40 ligand),” Lederman, S., L. Chess and M.J. Yellin.
6. U.S. Patent #6,340,459 B1 (Issued January 22, 2002) “Therapeutic applications for the anti-T-BAM (CD40-L) monoclonal antibody 5c8 in the treatment of reperfusion injury in non-transplant recipients”, Yellin, M.J., Lederman, S., and L. Chess.
7. U.S. Patent #6,358,944 B1 (Issued March 19, 2002) “Methods and compositions for treating generalized anxiety disorder”, Lederman, S., I. W. Iglehart.
8. U.S. Patent #6,403,091 B1 (Issued June 11, 2002) “Methods for inhibiting the rejection of a transplant organ in a subject with 5c8-specific antibodies”, Lederman, S, M.J. Yellin, and L. Chess.
9. U.S. Patent #6,410,710 B1 (Issued June 25, 2002) “Nucleic acid encoding TRAF-3 deletion isoform”, Lederman, S., W. van Eyndhoven.
10. U.S. Patent #6,451,310 B1 (Issued September 17, 2002) “A method for inhibiting an allergic response with a 5c8-specific antibody”, Lederman, S, M.J. Yellin, and L. Chess.
11. U.S. Patent #6,455,044 B1 (Issued September 24, 2002) “5c8 Antigen”, Lederman, S., M.J. Yellin, and L. Chess.
12. U.S. Patent #6,592,868 B1 (Issued July 15, 2003) “Methods for treating autoimmune disease”, Lederman, S., M.J. Yellin, and L. Chess.
13. U.S. Patent #6,610,294 B1 (Issued August 26, 2003) “Methods of inhibiting an autoimmune response in a human suffering from an autoimmune disease by administering an antibody that binds to a protein to which monoclonal antibody 5c8 binds”, Lederman, S., M.J. Yellin, and L. Chess.
14. U.S. Patent #6,793,924 (Issued September 21, 2004) “Protein recognized by an antibody that specifically binds an epitope that is specifically bound by monoclonal antibody 5c8”, Lederman, S., L. Chess and M.J. Yellin.
15. U.S. Patent #6,822,070 B2 (Issued November 23, 2004) “Truncated CRAF1 inhibits CD40 signaling.”, Baltimore, D, G. Cheng, Z-S Ye, S. Lederman, and A. Cleary.
16. U.S. Patent #6,849,415 B2 (Issued February 1, 2005) “TRAF -3 deletion isoforms and uses thereof”, Lederman, S., W. van Eyndhoven.
17. US Patent #7,070,777 (Issued July 4, 2006) “Method for inhibiting inflammation with an antibody that binds the 5C8 protein,” Lederman, S., L. Chess and M.J. Yellin
18. US Patent 12/145,792 “Compositions and Methods for Increasing Compliance with Therapies using Aldehyde Dehydrogenase Inhibitors and Treating Alcoholism” (notice of allowance) . Lederman, S.
19. Australia Patent AU 2002354017 “Compositions and Methods for Increasing Compliance with Therapies using Aldehyde Dehydrogenase Inhibitors and Treating Alcoholism”. Lederman, S.
20. Canada Patent CA 2463987 “Compositions and Methods for Increasing Compliance with Therapies using Aldehyde Dehydrogenase Inhibitors and Treating Alcoholism”. Lederman, S.
21. European Patent EP 1441708 “Compositions and Methods for Increasing Compliance with Therapies using Aldehyde Dehydrogenase Inhibitors and Treating Alcoholism”. Lederman, S.
22. New Zealand Patent NZ 532583 “Compositions and Methods for Increasing Compliance with Therapies using Aldehyde Dehydrogenase Inhibitors and Treating Alcoholism” Lederman, S.

Honors and awards

1. 1993 Dr. Harold and Golden Lamport Award for Excellence in Clinical Science Research
2. 1993 New York Arthritis Foundation Grant Reviewer
3. 1993 Ad Hoc Reviewer; Immunochemical Sciences Study Section, N.I.H.
4. 1993 Ad Hoc Reviewer; Aids and Related Research Study Section (1), N.I.H.
5. 1994-1996 Medical and Scientific Committee, N.Y. Chapter of the Arthritis Foundation
6. 1994-1995 Scientific Program Abstract Reviewer - Am. College of Rheumatology Nat'l Meeting
7. 1996 Ad Hoc Reviewer, American Cancer Society, Immunology Study Section
8. 1999 Scientific Program Abstract Reviewer - Am. College of Rheumatology Nat'l Meeting
9. 1998-2001 Grant Review Committee – Nat’l Arthritis Foundation, Cellular Immunology
10. 2000-2005 American Editor – Human Immunology