TNX-1500 / Tonix, Massachusetts General Hospital - LARVOL DELTA

Graft Survival and Rejection Risk with TNX-1500 as Monotherapy or in Combination with Conventional IS Agents in Nonhuman Primate Heart Transplants (WTC 2025) - "*Purpose: TNX-1500 (TNX) is a humanized IgG4 αCD154 mAb engineered to down-modulate FcγR2 binding to reduce the thromboembolism risk associated with ruplizumab (hu5c8 IgG1). Here in a NHP allo heart transplant model we report an expanded series of weekly dose TNX therapy (Rx), alone (monoRx) or in combination with mycophenolate mofetil (MMF), Rapamycin (Rapa), or Tacrolimus (Tac).* TNX was evaluated as mono Rx (30mg/kg 2x/wk x2, then 20mg/kg/wk; n=19) and combined with TNX+MMF (200 mg/d PO; n=4), TNX+Rapa (target trough 5-10 ng/ml; n=13), or TNX+Tac (target trough 3-5 ng/ml; n=7)... TNX-1500 demonstrated robust efficacy to prevent graft rejection during treatment in NHP, both as monoRx and in combination with conventional immunosuppressive agents. Notably, TNX+Rapa provided superior protection from CAV scores in the later post-Tx intervals. The absence of thromboembolic events predicts safety in clinical translation."

Combination therapy • Monotherapy • Anemia • Cardiovascular • Hematological Disorders • Transplant Rejection • Transplantation

Dual Blockade of CD154 and CD28 Co-Stimulation Pathways Mitigates Pathogenic Allo-Immunity and Enhances Survival in Cynomolgus Cardiac Transplantation (WTC 2025) - "*Purpose: TNX-1500 (TNX) is a novel humanized αCD154 mAb that contains the hu5c8 Fab region and an IgG4 Fc region engineered to modulate FcγR2 binding to reduce the risk of thromboembolic events seen with ruplizumab (hu5c8 IgG1) in previous clinical trials... The dual blockade of CD154 and CD28 co-stimulation pathways confers durable protection against pathogenic allo immunity in this stringent preclinical model, suggesting its potential for clinical translation."

Cardiovascular • Hematological Disorders • Hematological Malignancies • Lymphoma • Thrombosis • Transplantation • CD40LG • CTLA4

Is Proteinuria the Final Hurdle to Successful Pig Kidney Xenotransplantation? (WTC 2025) - "Group A baboons (n=3) received induction Rx with anti-thymocyte globulin, anti-CD20 mAb, and C1-esterase inhibitor, followed by maintenance Rx with 20mg/kg TNX-1500, rapamycin, +/- methylprednisolone, and +/- IL-6R blockade (tocilizumab). An optimized TNX-1500-based regimen prevented AMR and prolonged xenograft survival. However, proteinuria remains a critical challenge, causing urinary loss of therapeutic antibody, leading to inadequate immunosuppression and AMR. Overcoming proteinuria may be essential for achieving consistent long-term pig kidney graft survival."

Antibody-mediated Rejection • Cardiovascular • Chronic Kidney Disease • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Hematological Disorders • Infectious Disease • Nephrology • Peptic Ulcer • Pneumonia • Renal Disease • Respiratory Diseases • Thrombosis • Transplantation • CD40LG • IL6R

Tonix Pharmaceuticals and Makana Therapeutics Announce Collaboration Combining Tonix’s Anti-CD40L Monoclonal Antibody (TNX-1500) with Makana’s Genetically Engineered Organs in Preclinical and Clinical Xenotransplantation Studies (GlobeNewswire) - "Tonix Pharmaceuticals Holding Corp...and Makana Therapeutics, Inc...today announced a collaborative research agreement under which Tonix and Makana will study Tonix’s anti-CD40L (CD40 ligand, also called CD154) monoclonal antibody candidate, TNX-1500, in combination with Makana’s human-compatible organs and cells for the treatment of organ failure. The preclinical research and development collaboration has the potential to span multiple Makana programs including kidney, heart and islet cell transplant. The goal of the preclinical studies is to support the submission of an investigational new drug application (IND) to the U.S. Food and Drug Administration (FDA) to support compassionate use for patients undergoing xenotransplantation."

Licensing / partnership • Preclinical • Transplant Rejection

Experience with a Novel Delayed Immune Tolerance Protocol in Nonhuman Primates Based on αCD154, αCD2 and αCD28 (ISHLT 2025) - "Induction treatment for donor bone marrow transplantation (BMT) was administered after a 4-month delay period under TNX-1500; BMT induction was comprised of one (Group 1) or two (Group 2) doses of total body irradiation, thymic irradiation, and horse anti-thymocyte globulin (ATG) followed by two (Group 1) or five (Group 2) weekly doses of αCD2 and five weekly treatments with αCD28 and TNX-1500.Results One graft rejected during the delay period; two others exhibited moderate rejection while five exhibited normal histology...In Group 2, two monkeys succumbed during the post-BMT treatment period to CMV, with one achieving high lymphocyte chimerism. Three Group 2 animals developed lymphocyte chimerism but developed lethal post-transplantation lymphoproliferative disease at end of the treatment period.Conclusion Although the combination of αCD2 with αCD28 promotes lymphocyte chimerism in this delayed BMT model, the high incidence of PTLD and opportunistic infection with CMV..."

Clinical • Bone Marrow Transplantation • Cytomegalovirus Infection • Infectious Disease

Tonix’s TNX-1500 Shows Promise in Preventing Organ Transplant Rejections of Either Human or Pig Organs; Autoimmune Diseases Also a Target (Tonix Pharma Press Release) - "Earlier animal studies indicated that TNX-1500 is active at preventing rejection of organ grafts and preserving graft function, either as a single agent or in combination with low doses of traditional immunosuppressants. TNX-1500 is active whether the organ comes from the same species or from genetically engineered pigs. So far, TNX-1500 treatment in these animal transplantation studies has shown a dramatic reduction in thrombotic events, indicating that the protein engineering of TNX-1500's Fc region achieved its design goals...Although the lead indication for Tonix's TNX-1500 product candidate is the prevention of rejection of transplanted human kidneys, Tonix is also pursuing development of TNX-1500 for preventing rejection of genetically engineered pig organs. Ultimately, Tonix also plans to develop TNX-1500 as a treatment for autoimmune diseases."

Preclinical • Immunology • Transplant Rejection

Costimulation blockade: the next generation. (PubMed, Curr Opin Organ Transplant) - "The focus in transplantation is shifting toward safer, long-term therapies with greater accessibility. Investigational agents with subcutaneous delivery methods could overcome logistical challenges, improve adherence, and redefine posttransplant care. These advancements in costimulation blockade may enhance long-term graft survival and transform the management of KT recipients."

Journal • Cardiovascular • Transplantation • CD40LG

Tonix Pharmaceuticals Announces Positive Topline Results from Phase 1 Trial for TNX-1500, a Next Generation anti-CD40L mAb Candidate for Prevention of Kidney Transplant Rejection and Treatment of Autoimmune Diseases (GlobeNewswire) - P1 | N=NA | "The only treatment-emergent adverse event (TEAE) occurring in ≥ 3 participants among all TNX-1500 groups was aphthous ulcer, occurring in one participant each in the 3 mg/kg, 10 mg/kg, and 30 mg/kg groups; all were rated as mild, possibly related, and resolved in 2-10 days. There were no TEAEs assessed as related to KLH administration. No TEAEs led to study discontinuation and there were no serious adverse events...TNX-1500 at 10 mg/kg and 30 mg/kg blocked both the primary and secondary anti-KLH Ab responses, evidenced by the mean Ab level at all sampled timepoints (through Day 120) being below the lower limit of quantitation (400 µg/L). TNX-1500 at 3 mg/kg blocked the primary response to KLH Day 2 challenge and reduced the peak secondary response to KLH Day 29 challenge by approximately two thirds (69%) relative to the peak response to placebo."

P1 data • Immunology • Transplant Rejection

Enhanced Costimulation Blockade With αCD154, αCD2, and αCD28 to Promote Heart Allograft Tolerance in Nonhuman Primates. (PubMed, Transplantation) - "Intensive costimulation pathway blockade with αCD2, αCD154, and αCD28 promotes lymphocyte chimerism at the cost of high incidence of posttransplantation lymphoproliferative disease and opportunistic infections, preventing assessment of the effectiveness of the regimen to promote alloimmune tolerance."

Journal • Bone Marrow Transplantation • Cytomegalovirus Infection • Infectious Disease • Transplantation • CD40LG

New Developments and Therapeutic Drug Monitoring Options in Costimulatory Blockade in Solid Organ Transplantation: A Systematic Critical Review. (PubMed, Ther Drug Monit) - "The routine use of costimulation blockade in SOT is hindered by problems in efficacy compared with the standard of care. Costimulatory inhibitors could be combined in a calcineurin inhibitor-free regimen. Future PK/pharmacodynamic studies in costimulatory agents and personalized medicine could warrant TDM of these agents."

Journal • Review • Hepatology • Solid Organ Transplantation • Transplantation • CD40LG • CD80 • TNFSF4

Experience with a Novel Delayed Immune Tolerance Protocol in Nonhuman Primates Based on aCD154, aCD2 and aCD28 (ACS-CLINCON 2024) - "Induction treatment for donor bone marrow transplantation (BMT) was administered after a 4-month delay period under TNX-1500; BMT induction was comprised of one (Group 1) or two (Group 2) doses of total body irradiation, thymic irradiation, and horse anti-thymocyte globulin (ATG) followed by two (Group 1) or five (Group 2) weekly doses of αCD2 and five weekly treatments with αCD28 and TNX-1500... Although the combination of αCD2 with αCD28 promotes lymphocyte chimerism in this delayed BMT model, the high incidence of PTLD and opportunistic infection with CMV reflects overly intense immunosuppression and prevented assessment of the regimen’s effectiveness to promote alloimmune tolerance."

Clinical • Bone Marrow Transplantation • Cytomegalovirus Infection • Infectious Disease • Transplantation

A retained native kidney (with ureter ligation) prevents dehydration and calcium/phosphate imbalance after life-supporting TKO pig-to-baboon kidney transplantation (TTS 2024) - "Maintenance therapy comprised anti-CD154mAb (TNX-1500), rapamycin, methylprednisolone, and IL-6R blockade with tocilizumab. (1) Retention of one native kidney compensates for the deficiencies in the renin-angiotensin-aldosterone system documented previously after TKO pig kidney Tx in baboons. (2) Prevention of dehydration mitigates the low serum phosphate and high serum calcium levels documented previously. (3) This study suggests that, in clinical pig kidney xenoTx, retention of the native human kidneys will compensate for any endocrine deficiencies of the pig kidney graft."

Transplantation • CD40LG • IL6R

Delayed Immune Tolerance for Cardiac Allografts in Nonhuman Primates by Targeting CD, CD, and CD Costimulation Pathways (TTS 2024) - "Here we test whether a protocol additionally targeting CD28 and CD2 is sufficient for cardiac allograft acceptance or promotes expansion of regulatory T-cells. Donor bone marrow transplantation (BMT) was administered to recipients of MHC-mismatched heterotopic heart allografts after a 4-month delay period under TNX-1500 (anti-CD154)... The combination of anti-CD28 with multi-dose anti-CD2 often promotes lymphocyte chimerism in this delayed BMT model at levels that predict prolonged graft survival or long-term acceptance in kidney recipients. However, the high incidence of PTLD and opportunistic infection prevented the assessment of the regimen’s effectiveness in promoting alloimmune tolerance. Strategies to improve CMV control and PTLD prophylaxis merit investigation in this model."

Bone Marrow Transplantation • Cardiovascular • Cytomegalovirus Infection • Infectious Disease • CD40LG

Tonix Pharmaceuticals Announces Two Oral Presentations and One Poster Presentation Involving TNX-1500 (Fc-modified humanized anti-CD40L mAb) at the American Transplant Congress 2024 (GlobeNewswire) - "Tonix Pharmaceuticals...today announced two oral presentations and a poster presentation at the American Transplant Congress 2024, being held June 1-5, 2024 at the Pennsylvania Convention Center, Philadelphia, Pa. Details on each presentation can be found below."

Clinical • Transplant Rejection

Combined Blockade of the CD154 and CD28 Co-Stimulation Pathways Attenuates Pathogenic Alloimmunity and Prolongs Survival in Cynomolgus Cardiac Allografts (ATC 2024) - "*Purpose: TNX-1500 (TNX) is a novel humanized αCD154 mAb that contains the hu5c8 Fab region and an IgG4 Fc region engineered to modulate FcγR2 binding to reduce the risk of thromboembolic events seen with ruplizumab (hu5c8 IgG1) in previous clinical trials... Combined blockade of the CD154 and CD28 co-stimulation pathways is associated with durable protection from pathogenic alloimmunity in this stringent model, suggesting a promising approach for clinical translation."

Cardiovascular • Hematological Disorders • Thrombosis • CD40LG

Experience with a Novel Delayed Immune Tolerance Protocol in Nonhuman Primates Based on Anti-CD154, Anti-CD2, and Anti-CD28 (ATC 2024) - "Induction treatment for donor bone marrow transplantation (BMT) was administered after a 4-month delay period under TNX-1500 monotherapy; BMT induction was comprised of one (Group 1) or two (Group 2) doses of total body irradiation, thymic irradiation, and rabbit anti-thymocyte globulin (ATG) followed by two (Group 1) or four (Group 2) weekly doses of anti-CD2 and 4 weekly treatments with αCD28 and TNX-1500.* One graft rejected during the delay period; two others exhibited moderate rejection with preserved function while five exhibited normal histology and function. Although the combination of intensified αCD2 with αCD28 promotes robust lymphocyte chimerism in this well-established delayed BMT model, the high incidence of PTLD and opportunistic infection with CMV reflects overly intense immunosuppression and prevented assessment of the regimen's effectiveness to promote alloimmune tolerance in this model."

Clinical • Bone Marrow Transplantation • Cytomegalovirus Infection • Infectious Disease • Transplant Rejection • Transplantation • CD40LG

Tonix Pharmaceuticals Announces Translation of Preclinical Pharmacokinetic Parameters of TNX-1500 (Fc-modified humanized anti-CD40L mAb) Supports Monthly i.v. Dosing in Humans (GlobeNewswire) - "Tonix Pharmaceuticals....today announced the results of modeling key human pharmacokinetic (PK) properties for TNX-1500 (Fc-modified humanized anti-CD40L monoclonal antibody, or mAb) from animal studies. TNX-1500 is in development for the prevention of rejection in solid organ and bone marrow transplantation and for the treatment of autoimmune disorders....'We look forward to the results of our Phase 1 PK and pharmacodynamic trial in the third quarter of 2024 and to advancing TNX-1500 as a promising candidate for prevention of organ and bone marrow transplant rejection and for treating autoimmune conditions.'"

P1 data • PK/PD data • Preclinical • Transplant Rejection

Tonix Pharmaceuticals Completes Clinical Stage of Phase 1 Trial for TNX-1500 (Fc-modified humanized anti-CD40L mAb) in Healthy Volunteer (GlobeNewswire) - "TNX-1500 is in development for the prevention of rejection in solid organ and bone marrow transplant and for the treatment of autoimmune disorders....'We look forward to the results of this Phase 1 trial, which are expected in the third quarter of this year, and to continuing the development of TNX-1500 as a promising candidate in an important therapeutic space.'"

P1 data • Immunology • Transplant Rejection

Tonix Pharmaceuticals Announces Two Publications of Data in American Journal of Transplantation Showing TNX-1500 (anti-CD40L mAb (Bloomberg) - "Tatsuo Kawai...said, 'The blockade of the CD40L-CD40 pathway with anti-CD40L mAbs has been the most promising immunomodulatory approach to prevent allograft rejection...The therapeutic effects of TNX-1500 to consistently inhibit rejection of mismatched kidney allografts were not associated with infectious or thromboembolic complications, suggesting that clinical studies are warranted to evaluate TNX-1500 for transplant indications.'"

Media quote

TNX-1500, an Fc-modified Anti-CD154 Antibody, Prolongs Nonhuman Primate Renal Allograft Survival. (PubMed, Am J Transplant) - "To prevent thromboembolic complications, an IgG4 anti-CD154 mAb, TNX-1500, which retains the Fab antigen binding region of ruplizumab (humanized 5c8, BG9588) was modified by protein engineering to decrease Fc binding to FcγRIIa while retaining certain other effector functions and pharmacokinetics comparable to natural antibodies. Here we report that TNX-1500 treatment is not associated with platelet activation in vitro and consistently inhibits kidney allograft rejection in vivo without clinical or histologic evidence of prothrombotic phenomena. We conclude that TNX-1500 retains efficacy similar to 5c8 to prevent kidney allograft rejection while avoiding previously identified pathway-associated thromboembolic complications."

Journal • Cardiovascular • Immune Modulation • Transplant Rejection • CD40 • CD40LG

Tonix Pharmaceuticals Announces New Data Involving TNX-1500 (Fc-modified dimeric anti-CD40L mAb) in Heart Xenotransplantation in Animal Models at the ACS Clinical Congress and IPITA-IXA-CTRMS Joint Congress (GlobeNewswire) - "Tonix Pharmaceuticals...today announced data from two oral presentations which were delivered recently at the American College of Surgeons (ACS) Clinical Congress 2023....The data involve Tonix’s TNX-1500 (Fc-modified dimeric anti-CD40L monoclonal antibody [mAb]) which is currently in Phase 1 development for the prevention of organ transplant rejection....'The results of these preclinical studies are encouraging and demonstrate the potential of genetically engineered pig hearts in the context of a clinically applicable regimen...We are currently enrolling in a Phase 1 trial in healthy volunteers to support the development of TNX-1500 for the prevention of allograft rejection.'"

Preclinical • Trial status • Transplant Rejection

Tonix Pharmaceuticals Announces Publication of Data in the Journal Nature Involving TNX-1500 (Fc-modified dimeric anti-CD40L mAb) for the Prevention of Rejection in Kidney Xenotransplantation in Animal Models (GlobeNewswire) - "Tonix Pharmaceuticals...today announced that a study published in the Journal Nature by faculty at the Center for Transplantation Sciences, Massachusetts General Hospital (MGH) in collaboration with biotechnology company, eGenesis, utilized TNX-1500 (Fc-modified dimeric anti-CD40L monoclonal antibody [mAb]) as part of the immune modulating regimen to prevent organ transplant rejection....Preclinical studies in non-human primates demonstrated that TNX-1500 showed activity in preventing allograft and xenograft organ rejection and was well tolerated."

Preclinical • Transplant Rejection

Tonix Pharmaceuticals Initiates Phase 1 Trial of TNX-1500 (Fc-modified humanized anti-CD40L mAb) in Healthy Volunteers (GlobeNewswire) - "Tonix Pharmaceuticals...today announced the initiation of a Phase 1 single ascending dose escalation study of TNX-1500 (Fc-modified humanized anti-CD40L monoclonal antibody or mAb) in healthy volunteers. The primary objectives of the study are to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenous (IV) TNX-1500....Initiation of this first-in-human study is intended to support dosing in a planned Phase 2 trial in kidney transplant recipients."

Trial status • Graft versus Host Disease • Immunology • Transplant Rejection

Tonix Pharmaceuticals Announces Presentations Involving TNX-1500 (anti-CD40L mAb) at the 2023 American Transplant Congress (GlobeNewswire) - "Tonix Pharmaceuticals Holding Corp...announced an upcoming oral presentation by Ryo Otsuka, Ph.D., and poster presentation by Kohei Kinoshita, M.D at the 2023 American Transplant Congress (ATC)...The Congress is being held June 3-7, 2023, in San Diego, Calif. The research involves studies of Tonix’s TNX-1500 (Fc-modified anti-CD40L monoclonal antibody) for the prevention of renal and cardiac allograft rejection."

Preclinical • Transplant Rejection • Transplantation

Fc-Modified Anti-Cd154 Mab Induced Long Term Renal Allograft Survival without Thromboembolic Complications (ATC 2023) - "Herein, we evaluated in vitro and in vivo, a novel Fc-modified anti-CD154 mAb (TNX-1500 or TNX), in which Fc was modified by protein engineering to decrease binding to FcγRII...In Group 2, Mycophenolate mofetil (MMF) was added but TNX was reduced to every two weeks after 6 weeks. In Group 3 (n=3), the combination of rapamycin with TNX was evaluated... TNX reliably inhibited renal allograft rejection without thromboembolism in NHPs."

Cardiovascular • Gastrointestinal Disorder • Transplant Rejection • Transplantation • CD40LG • SELP