Updated results from its Phase 1 multi-center, open-label, monotherapy study of TRPH-222 (formerly called CAT-02-106) in heavily pre-treated patients with relapsed and/or refractory (R/R) B-cell non-Hodgkin’s lymphoma (NHL) shows positive results.

TRPH-222 is an investigational antibody-drug conjugate being developed by Triphase Accelerator.

Antibody-drug Conjugates or ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies (mAbs) specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.

TRPH-222 employs RED-106, a proprietary non-cleavable 4AP linker, to deliver a microtubule-inhibiting maytansine payload (with a DAR of 1.8) to CD22-expressing cells. The anti-CD22 humanized antibody was modified to allow this site-specific conjugation.[1]

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Using Hydrazino-Pictet-Spengler (HIPSTM) chemistry, scientists developed a novel third-generation stable linker-conjugation technology known as SMARTag®. This technology platform offers a practical and efficient chemoenzymatic solution for site-specific protein modifications. A bioorthogonal aldehyde handle is introduced through the oxidation of a cysteine residue, embedded in a specific peptide sequence (CxPxR), to the aldehyde-bearing formylglycine (fGly). This enzymatic modification is carried out by the formylglycine-generating enzyme (FGE).[2]

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Licensed from Catalent Biologics, the SMARTag® technology, originally developed by Redwood Bioscience, enables site-specific, controlled drug-protein conjugation and uses only naturally occurring modifications to proteins requiring minimal cell-line engineering. This allows scientists to generate homogenous bioconjugates engineered to improve performance.[2]

CD22 as a target
In the treatment of B-cell malignancies, immunotherapeutic drugs including antibodies, antibody-drug conjugates, and chimeric antigen receptor T-cells, are playing an increasingly important role.

CD22, a B-cell-restricted cell surface sialoglycoprotein uniquely present on B-cells, is an important modulator of B-cell signaling and survival and is expressed across all subtypes of B-cell lymphomas. As a result, it is an appealing therapeutic target for B-cell malignancies.[3]

The approval of Inotuzumab ozogamicin (Besponsa®; Pfizer/Wyeth Pharmaceuticals) in 2017, an ADC that combines anti-CD22 mAb with calicheamicin, an enediyne antibiotic that mediates apoptosis and is indicated for the treatment of relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL), supports the rationale for CD22 targeting in these B-cell diseases.[4]

Safety and tolerability
This first-in-human clinical trial was designed to evaluate the safety, tolerability, and pharmacokinetics of TRPH-222 monotherapy.

As of January 7, 2022, 32 patients with R/R NHL had been enrolled: 15 indolent (14 follicular lymphomas; FL) and 1 marginal zone lymphoma; MZL)), 17 aggressive histologies (15 diffuse large B-cell lymphomas; DLBCL), 1 transformed follicular lymphoma (TFL), and 1 mantle cell lymphoma (MCL)), with a median of 4 (1-9) prior lines of therapy. A total of 22 patients were enrolled in dose-escalating cohorts of TRPH-222 (0.6 mg/kg to 10 mg/kg), and 10 patients in the dose-expansion cohort (7.5 mg/kg TRPH-222).

The study results show that adverse events were more prevalent at doses ≥7.5 mg/kg and less prevalent at lower doses. There was also a trend to higher grade adverse events in patients with aggressive histologies, compared to indolent ones.The most frequent (≥ 5%) treatment-emergent related adverse events (Grade ≥3) included thrombocytopenia (34%), neutropenia (22%), ALT/AST elevation (6%), dry eye (6%) and blurred vision (6%).

Cytopenias were non-febrile, infrequent, late-onset, asymptomatic, and resolved without significant intervention. Ocular findings were consistent with known epithelial keratopathy of ADCs and were generally low grade. Overall, TRPH-222 has a favorable safety profile with most AEs being predominantly low grade, tolerable, easily managed, and reversible.

Efficacy
Preliminary efficacy results in the trial suggest evidence of anti-tumor activity, most notably in patients with R/R FL. Of the 13 response-evaluable FL patients, 5 complete responses (CR) and 2 partial responses (PR) were observed, with an overall response rate (ORR) of 54% and a complete response rate (CRR) of 38%. Responses were generally early, durable and CRs were maintained off-therapy, with a median duration of response (mDOR) of 24.9 months (95% CI: 2.2, NR) in R/R FL. Beyond FL, CRs were also observed in 1 DLBCL patient and in 1 MCL patient.

Francisco Hernandez-Ilizaliturri, M.D. is Chief Lymphoma Section, Professor of Medicine, Department of Medicine, Head, Lymphoma Translational Research Lab and Associate Professor, Department of Immunology at Roswell Park Comprehensive Cancer Center, the nation’s first cancer center, recgnised for setting the standard for today’s multidisciplinary approach to the highest quality cancer care. Photo courtesy: © 2020 - Roswell Park Comprehensive Cancer Center, Buffalo, NY.
Francisco Hernandez-Ilizaliturri, M.D. is Chief Lymphoma Section, Professor of Medicine, Department of Medicine, Head, Lymphoma Translational Research Lab, and Associate Professor, Department of Immunology at Roswell Park Comprehensive Cancer Center, the nation’s first cancer center, recognized for setting the standard for today’s multidisciplinary approach to the highest quality cancer care. Photo courtesy: © 2020 – Roswell Park Comprehensive Cancer Center, Buffalo, NY. Used. with permission.

“TRPH-222 is a novel CD22-targeting antibody-drug conjugate with a unique efficacy and safety profile that has successfully passed the Phase 1 test. It demonstrated robust clinical activity in NHL, with durable complete responses that were enriched in FL patients. I particularly liked that my patients who achieved remissions with TRPH-222 were able to discontinue study drugs and remain in remission for extended periods of time,” noted Francisco Hernandez-Ilizaliturri, M.D., Chief of the Lymphoma Section at Roswell Park, and lead investigator for the TRPH-222-100 study.

“The durable complete responses and minimal toxicity profile associated with TRPH-222 highlight its potential to be widely integrated into current treatment regimens,” Hernandez-Ilizaliturri added.

“My experience with TRPH-222 is that it is a highly active drug, is well-tolerated, and has a good fit in FL. It was straightforward to administer to patients, with little concern for adverse events and no need for continual close monitoring,” noted John Kuruvilla, MD, Division of Medical Oncology and Hematology, Princess Margaret Cancer Center, one of the primary investigators on the TRPH-222-100 study.

John Kuruvilla, M.D., Division of Medical Oncology and Hematology, Princess Margaret Cancer Center and Department of Medicine, University of Toronto, Toronto, ON, Canada, is one of the primary investigators on the TRPH-222-100 study.© 2021 University of Toronto, Toronto, ON, Canada. Used with permission.

“In sequencing treatments pre or post CAR-T therapy, I would choose a CD22-targeted ADC over CD19-targeted therapies prior to a CD19 CAR-T regimen due to CD19 antigen shedding. An agent like TRPH-222 could easily be incorporated into CD19 CAR-T treatment algorithms,” Kuruvilla added.

Key Results

  • TRPH-222 monotherapy is well tolerated up to 10 mg/kg, with a low incidence of AEs commonly associated with ADCs, such as thrombocytopenia, neutropenia, and liver transaminase increases. Most AEs seen with TRPH-222 were predominantly low grade, tolerable, easily managed and reversible.
  • Seven complete responses (CR: 5 FL, 1 DLBCL, 1 MCL) and three partial responses (PR: 2 FL, 1 TFL) have been observed at doses from 0.6 to 10 mg/kg. Five patients with metabolic CRs that were confirmed after 3 additional cycles are now off treatment and continue in CR; 3 patients remain in CR with responses maintained for up to 25 months.
  • The observed data support further clinical studies of TRPH-222, including combinations with other anti-tumor agents in B-cell lymphoma patients. Triphase is preparing for upcoming conversations with regulatory agencies on a Phase 2 study plan.

“As a Toronto biotech company with strong local support from academic stakeholders, we look forward to advancing TRPH-222 in the clinic, as well as to growing our pipeline over the next few years,” concluded Ilse Treurnicht, Ph.D., Triphase’s Executive Chairperson.

Clinical trials
Study of TRPH-222 in Patients With Relapsed and/or Refractory B-Cell Lymphoma – NCT03682796.

Highlights of Prescribing Information
Inotuzumab ozogamicin (Besponsa®; Pfizer/Wyeth Pharmaceuticals) (Prescribing Information)

Webinar: TRPH-222 Preclinical Development and Interim Phase I Data: Enhancing Clinical Safety and Overcoming ADC Manufacturing Challenges with SMARTag® Technology (On-demand).

Reference
[1] Drake P. Catalent’s SMARTag® ADC Stands Out in the Crowd of HER2-targeted Conjugates. ADC Review | Journal of Antibody-drug Conjugates; September 29, 2020 [Article]
[2] Liu J, Barfield RM, Rabuka D. Site-Specific Bioconjugation Using SMARTag® Technology: A Practical and Effective Chemoenzymatic Approach to Generate Antibody-Drug Conjugates. Methods Mol Biol. 2019;2033:131-147. doi: 10.1007/978-1-4939-9654-4_10. PMID: 31332752.
[3] Shah NN, Sokol L. Targeting CD22 for the Treatment of B-Cell Malignancies. Immunotargets Ther. 2021 Jul 6;10:225-236. doi: 10.2147/ITT.S288546. PMID: 34262884; PMCID: PMC8275043.
[4] Aujla A, Aujla R, Liu D. Inotuzumab ozogamicin in clinical development for acute lymphoblastic leukemia and non-Hodgkin lymphoma. Biomark Res. 2019 Apr 11;7:9. doi: 10.1186/s40364-019-0160-4. PMID: 31011424; PMCID: PMC6458768.

This article was first published in ADC Review | Journal of Antibody-drug Conjugates.

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