RE:RE:RE:CD8+ TiLs and T-cell exhaustion 2023 - Janux Therapeutics is betting that its pipeline of biomarker-driven T-cell engagers will overcome limitations typically seen in this class of immunotherapies, such as cytokine release syndrome and a short duration of response.
Bispecific T-cell engager (BiTE) immunotherapies comprise two epitopes: one that binds a tumor-associated antigen expressed on the tumor cell and one that binds a T-cell receptor antigen. The purpose of the design is to recruit T cells directly to the tumor microenvironment and avoid mechanisms of tumor evasion and resistance to checkpoint inhibitors.
Amgen's Blincyto (blinatumomab), which binds CD19 on B-cell lymphoblasts and CD3 on T cells, was the first BiTE immunotherapy approved by the US Food and Drug Administration in a cancer indication. The agency granted accelerated approval to the drug in 2014 as a treatment for patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) and for CD19-positive B-cell precursor ALL in 2018. Those accelerated approvals have since been converted to full approvals.
Other BiTE immunotherapies approved by the FDA include Janssen's BCMA/CD3 T-cell engager Tecvayli (teclistamab) in October 2022 and Roche's CD20/CD3-directed T-cell engager Lunsumio (mosunetuzumab) in December 2022 for multiple myeloma and follicular lymphoma, respectively.
However, success in solid tumors has been more elusive with BiTE immunotherapies due to mechanisms that suppress T cells within the tumor microenvironment and limit T-cell infiltration. Toxicities resulting from off-target effects on healthy tissue such as neurotoxicity and cytokine release syndrome have also challenged the use of this class of drugs in solid tumors.
San Diego-headquartered Janux was founded in 2017 to develop T-cell engagers with high tumor-specific activity. The central problem faced by drugmakers in this space, according to Janux President and CEO David Campbell, is that there are very few targetable antigens on a tumor cell that are truly cancer specific. "Invariably, they're also expressed in healthy tissue," said Campbell.
Janux is hoping to tackle the problem by designing molecules with a peptide "mask" covalently bound to the tumor antigen binding domain, either CD3 or CD28, via a tumor-specific cleavable peptide linker. The mask prevents the antibody from binding to a cell until it is removed by tumor-specific proteases, thereby avoiding healthy cells.
Janux is building two lines of products using this technology. The tumor-activated T-cell engager (TRACTr) platform produces T-cell engagers with a tumor antigen-binding domain and a CD3 T-cell binding domain. In contrast, the tumor-activated immunomodulator (TRACIr) platform produces bispecifics with a tumor antigen-binding domain and a costimulatory CD28 binding domain.
In preclinical studies, Janux's lead agent JANX007, which is a prostate-specific membrane antigen (PSMA)- and CD3-directed T-cell engager, showed enhanced safety and pharmacokinetic properties and activated T cells at 500-fold lower potency compared to a non-masked PSMA-directed T-cell engager. PSMA is overexpressed in more than 80 percent of prostate cancers.
Based on these preclinical insights, the company is conducting a Phase Ia trial in which metastatic castration-resistant prostate cancer (mCRPC) patients will receive JANX007 by intravenous infusion once a week in 21-day cycles. Investigators will increase the dose until a maximum-tolerated dose is identified, and then in the expansion stage, patients will receive doses at previously identified tolerable levels. Investigators are monitoring prostate-specific antigen (PSA) levels and PSMA expression in relation to patient response.
Janux's second clinical stage program is an EGFR/CD3-directed T-cell engager, JANX008. In preclinical studies, JANX008 demonstrated improved safety and pharmacokinetics compared to a non-masked EGFR-directed T-cell engager and had potent activity in multiple ex vivo and in vivo colorectal cancer models.
Based on this, the firm began a Phase I trial of the drug in April in patients with advanced or metastatic solid tumors, focusing on colorectal cancer, squamous cell carcinoma of the head and neck, non-small cell lung cancer, and renal cell carcinoma. Campbell said the company chose those four tumor types because EGFR is overexpressed in anywhere from 50 percent to 95 percent of patients.
According to Campbell, an EGFR-directed T-cell engager has the advantage over a small molecule EGFR inhibitor in that it can trigger the immune system to recognize and eliminate the tumor. "What we've all seen from the early checkpoint antibodies … is that when that immune system is triggered — and triggered well — some patients actually have such a long-lived response that you could almost use the word cure," he said.
Janux is hoping it can bring the long-lasting responses seen in some patients with Merck's Keytruda (pembrolizumab) and Bristol Myers Squibb's Opdivo (nivolumab) to those with EGFR-expressing solid tumors using its T-cell engager approach, though Campbell cautioned that its therapy programs are too early in development to demonstrate those types of enduring benefits. Additionally, Campbell said the resistance mechanisms associated with approved EGFR inhibitors are simply not relevant to EGFR-directed T-cell engagers because while mutations in EGFR can contribute to resistance to EGFR inhibitors, they do not affect T-cell engagers, which will recruit T cells when EGFR expression is present regardless of any mutations.
Janux is also developing two TRACTr programs under a 2020 collaboration agreement with Merck. In exchange for an exclusive worldwide license to products developed from the collaboration.
According to Campbell, Janux is "in dialogue" with most of the major players in the pharmaceutical industry regarding further partnership opportunities for its programs.
Cetuximab is the most widely studied anti-EGFR monoclonal antibody. Other monoclonal antibody agents under investigation are panitumumab, matuzumab, MDX-447, nimutozumab, and mAb806. Extensive research has also evaluated the efficacy of EGFR tyrosine kinase inhibitors such as erlotinib, gefitinib, EKB-569, lapatinib (GW572016), PKI-166, and canertinib (CI-1033). All of these agents have been studied for the treatment of colorectal, lung, breast, pancreatic, renal, head and neck, gynecologic, and prostate cancer. Currently, cetuximab and panitumumab are FDA approved for the treatment of metastatic colorectal cancer. Additionally, cetuximab is approved for head and neck cancer. Erlotinib is FDA approved for advanced/metastatic lung cancer. Erlotinib in combination with gemcitabine is approved for advanced/metastatic pancreatic cancer treatment.
https://www.precisionmedicineonline.com/precision-oncology/janux-therapeutics-aiming-develop-safer-t-cell-engagers-enduring-efficacy