Preclinical data for camidanlumab tesirine (formerly ADCT-301; ADC Therapeutics), published in the Journal for ImmunoTherapy of Cancer, the online journal of the Society for Immunotherapy of Cancer, supports continued evaluation of CD25-targeted ADC in Phase Ib clinical trial in selected advanced solid tumors.[1]

CD25, also known as interleukin (IL)-2Rα, is part of the heterotrimeric IL-2 receptor that regulates normal immune function and is widely expressed on the surface of leukemias and lymphomas.[1]

Camidanlumab tesirine (formerly ADCT-301) is an antibody-drug conjugate (ADC) comprised of a monoclonal antibody that binds to CD25 (HuMax®-TAC, licensed from Genmab A/S), conjugated to the pyrrolobenzodiazepine (PBD) dimer payload, tesirine.[2]

In preclinical models, camidanlumab tesirine, which is currently being evaluated in multiple clinical trials in Hodgkin and non-Hodgkin’s lymphoma (NCT02432235 and NCT04052997), has shown with promising interim results.[2]

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Once bound to a CD25-expressing cell, camidanlumab tesirine is internalized into the cell where enzymes release the PBD-based warhead killing the cell. This applies to CD25-expressing tumor cells, and also to CD25-expressing Tregs.

Regulatory T cells (Tregs) contribute to an immunosuppressive tumor microenvironment and play an important role in the establishment and progression of tumors with high Tregs infiltration and present a major obstacle to tumor eradication by immunotherapies.  Over the last decades, researchers have developed various strategies in an attempt to deplete or block Tregs. The results of these attempts have, however, been limited.[1]

Bystander killing
The intra-tumoral release of its PBD payload may also cause bystander killing of neighboring tumor cells and PBDs have also been shown to induce immunogenic cell death. All these properties of camidanlumab tesirine may enhance immune-mediated anti-tumor activity.

Camidanlumab tesirine is being evaluated in a pivotal Phase II clinical trial in patients with relapsed or refractory Hodgkin lymphoma, as well as in a Phase Ia/Ib clinical trial in patients with relapsed or refractory Hodgkin lymphoma and non-Hodgkin lymphoma and a Phase Ib clinical trial in solid tumors.

The study evaluated the antitumor activity of a pyrrolobenzodiazepine (PBD) dimer-based, CD25-targeted ADC, either alone or in combination with a checkpoint inhibitor, in CD25-negative syngeneic colon cancer models that exhibit tumor infiltration of CD25-expressing regulatory T cells (Tregs). Data demonstrated that single low doses of the CD25-targeted ADC resulted in potent and durable antitumor activity against established CD25-negative solid tumors with infiltrating Tregs, both as a monotherapy and in combination with an anti-PD1 checkpoint inhibitor.

ADCs as immunotherapeutic agents
Based on the results of the study, the investigators conclude that a PBD dimer-based, CD25-targeted ADC is able to deplete Tregs and eradicate established tumors via antitumor immunity. This represents a novel approach to efficiently deplete Tregs via a very potent DNA damaging toxin known to induce immunogenic cell death.[1]

“CD25 is expressed on Tregs that infiltrate the local tumor environment. We were pleased to see that our CD25-targeted ADC depleted CD25-expressing Tregs and not only showed strong anti-tumor activity as a monotherapy in preclinical models, but it also enhanced the activity of anti-PD1 treatment in these models,” noted  Patrick van Berkel, Ph.D., Senior Vice President of Research and Development at ADC Therapeutics.

“This study provides proof of concept for a new application of ADCs as immunotherapeutic agents and supports the continued evaluation of camidanlumab tesirine in our ongoing Phase Ib clinical trial in patients with selected advanced solid tumors. We look forward to advancing the exploration of camidanlumab tesirine as a novel immune-oncology approach for the treatment of solid tumors,” Van Berkel concluded.

Clinical trials
Study of ADCT-301 in Patients With Relapsed or Refractory Hodgkin and Non-Hodgkin Lymphoma – NCT02432235
Study to Evaluate the Efficacy and Safety of Camidanlumab Tesirine (ADCT-301) in Patients With Relapsed or Refractory Hodgkin Lymphoma – NCT04052997
Study of ADCT-301 in Patients With Selected Advanced Solid Tumors – NCT03621982

Reference
[1] Zammarchi F, Havenith K, Bertelli F, et al. CD25-targeted antibody-drug conjugate depletes regulatory T cells and eliminates established syngeneic tumors via antitumor immunity. Journal for ImmunoTherapy of Cancer2020;8:e000860. doi:10.1136/jitc-2020-000860 [Download the Article]
[2] Flynn MJ, Zammarchi F, Tyrer PC, Akarca AU, Janghra N, Britten CE, Havenith CEG, Levy JN, et al. ADCT-301, a pyrrolobenzodiazepine (PBD) dimer-containing antibody-drug conjugate (ADC) targeting CD25-expressing hematological malignancies. Mol Cancer Ther 2016;15:2709–21.doi:10.1158/1535-7163.MCT-16-0233 [Pubmed][Article]

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