Authored by Brian Koffman, MDCM (retired), MSEd
Bottom Line:
Bispecific antibodies show promise in CLL but can cause CRS and neurotoxicity. AZD5492 is a novel trispecific antibody that engages mainly CD8+ T cells in the hope of reducing adverse events.
Who Performed the Research and Where Was it Presented:
Rachel Lawrence of AstraZeneca presented this pre-clinical oral presentation at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
The potential of the bispecific antibodies is stifled by their toxicities.
This is a pre-clinical trial. There are no human data yet, but they are coming. This research is pushing for an exciting new refinement of an already strong immunotherapy.
All the experimental bispecific and the new trispecific (three-armed) AZD5492 antibodies being developed for chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) work by targeting the cancer cells and, unfortunately, all normal B cells with their CD20 antibody arm.
However, unlike all the other bispecific monoclonal antibodies that engage all T cells (both CD4+ and CD8+), with their CD3 arm, the novel trispecific AZD5492 preferentially attaches to the CD8+ T cells by targeting CD8 and TCR (T- cell receptor) on their second and third arms. The hope is that this will lead to less cytokine release and, therefore, less cytokine release syndrome (CRS) and neurotoxicity without lessening the potent cancer-killing of the immunotherapy. While it is an oversimplification, CD8+ T are considered the actual killer (cytotoxic) T cells, and CD4+ T cells are the helper cells that release cytokines to guide and enhance the attack on the cancer.
Methods and Participants:
This was pre-clinical research done in humanized mice engrafted with B cell tumors and in healthy non-human primates (cynomolgus monkeys).
Results:
In the mice:
- AZD5492 reduced the B cell tumor load in an effective and dose-dependent manner.
- Compared to conventional bivalent CD20xCD3 bispecific antibodies, there was significantly less systemic cytokine production but similar anti-cancer activity.
In cynomolgus monkeys followed for one month post dosing:
- CD19+ and CD20+ B cells were significantly and persistently reduced in the blood and in tissues (lymph nodes, spleen, and bone marrow). Keep in mind that these were normal monkeys with no B cell lymphomas, including no CLL. What was found was that the monkey’s normal B lymphocytes were depleted by the study drug.
- Cytokine levels went up with the first dose, but there didn’t appear to be any clinical toxicity.
Conclusions:
AZD5492 is a new type of T cell engager for the treatment of CLL / SLL and other B cell lymphomas. Compared to epcoritamab and the other CD20xCD3 bispecific antibodies, it seems to cause less cytokine release in mice and to be safe and well tolerated in monkeys. However, the results for mice and monkeys don’t always equate with the results for humans. The hope is that AZD5492 will prove to be a safer and equally effective immunotherapy for CLL / SLL that is better tolerated and easier to manage. That could expand the uptake of this immunotherapy in CLL / SLL. Its mechanism of action and this pre-clinical data give reason to be hopeful, but it is very early in the process. The first in-human study is now open for patients with relapsed / refractory non-Hodgkins lymphoma and CLL.
Links and Resources:
Listen to Dr. Koffman’s monologue below.
Read the ASH 2024 abstract: Pre-Clinical Evaluation of AZD5492, a Novel CD8-Guided T Cell Engager, for B-Non Hodgkin Lymphoma Indications.
To learn about the “TITANium” clinical trial using AZD5492, visit: A Study to Evaluate Safety, PK, PD and Efficacy of AZD5492, a T Cell-engaging Antibody Targeting CD20 in Subjects With R/R B-Cell Malignancies.
