ASH 2025 | Targeting ROR1 and ROR2 for the treatment of CLL and other B-cell malignancies

Yeah, we’ve been interested for some time about an orphan receptor called ROR1, and we first discovered that it’s expressed in CLL, but not in normal B-cells, and that gave us sort of an excitement that we might have a hook on the leukemia, be able to target ROR1 and not actually affect normal B-cells. As you know, the use of anti-CD20 antibodies targets not only the leukemia cells, but also normal B-cells. And consequently, we’ve seen that there’s a depletion of normal B-cells and a lowering of serum immunoglobulin levels that is associated with increased immune suppression and increased prevalence of infection after therapy. So being able to target the leukemic cells specifically has long been a recognized goal of ours. We did establish antibodies that we found could block the signaling of the ROR1 molecule and this was very important, we thought, could be used, but it did not really activate killing of the leukemic cells and we actually have been able to observe the outcome of clinical trials done with this antibody that blocked signaling, we’ve had some very interesting observations. But more specifically with regard to antibodies that can directly kill the tumor cells, such as rituximab or more recently obinutuzumab, the antibodies can be engineered to be able to direct what’s called antibody-dependent cellular cytotoxicity, or ADCC. ADCC uses the body’s own immune system with T-cells and NK-cells that have an Fc receptor, which is called CD16. And using the Fc receptor, they can actually go after cells that are labeled or targeted with the antibodies. And so we designed ways to modify the antibodies that allowed the CD16 molecule to bind very avidly. And that allowed the NK-cells and the T-cells the ability to go out and target the leukemic cells that express ROR1. We’re very excited about the potential of using these antibodies. And in data that’s going to be presented here, we have the data on not just ROR1, but another antibody, which we’ve been working on, ROR2. We found that both ROR1 and ROR2 are expressed, for example, on hairy cell leukemia. And so I think that this allows us to target both antigens at the same time and see what happens. And I think with one antibody, we’re able to gain the ability to target the leukemic cells with efficiency that’s on par with rituximab, which everyone knows has been quite effective and useful in therapy of patients with B-cell malignancies. But the combination actually seems to have an additive effect. And so therefore, we think that the combination strategy with these new engineered antibodies might actually be very effective in being able to clear the leukemic cells and also mitigate the risk of further immune suppression that we have with our anti-CD20 antibodies.

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