New Treatment Pathways for CD73-Expressing Tumors

Tumor Cell: ©nevio - stock.adobe.com

Cidara Therapeutics aims to commence trials of CBO421, a CD73-targeting drug Fc conjugate (DFC) and a promising development candidate, in the coming year. Investigational new drug (IND)-enabling studies and FDA meetings are crucial for shaping the protocol of a phase 1/1b study of the agent for treating solid cancers.¹

CBO421 has a unique combination of small molecule and monoclonal antibody attributes. While small molecules excel in accessing cryptic binding sites, their tendency to penetrate cells can lead to off-target toxicities, posing dosing limitations, especially in oncology. The CBO421 agent overcomes these challenges by enhancing small molecule potency through multiple copies.

Preclinical findings of CBO421 were presented at the Society for Immunotherapy of Cancer (SITC) Annual Meeting, held November 1-5, 2023. In animal-to-tumor models, CBO421 demonstrated specific activity as a monotherapy and enhanced potency in combination with a PD-1 inhibitor in the treatment of CD73-expressing solid tumors.

Addressing an unmet need in immuno-oncology, CBO421's smaller size facilitates deeper tumor penetration, suggesting a potential for a broader patient response compared to with existing therapies. Notably, its subcutaneous or intramuscular administration aligns with the trend of next-generation PD-1 inhibitors, offering a significant advantage over monoclonal antibodies and facilitating complementary administration with PD-1 inhibitors.

In an interview with Targeted Oncology^TM, Jeff Stein, PhD, president and chief executive officer of Cidara Therapeutics, CBO421’s manufacturer, discussed the future of CD73-targeting agents.

Jeff Stein, PhD

Targeted Oncology: What is CBO421?

Stein:The CBO421 is a development candidate, and our goal is to initiate clinical trials in the middle of next year. Currently, we are finalizing the IND-enabling studies and scheduling meetings with the FDA. These discussions are crucial for settling the protocol details for the upcoming phase 1/1b study. This study will assess the efficacy of CBO421 both as a standalone treatment and in combination with a PD-1 inhibitor.

What makes this molecule particularly exciting is that it combines the attributes of both small molecules and monoclonal antibodies. Each of these has its own set of strengths and weaknesses. Small molecules can access cryptic binding sites that are not available to most monoclonal antibodies. They can bind to go to[and] active sites. But a downside of small molecules is that they do penetrate cells, and so they can be responsible for off-target toxicities, which can lead to dosing limitations, particularly in oncology.

Also, they tend not to have very long half-lives. Consequently, since the small molecules are developed to be orally available, there are limitations on how potent you one can make them.

[We are] really limited in chemical space if [we] want to have an oral drug [and see] how much potency [we] can dial in without inducing undue toxicities. With our [DFC system], we use small molecules. In the case of CBO421, you can see there are multiple copies of that small molecule inhibitor on each DFC. The ability to array multiple copies enhances the potency of the small molecules.

The fact that we don’t need to make these orally available provides us greater flexibility in the chemical space to engineer exquisitely potent molecules. By having multiple copies of those on each DFC, there’s an amplification of potency such that one molecule has much more potency than a single small molecule by itself. And then, the whole toxicity aspect is greatly improved, because these don’t penetrate cells. We do have a limitation of targeting external targets on tumors.

What findings were presented at SITC 2023?

At the SITC conference, it was really the first robust disclosure of CBO421. It also shows that, like monoclonal antibodies, it results in receptor internalization. That’s an advantage that monoclonal antibodies have over small molecules, but because CBO421 is a biologic, it has both activities, so it results in receptor internalization as well as having that exquisitely high potency of a small molecule hitting the CD73 target.

It clearly shows specific activity as a monotherapy, which is required and differentiates it from other CD73 inhibitors in how robust that activity is. Then we show that in combination with a PD-1 inhibitor, you see [there is] an enhancement of potency to the extent that we get a high proportion of complete responses in these animal-to-tumor models.

What unmet needs still exist?

The unmet need is really getting a larger proportion of patients that will respond. So immuno-oncology, obviously, is a very successful area. In patients where it works, it works quite well. The problem is that only a small proportion of patients respond to immuno-oncology therapy. What we have shown with CBO421, is that because it’s a smaller molecule than monoclonal antibodies, it actually penetrates tumors to a greater extent. The animal efficacy data we show clearly indicates that we have an opportunity to get a broader response rate of CBO421, which means that we think that a higher proportion of patients can be responsive to CBO421 compared [with] existing small molecule or monoclonal antibodies.

We see with this molecule, there are two 2 things I think bode well for the program. Number 1 is that, unlike monoclonal antibodies, we’ve already demonstrated clinically in our influenza program that it can be administered subcutaneously or intramuscularly. We get very high exposure. The trend in next-generation PD-1 inhibitors is that they are really focused on administering them by a subcutaneous administration. That’s going to be an really important advantage over any monoclonal antibody, because CD73 inhibitors will never be developed as a standalone drug. They will always be developed to enhance the potency of a PD-1 inhibitor, so it will be important that you can have similar routes or the same route of administration.

REFERENCES:

1. DöhrmannS, Levin J, Dedeic N, et al. Discovery of CBO421, a first-in-class drug FC conjugate (DFC), targeting CD73 in cancer. Presented at the Society for Immunotherapy of Cancer Annual Meeting 2023; November 1-5, 2023; San Diego, California. Abstract 1195.