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CD46 as an Imaging and Therapeutic Target for Prostate Cancer

CD46 is a type I membrane protein that binds to C3b and C4b, offering protection against complement-dependent cytotoxicity.1 In essence, it is an inhibitor complement receptor that serves as a negative regulator of the complement system.2 Therefore, it is logical that it would be upregulated during tumorigenesis to help early cancer cells evade immune detection and complement-dependent killing.3 In evaluating metastatic castration-resistant prostate cancer patients, CD46 mRNA levels are actually even higher than prostate-specific membrane antigen (PSMA); this could potentially be an encouraging imaging and therapeutic target, given the prior successes of PSMA-targeting in both of these areas.4

Not only is CD46 overexpressed in primary prostate tumor tissue and metastatic castration-resistant prostate cancer, but it is also highly expressed in neuroendocrine prostate cancer.4 Importantly, it is expressed at low levels in normal tissues. Non-clinical studies show that treatment with an androgen receptor pathway inhibitor (e.g. abiraterone or enzalutamide) upregulates cell surface expression of CD46.

As a result, FOR46 was developed as a novel antibody drug conjugate against CD46. It includes Ys5FL, which is a fully human IgG1 monoclonal antibody that targets a tumor-selective epitope of CD46.4,5 The payload is monomethyl auristatin E, a well-established toxophore, used in other successful antibody drug conjugates e.g. enfortumab vedotin. Pre-clinical xenograft studies using DU145 prostate cancer subcutaneous and intrafemoral models have shown a dose-dependent growth inhibitory effect on tumor volume.4

An initial Phase 1a/1b clinical trial with FOR46 as monotherapy enrolled 33 patients in phase 1a and 10 patients in phase 1b with metastatic castration-resistant prostate cancer.6 Fourteen of 31 evaluable patients (45.2%) achieved a 50% or greater PSA decline with 10 (32.3%) being confirmed responses. Of the 18 patients with measurable disease, 8 of 18 (44.4%) had some degree of tumor regression, while 4 (22.2%) had a confirmed partial response. Key toxicities of neutropenia and fatigue were noted in patients with body mass indices >30 and subsequent dosing was calculated using adjusted body weight, rather than actual weight.

Most recently, at ASCO 2024, we saw the first hints of combination FOR46 with enzalutamide data in patients with metastatic castration-resistant prostate cancer.7 This is an ongoing, actively enrolling phase 1b/2 clinical trial using this combination treatment in patients who have progressed after receipt of prior abiraterone acetate. Of the 17 patients with reported data, 12 of 17 (71%) experienced a post-treatment decline in PSA level. What is fairly impressive is that 5 of the 12 patients with PSA decline had previously received and progressed on enzalutamide. Two of 17 (11.8%) patients had a 50% or greater PSA decline from baseline. The most common treatment-related adverse events were fatigue (65%), peripheral sensory neuropathy (47%), decreased appetite (41%), and neutropenia (18%), with 12% being a grade 3 event. Accrual is currently ongoing to the phase 2 portion of the trial and [89Zr]-YS5 PET imaging is being performed at baseline in a companion study to determine its potential utility as a treatment selection biomarker.

Below, I list a couple of actively accruing trials that target CD46. This includes not only a therapeutic trial but a trial focused on novel prostate cancer imaging of CD46.

Ongoing clinical trials that target CD46 in prostate cancer

  • [89Zr]-DFO-YS5 PET imaging CD46 (NCT05245006)
  • FOR46 in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (NCT05011188)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Cardone J, et al. CD46 in innate and adaptive immunity: an update. Clin Exp Immunol 2011; 164:301-11.
  2. Liszewski MK, et al. Complement regulator CD46: genetic variants and disease associations. Hum Genomics 2015; 9:7.
  3. Fishelson Z, et al. Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors. Mol Immunol 2003; 40:109-23.
  4. Su Y, et al. Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer. JCI Insight 2018; 3:e121497.
  5. Sherbenou DW, et al. Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells. J Clin Invest 2016; 126:4640-53.
  6. Aggarwal RR, et al. FOR46 Shows Early Antitumor Activity in Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 40, 2022 (suppl 16; abstr 3001).
  7. Shakhnazaryan N, et al. A phase 1b dose escalation study of FOR46, a novel antibody-drug conjugate targeting a tumor-specific epitope of CD46, in combination with enzalutamide (Enza) in patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol 42, 2024 (No 16_suppl abstr 5066).