CC-1 Antibody

What is the structural design of CC-1 antibody?

CC-1 is designed in an IgG-based bispecific antibody format (IgGsc) originally published by Coloma and Morrison. The antibody contains humanized 10B3 domains and a humanized form of the CD3 antibody UCHT1. This IgGsc format differs from alternative formats like Fabsc in valency and molecular weight. The structure includes specific point mutations or deletions to ensure abolishment of Fc receptor binding, preventing undesired T-cell activation while maintaining binding to FcRn . Analysis by SDS-PAGE and gel filtration confirms the expected molecular weights and lack of significant aggregation tendencies .

What is the mechanism of action for CC-1 antibody?

CC-1 functions through dual targeting of PSMA (prostate-specific membrane antigen) on tumor cells and CD3 on T cells. The antibody binds to a unique PSMA epitope expressed on malignant cells in prostate carcinoma and in approximately 50% of squamous cell carcinoma of the lung . This binding facilitates targeted T-cell recruitment and activation specifically at tumor sites. Unlike conventional bispecific antibodies, CC-1's design ensures that T-cell activation occurs strictly at target sites, reducing off-target toxicity while preserving efficacy . This target-restricted activity represents a significant advancement over existing approaches where systemic T-cell activation leads to dose-limiting toxicities.

How does CC-1 differ from other T cell-engaging bispecific antibodies?

CC-1 distinguishes itself through several key features:

• Target-restricted activity: Unlike many bispecific antibodies that cause systemic T-cell activation, CC-1 demonstrates fully target cell-restricted T cell activity .

• IgG-based format: The IgGsc format provides prolonged half-life compared to smaller bispecific formats .

• PSMA epitope specificity: CC-1 binds a unique PSMA epitope, allowing it to target both prostate cancer and certain lung cancers .

• Modified Fc region: The antibody contains specific mutations to abolish FcR binding, preventing non-specific T-cell activation while maintaining FcRn binding for extended half-life .

• Clinical pharmacokinetics: CC-1 achieves serum concentrations up to 200-500 ng/ml, which is more than two orders of magnitude higher than benchmark bispecific antibodies like Blinatumomab .

What strategies were employed to reduce off-target T-cell activation with CC-1?

Several sophisticated engineering strategies were implemented to minimize off-target effects:

• Fc silencing mutations: A combination of point mutations or deletions was employed to abolish Fc receptor binding, which was confirmed experimentally. The modified CC-1 does not bind to any FcR except FcRn, which is essential for maintaining circulation half-life .

• Unique PSMA epitope selection: By targeting a specific PSMA epitope, CC-1 achieves more precise targeting of malignant cells .

• Optimized IgGsc format: The IgGsc format was specifically selected to ensure strict target-restricted T-cell activation, reducing systemic effects .

• Minimal aggregation tendency: The CD3 targeting component was previously selected for minimal aggregation tendency, which helps prevent non-specific activation .

What is the clinical management approach for cytokine release syndrome (CRS) during CC-1 therapy?

Management of CRS is a critical component of CC-1 clinical protocols:

In clinical studies, preemptive administration of tocilizumab (an anti-IL-6R antibody) was employed as soon as patients developed fever ≥38.5°C. This approach was selected over intravenous steroids because tocilizumab does not interfere with T-cell activation either in vitro or in vivo . When managed this way, most patients experienced only manageable CRS (maximum grade 2) in 88% of cases, with no further CC-1 related toxicities beyond grade 1-2 hypertension (46%) and xerostomia (8%) .

For researchers designing protocols, this represents an important methodological consideration, as the preemptive tocilizumab approach allows for reaching higher therapeutic doses while protecting patients from severe CRS .

How does tumor microenvironment influence CC-1 efficacy?

The efficacy of CC-1 is uniquely influenced by its dual ability to target both malignant cells and tumor neovasculature. PSMA expression on tumor neovasculature improves accessibility of the tumor site for immune effector cells, which is a critical prerequisite for success in solid tumors . This vascular targeting represents an advantage for overcoming the immunosuppressive tumor microenvironment barriers that have limited other immunotherapeutic approaches.

Researchers investigating CC-1 should assess both direct tumor cell expression of PSMA and vascular PSMA expression in their experimental models to accurately predict potential efficacy. Methodologically, this requires dual immunohistochemical assessment approaches rather than simple tumor cell analysis .

What are the considerations for dose optimization in CC-1 clinical research?

The dose optimization strategy for CC-1 employs an innovative approach:

Clinical trials utilize a novel intra-individual dose escalation design to rapidly reach the target dose (826μg) . This methodology allows for:

• Faster identification of maximum tolerated dose (MTD)

• Reduced patient exposure to sub-therapeutic doses

• More efficient phase I trial completion

This approach enabled researchers to define MTD without dose-limiting toxicities (DLTs) upon treatment of the 9th and 14th patients, respectively . For researchers designing similar studies, this intra-individual escalation design represents a methodological innovation that could accelerate early-phase clinical development.

What biomarkers are recommended for monitoring CC-1 efficacy?

Based on clinical experience, several biomarkers have proven valuable for monitoring CC-1 activity:

• PSA levels: A rapid and profound decline of elevated PSA levels was observed in nearly all patients, with up to 60% reduction compared to baseline . Serial PSA measurements can track therapeutic response.

• T-cell activation markers: All patients demonstrated profound T-cell activation, which can be monitored via flow cytometry for activation markers .

• Serum cytokine profiles: As CRS is a common on-target effect, monitoring cytokine profiles provides insight into immune activation dynamics .

• PSMA expression: Pre-treatment assessment via MRT and PET scans with PSMA-specific tracers is essential to confirm target expression .

For researchers, implementing a comprehensive biomarker strategy that incorporates these parameters provides a multi-dimensional view of therapeutic activity.

What approaches are recommended for studying combinatorial strategies with CC-1?

When designing combinatorial approaches with CC-1, researchers should consider:

• Checkpoint inhibitor combinations: The favorable safety profile of CC-1 makes it suitable for combination with immune checkpoint inhibitors, as demonstrated in the ongoing clinical trial for SCC of the lung (NCT04496674) .

• Assessment of treatment sequencing: Strategic timing of CC-1 administration relative to other therapies may impact efficacy and toxicity profiles.

• Cytokine preconditioning: Considering the role of the tumor microenvironment, studies examining pre-treatment with cytokine-modulating agents could be valuable.

• Early intervention approaches: Based on the promising results in the hormone-sensitive biochemical recurrence setting, studies examining CC-1 in earlier disease stages where tumor burden is lower may offer enhanced efficacy with reduced toxicity .

What in vitro assays best capture CC-1's mechanism of action?

To properly evaluate CC-1's activity in experimental settings, researchers should employ:

• Target-restricted T cell activation assays: These should measure T-cell activation specifically in the presence of PSMA-expressing target cells.

• Mixed lymphocyte-tumor cell co-cultures: Using PSMA+ and PSMA- tumor cell lines to demonstrate specificity.

• FcR binding assays: To confirm the absence of non-specific Fc-mediated effects .

• 3D spheroid penetration models: To assess the ability of CC-1 to facilitate T-cell infiltration into solid tumor structures.

• Tumor vasculature co-culture systems: To evaluate the dual targeting of tumor cells and neovasculature.

What patient populations are being evaluated for CC-1 therapy?

Current clinical investigations are exploring CC-1 in multiple clinical scenarios:

• Metastatic castration-resistant prostate carcinoma (mCRPC): The primary indication being studied in the NCT04104607 trial .

• Squamous cell carcinoma of the lung: Being explored in combination with checkpoint inhibition in NCT04496674 .

• Hormone-sensitive biochemical recurrence (BCR) of prostate cancer: As first-line treatment in patients with low tumor burden, where lower side effects and long-lasting efficacy are expected (NCT05646550) .

This diversified clinical development strategy highlights the potential versatility of CC-1 across multiple PSMA-expressing malignancies and disease stages.

How does the pharmacokinetic profile of CC-1 compare to other therapeutic antibodies?

CC-1's pharmacokinetic profile demonstrates several advantages:

In first-in-human applications, CC-1 achieved serum concentrations of up to 200–500 ng/ml, which is more than two orders of magnitude higher than those achieved with benchmark bispecific antibodies like Blinatumomab . This superior pharmacokinetic profile is attributable to:

• The IgGsc format, which provides extended circulation time

• Retained FcRn binding despite Fc silencing mutations

• Optimized antibody design with minimal aggregation tendency

Researchers should consider these pharmacokinetic advantages when comparing CC-1 to other immunotherapeutic approaches or when designing dosing schedules.

What are the emerging applications of CC-1 beyond prostate cancer?

The unique PSMA epitope targeted by CC-1 has applications beyond prostate carcinoma:

• Squamous cell carcinoma of the lung: Up to 50% of these patients express the PSMA epitope recognized by CC-1, opening therapeutic opportunities in this indication .

• Tumor neovasculature targeting: PSMA expression on tumor vasculature in various solid tumors suggests potential applications beyond the currently studied indications .

For researchers exploring new applications, validation of PSMA expression patterns in candidate tumor types is an essential preliminary step. Methodologically, this requires both tumor cell and vascular staining approaches to fully assess targeting potential.