AG-01 Antibody Therapy for Advanced Cancers

Overseen by Katherine Tkaczuk, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: A&G Pharmaceutical Inc.

Must not be taking: Investigational agents

Disqualifiers: Uncontrolled illness, CNS metastases, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests AG01, a protein that targets PGRN/GP88 on cancer cells, in patients with advanced cancers who haven't responded to other treatments. The goal is to see if AG01 can help control cancer growth by binding to PGRN/GP88. AG01 is a treatment that has been shown to reduce the growth and spread of certain cancer cells.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you must stop taking your current medications. However, you must be at least 4 weeks after your last dose of chemotherapy or radiation therapy (6 weeks for mitoxantrone or mitomycin therapy) and cannot be on any other investigational agents or have participated in an investigational drug study within 28 days prior to starting this trial.

What data supports the idea that AG-01 Antibody Therapy for Advanced Cancers is an effective treatment?

The available research shows that progranulin (GP88) is linked to cancer progression and survival, particularly in breast cancer. High levels of GP88 are associated with worse outcomes in breast cancer patients. While the research does not directly test AG-01 Antibody Therapy, it suggests that targeting GP88 could be beneficial. This implies that AG-01, which targets GP88, might help improve outcomes for patients with advanced cancers by potentially reducing cancer progression and improving survival. ^{1 2 3 4 5}

What safety data is available for AG-01 Antibody Therapy?

The provided research does not contain specific safety data for AG-01 Antibody Therapy or its related names (AG01 Compound, Anti-Progranulin/GP88 Antibody, Anti-Progranulin Monoclonal Antibody AG01). The studies focus on different antibodies and their safety profiles, such as anti-LRG1 ADC, anti-AGR2 monoclonal antibody, and TAK-264, but none mention AG-01 or its variants. Therefore, no direct safety data for AG-01 is available in the provided research. ^{6 7 8 9 10}

Is the AG01 Compound treatment a promising therapy for advanced cancers?

Yes, the AG01 Compound, which targets progranulin (GP88), shows promise as it is involved in cancer growth and survival. Studies suggest that GP88 plays a significant role in tumor development and progression, making it a valuable target for cancer treatment. ^{1 2 4 11 12}

Research Team

Katherine Tkaczuk, MD

Principal Investigator

University of Maryland, Baltimore

Eligibility Criteria

This trial is for adults with advanced solid tumors who have failed standard treatments. It includes those with specific types of lung, breast, and mesothelioma cancers. Participants must have measurable metastatic lesions, be in a stable condition, and use effective contraception. Those with certain recent malignancies or uncontrolled illnesses are excluded.

Inclusion Criteria

I am eligible regardless of my gender or ethnicity.

I am able to care for myself and perform daily activities.

You have at least one visible and measurable spread of cancer according to specific medical guidelines.

Exclusion Criteria

I am not currently on any experimental drugs and haven't been in the last 28 days.

I am not pregnant or breastfeeding.

I haven't had any cancer except skin cancer or in-situ cancer in the last 2 years.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (1A)

Participants receive increasing doses of AG01 to evaluate maximum tolerated dose and safety

28 days per cycle

2 infusions per cycle (Day 1 and Day 15)

Dose Expansion (1B)

Participants receive AG01 at the recommended phase 2 dose to further evaluate safety and efficacy

28 days per cycle

2 infusions per cycle (Day 1 and Day 15)

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days post-treatment

1 visit (in-person)

Treatment Details

Interventions

• AG01 Compound (Monoclonal Antibodies)

Trial Overview AG01, an anti-Progranulin/Glycoprotein88 antibody designed to target cancer cells, is being tested for safety and the maximum tolerated dose in phase 1A. Phase 1B will expand on this to find the optimal dose for future studies based on participants' responses.

Participant Groups

Group I: AG-01-1B mesothelioma Experimental Treatment 1 Intervention

Subjects with mesothelioma who received at least 1 SOC therapy for metastatic/recurrent mesothelioma per NCCN guidelines or not a candidate for SOC therapy.

Group II: AG-01 treated group phase 1A Experimental Treatment 1 Intervention

For dose escalation, subjects will be treated with increasing doses of AG01 from 1 mg/kg to 8 mg/kg. The duration of each treatment cycle is 28 days with two infusions of AG01 every 14 days.

Group III: AG-01 1B triple negative breast cancer treated group Experimental Treatment 1 Intervention

TNBC is defined as ER and/or PR \< 1% by IHC, HER2 \<3+ by IHC and/or FISH negative, subjects must have received 1 or more standard of care (SOC) therapies for metastatic TNBC. If PD(L)1-positive, must have received a combination of chemotherapy and a PD (L)-1 agent (Pembrolizumab), unless not a candidate for these therapies If gBRCA 1 or 2 mutation is present, must have received SOC therapies including a PARPi, unless not a candidate for these therapies. Sacituzumab Govitecan ADC is FDA approved for treatment of advanced TNBC, prior exposure to this therapy does not preclude eligibility in the current study.

Group IV: AG-01 1B NSCLC Experimental Treatment 1 Intervention

Subjects with metastatic/recurrent NSCLCA failed 2 or more SOC therapies, including platinum-based chemotherapy and an anti-PD (L) -1 agent (sequentially or consecutively), Subjects with sensitizing mutations/alterations/rearrangements are eligible if received 1 or more SOC agent/s targeting these mutations unless not a candidate for these therapies.

Group V: AG-01 1B Hormone-resistant breast cancer Experimental Treatment 1 Intervention

Hormone-resistant breast cancer is defined as, ER and/or PR \>1%, HER2 \<3+ by IHC and/or FISH negative, received 1 or more hormonal (HT) therapies or HT/CD4/6 kinase inhibitor or HT/MTOR inhibitor for treatment of metastatic breast cancer. If the tumor has known PIK3CA mutation, HT/Alpelisib combination should be considered unless not a candidate for this therapy.

Who Is Running the Clinical Trial?

A&G Pharmaceutical Inc.

Lead Sponsor

Trials

1

Recruited

80+

University of Maryland Greenebaum Cancer Center

Collaborator

Trials

15

Recruited

430+

Findings from Research

Researchers successfully developed monoclonal antibodies (mAbs) against the F domain of human progranulin (GrnF) using a yeast expression system, which involved immunizing BALB/c mice with a purified fusion protein.

Two specific hybridoma cell lines (1G6 and 4E8) were created, both producing IgG1 subclass antibodies that can specifically recognize GrnF, indicating potential for further research and therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Preparation and characterization of monoclonal antibodies against F domain of human progranulin]. Li, Y., Ren, D., Xia, H.[2018]

In a study of 101 patients with metastatic breast cancer, lower serum levels of GP88 (< 55 ng/mL) were associated with a four-fold increase in overall survival compared to higher levels, indicating its potential as a prognostic marker.

Serum GP88 levels correlated significantly with disease status, showing promise for monitoring treatment response and disease progression, suggesting it could be a cost-effective tool alongside traditional imaging methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Serum Progranulin Levels With Disease Progression, Therapy Response and Survival in Patients With Metastatic Breast Cancer. Tkaczuk, KHR., Hawkins, D., Yue, B., et al.[2023]

Progranulin (PGRN) is found to be highly expressed in osteosarcoma (OS) tissues, and its elevated levels are linked to poor patient prognosis, indicating its potential role as a biomarker for cancer severity.

Knocking down PGRN in OS cells significantly reduced their proliferation and migration while increasing cell death, suggesting that targeting PGRN could be a therapeutic strategy; this effect is mediated through the activation of the MAPK signaling pathway influenced by hypoxic conditions and mesenchymal stem cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activation of PGRN/MAPK axis stimulated by the hypoxia-conditioned mesenchymal stem cell-derived HIF-1α facilitates osteosarcoma progression. Shang, C., Ou, X., Zhang, H., et al.[2022]

In a study involving 29 patients with viral hepatitis C, those who developed hepatocellular carcinoma after treatment had significantly higher serum GP88 concentrations compared to those who did not, indicating GP88 as a potential predictive biomarker.

Patients with sustained high serum GP88 levels post-treatment or minimal changes in GP88 concentrations were at a greater risk for developing hepatocellular carcinoma, suggesting that monitoring GP88 could help identify individuals at higher risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serum GP88 as a predictive biomarker for hepatocellular carcinoma in patients with viral hepatitis C after direct-acting antiviral agents. Ishida, H., Takemura, M., Suetsugu, A., et al.[2022]

Progranulin directly influences the growth, migration, and invasion of human colon cancer cells, with reduced tumor activity observed in cells where progranulin was knocked down and increased activity in cells overexpressing progranulin.

The study suggests that targeting progranulin could be a promising therapeutic strategy for treating human colon cancer, as its effects on cancer cell behavior can be modulated by specific inhibitors like neamine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Progranulin on Migration and Invasion of Human Colon Cancer Cells. Zhao, J., Li, X., Liu, J., et al.[2018]

The study developed a novel antibody-drug conjugate (ADC) targeting LRG1, which is abundant in tumor microenvironments and contributes to vascular dysfunction, potentially improving therapeutic delivery.

In vivo tests showed that this ADC increased survival compared to the antibody alone and had similar anti-tumor effects as standard chemotherapy, but without the associated side effects, indicating its potential as a safer cancer treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leucine-rich alpha-2-glycoprotein 1 (LRG1) as a novel ADC target. Javaid, F., Pilotti, C., Camilli, C., et al.[2023]

The novel anti-AGR2 monoclonal antibody mAb18A4 effectively inhibited lung cancer progression and metastasis in mice without causing adverse side effects on major organs or blood, highlighting its safety as a potential cancer treatment.

mAb18A4 works by activating the p53 pathway and inhibiting the ERK1/2-MAPK pathway, leading to reduced cancer cell proliferation, increased apoptosis, and significant tumor size reduction in xenograft models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anterior Gradient-2 monoclonal antibody inhibits lung cancer growth and metastasis by upregulating p53 pathway and without exerting any toxicological effects: A preclinical study. Negi, H., Merugu, SB., Mangukiya, HB., et al.[2020]

The novel monoclonal antibody ST2485 shows promising potential for therapeutic applications, demonstrating comparable efficacy to the previously studied antibody ST2146 and outperforming the clinical trial antibody BC2 in various tests.

Combining ST2485 with ST2146 enhances tumor targeting, achieving a tumor-to-blood ratio greater than 24 in a xenograft model, indicating that this antibody mixture could significantly improve the effectiveness of pretargeted antibody-guided radioimmunotherapy (PAGRIT).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved tumor targeting by combined use of two antitenascin antibodies. Petronzelli, F., Pelliccia, A., Anastasi, AM., et al.[2007]

TAK-264, an investigational antibody-drug conjugate, demonstrated a manageable safety profile in adult patients with advanced gastrointestinal cancers, with the maximum tolerated dose established at 1.8 mg/kg and common side effects including nausea and neutropenia.

Preliminary results indicated potential antitumor activity, with one patient showing a partial response and three others achieving stable disease, suggesting that TAK-264 may be a promising treatment option for certain gastrointestinal malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of the Investigational Anti-Guanylyl Cyclase Antibody-Drug Conjugate TAK-264 (MLN0264) in Adult Patients with Advanced Gastrointestinal Malignancies. Almhanna, K., Kalebic, T., Cruz, C., et al.[2022]

TAK-264, an investigational antibody-drug conjugate targeting guanylyl cyclase C (GCC), effectively binds and kills GCC-expressing cancer cells in vitro, demonstrating its potential as a targeted therapy for metastatic colorectal cancer and other GCC-expressing tumors.

In xenograft models, TAK-264 induced significant tumor regressions and long-term growth inhibition, although some tumors showed resistance, indicating that while the treatment is promising, further evaluation is needed to understand its limitations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A monomethyl auristatin E-conjugated antibody to guanylyl cyclase C is cytotoxic to target-expressing cells in vitro and in vivo. Gallery, M., Zhang, J., Bradley, DP., et al.[2022]

Progranulin/GP88 plays a significant role in cancer by acting as a growth and survival factor, influencing processes like drug resistance, migration, and inflammation within the tumor microenvironment.

The review highlights that progranulin levels in tumor tissues and circulation can serve as important prognostic factors for various cancers, indicating its potential as a biomarker for disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progranulin/GP88, A Complex and Multifaceted Player of Tumor Growth by Direct Action and via the Tumor Microenvironment. Serrero, G.[2022]

The study demonstrated that the single-chain antibody fragment (131)I-anti-ProGRP(31-98) scFv has a rapid clearance from the bloodstream and low accumulation in normal tissues, making it a promising candidate for targeted radioimmunoimaging in small cell lung cancer (SCLC).

Imaging of SCLC xenografts was successful as early as 1 hour post-injection, with optimal imaging at 24 hours, indicating that this antibody fragment can effectively highlight tumors while minimizing exposure to healthy tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary radioimmunoimaging and biodistribution of ¹³¹iodine-labeled single-chain antibody fragment against progastrin-releasing peptide(₃₁₋₉₈) in small cell lung cancer xenografts. Hong, Z., Shi, Y., Liu, Z., et al.[2016]

References

1. China pubmed.ncbi.nlm.nih.gov

[Preparation and characterization of monoclonal antibodies against F domain of human progranulin]. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Association of Serum Progranulin Levels With Disease Progression, Therapy Response and Survival in Patients With Metastatic Breast Cancer. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Activation of PGRN/MAPK axis stimulated by the hypoxia-conditioned mesenchymal stem cell-derived HIF-1α facilitates osteosarcoma progression. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Serum GP88 as a predictive biomarker for hepatocellular carcinoma in patients with viral hepatitis C after direct-acting antiviral agents. [2022]

5. Pakistan pubmed.ncbi.nlm.nih.gov

Effect of Progranulin on Migration and Invasion of Human Colon Cancer Cells. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Leucine-rich alpha-2-glycoprotein 1 (LRG1) as a novel ADC target. [2023]

7. Ireland pubmed.ncbi.nlm.nih.gov

Anterior Gradient-2 monoclonal antibody inhibits lung cancer growth and metastasis by upregulating p53 pathway and without exerting any toxicological effects: A preclinical study. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Improved tumor targeting by combined use of two antitenascin antibodies. [2007]

9. United States pubmed.ncbi.nlm.nih.gov

Phase I Study of the Investigational Anti-Guanylyl Cyclase Antibody-Drug Conjugate TAK-264 (MLN0264) in Adult Patients with Advanced Gastrointestinal Malignancies. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

A monomethyl auristatin E-conjugated antibody to guanylyl cyclase C is cytotoxic to target-expressing cells in vitro and in vivo. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Progranulin/GP88, A Complex and Multifaceted Player of Tumor Growth by Direct Action and via the Tumor Microenvironment. [2022]

12. China pubmed.ncbi.nlm.nih.gov

Preliminary radioimmunoimaging and biodistribution of ¹³¹iodine-labeled single-chain antibody fragment against progastrin-releasing peptide(₃₁₋₉₈) in small cell lung cancer xenografts. [2016]