Background PRO 140 is a humanized monoclonal antibody targeting CCR5 with potent antiviral activity in patients with CCR5-tropic HIV-1 infection. In phase 2b studies, we evaluated the long-term efficacy, safety, and tolerability of PRO 140 monotherapy in maintaining viral suppression for over 24 months in patients who were stable on combination antiretroviral therapy on entry into the trials. Methods and Results Forty-one adult patients, infected exclusively with CCR5-tropic HIV-1 with viral loads <50 copies/mL, were switched from daily oral combination ART regimens to weekly PRO 140 monotherapy for 12 weeks. Participants who completed 12 weeks of treatment without experiencing virologic rebound were allowed to self-administer PRO 140 as a 350 mg subcutaneous injection weekly, for up to an additional 160 weeks. Participants were monitored bi-weekly for one year, and every four weeks thereafter for virologic rebound. PRO 140 provided virologic suppression in 23/41 (56.1%) participants for 12 weeks and was well tolerated. Ten (10) participants are currently ongoing, of which nine participants have completed more than two years of monotherapy treatment (47-129 weeks). Participants experiencing virologic rebound achieved full viral suppression upon re-initiation of oral combination ART regimen. Anti-PRO 140 antibodies were not detected in any patient, and no drug-related major adverse events or treatment discontinuations were reported. Conclusions PRO 140 has a potential to address an unmet need for a long-acting, single-agent, maintenance regimen for HIV infection in selected patients. Studies are underway to determine host and/or virologic factors that may predict treatment success on PRO 140 monotherapy. Moreover, it has sufficient potency for a prolonged period of monotherapy that it would be an excellent component of a multi long-acting drug combination.
In the absence of a prophylactic vaccine, the use of antiretroviral therapy (ART) as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition by uninfected individuals is a promising approach to slowing the epidemic, but its efficacy is hampered by incomplete patient adherence and ART-resistant variants. Here, we report that competitive inhibition of HIV Env-CCR5 binding via the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of CCR5-tropic SHIVSF162P3. Injection of Leronlimab weekly at 10 mg/kg provides significant but partial protection, while biweekly 50 mg/kg provides complete protection from SHIV acquisition. Tissue biopsies from protected macaques post challenge show complete CCR5 receptor occupancy and an absence of viral nucleic acids. After Leronlimab washout, protected macaques remain aviremic, and adoptive transfer of hematologic cells into naïve macaques does not transmit viral infection. These data identify CCR5 blockade with Leronlimab as a promising approach to HIV prophylaxis and support initiation of clinical trials.
CCR5 plays a central role in infectious disease, host defense, and cancer progression, thereby making it an ideal target for therapeutic development. Notably, CCR5 is the major HIV entry co-receptor, where its surface density correlates with HIV plasma viremia. The level of CCR5 receptor occupancy (RO) achieved by a CCR5-targeting therapeutic is therefore a critical predictor of its efficacy. However, current methods to measure CCR5 RO lack sensitivity, resulting in high background and overcalculation. Here, we report on two independent, flow cytometric methods of calculating CCR5 RO using the anti-CCR5 antibody, Leronlimab. We show that both methods led to comparable CCR5 RO values, with low background on untreated CCR5+CD4+ T cells and sensitive measurements of occupancy on both blood and tissue-resident CD4+ T cells that correlated longitudinally with plasma concentrations in Leronlimab-treated macaques. Using these assays, we found that Leronlimab stabilized cell surface CCR5, leading to an increase in the levels of circulating and tissue-resident CCR5+CD4+ T cells in vivo in Leronlimab-treated macaques. Weekly Leronlimab treatment in a chronically SIV-infected macaque led to increased CCR5+CD4+ T cells levels and fully suppressed plasma viremia, both concomitant with full CCR5 RO on peripheral blood CD4+ T cells, demonstrating that CCR5+CD4+ T cells were protected from viral replication by Leronlimab binding. Finally, we extended these results to Leronlimab-treated humans and found that weekly 700 mg Leronlimab led to complete CCR5 RO on peripheral blood CD4+ T cells and a statistically significant increase in CCR5+CD4+ T cells in peripheral blood. Collectively, these results establish two RO calculation methods for longitudinal monitoring of anti-CCR5 therapeutic antibody blockade efficacy in both macaques and humans, demonstrate that CCR5+CD4+ T cell levels temporarily increase with Leronlimab treatment, and facilitate future detailed investigations into the immunological impacts of CCR5 inhibition in multiple pathophysiological processes.
Introduction: Triple Negative Breast Cancer (TNBC) represents the most deadly form of invasive disease. It is associated with clinical and pathological features of highly proliferative and rapidly spreading cancer demonstrating higher incidence in younger women, particularly of African-American ethnicity and accounting for a disproportionately high percentage of early development of metastatic disease and breast-cancer-related death. While chemotherapy remains the main treatment option for both primary and metastatic TNBC (mTNBC) there is no optimized therapy for its management due to tumor heterogeneity, leaving the condition with an unmet medical need. Recent preclinical research demonstrated an important role for chemokine receptor type 5 (CCR5) in modulating cell migration and immune microenvironment suggesting a potential new therapeutic target in mTNBC [Jiao X et al, Can Res 2018;78:1657-71]. Leronlimab (PRO 140) is a humanized IgG4,к monoclonal antibody (mAb) to the C-C chemokine receptor type 5 (CCR5). Leronlimab has been administered and generally well tolerated in more than 750 healthy and HIV-1 infected individuals in Phase I/II/III studies. An ongoing Phase Ib/II study is being conducted to assess the safety and clinical outcomes of leronlimab combined with carboplatin in patients with untreated CCR5+ metastatic Triple Negative Breast Cancer (mTNBC). Methods: Eligible patients are required to have confirmed HER2 negative, ER <1%, PR<1% and demonstrate CCR5+ by immunohistochemistry assay (IHC) (>10% of primary or metastatic cancer cells shows membranous staining and/or high predominance of CCR5+ tumor-infiltrating leukocytes (see representative IHC staining images below) Phase Ib of the CD07_TNBC study is a multicenter, single arm, dose escalation phase with 3 dose levels of leronlimab administered in combination with a fixed dose of carboplatin at AUC 5. The starting dose is 350 mg with escalation to 525 mg and 700 mg in the absence of dose-limiting toxicities. Leronlimab is administered as subcutaneous injection in the abdomen weekly and can be self-administered by subjects at home after proper training by a healthcare professional. Carboplatin is administered at AUC 5 every 3 weeks. The maximum tolerated dose (MTD) of leronlimab determined during the Phase Ib portion will be administered to 30 patients during the Phase II portion of the study. Correlative Data: Blood samples are collected at Day 1 of each treatment cycle (every 21 days) to assess changes in circulating tumor cells (CTCs) and cancer associated macrophage-like cells (CAMLs) after treatment and to perform correlative analysis with CCR5 expression. Conclusions: Leronlimab (PRO 140), a CCR5 antagonist mAb, in combination with carboplatin is currently enrolling newly diagnosed mTNBC. The preliminary analysis shows safety and tolerability of the combination and continue to enroll patients with initial promising clinical activity, potentially suggesting the future availability of a new effective agent in the management of this serious condition. Citation Format: Massimo Cristofanilli, Milana Dolezal, Jay Lalezari, Hallgeir Rui, Bruce Patterson, Cha-Mei Tang, Daniel Adams, Qiang Zhang, Kazem Kazempour, Nader Pourhassan, Natalie Rabb, Kush Dhody. Phase Ib/II study of leronlimab (PRO 140) combined with carboplatin in CCR5+ mTNBC patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT233.
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