Abstract 5263
Background
Balixafortide is a very potent, well tolerated and highly selective next generation CXCR4 antagonist derived over the past decade through multiple rounds of optimization starting from the natural product polyphemusin. Clinical proof-of-concept was achieved in a Ph 1/2 study in combination with Eribulin in metastatic HER2-neg breast cancer. The anti-cancer effects and pluripotent action of Balixafortide may include sensitization of tumor cells to chemotherapy, suppression of metastatic spread, inhibition of angiogenesis, and activation of the immune system.
Methods
Balixafortide was tested in a HTRF-based CXCR4 ligand binding assay, in functional assays (Calcium flux and beta arrestin), and further profiled in a large panel of other receptors including CXCR7. Effects on tumor cell sensitization were followed with an intracellular pERK / pAKT signaling assay. Tumor cell migration was assessed by chemotaxis assays, and inhibition of angiogenesis was determined by HUVEC sprouting. Evidence for immune cell activation came from evaluation of corresponding marker such as interferon gamma. Balixafortide was in detail profiled in an extensive in vitro ADME panel.
Results
Balixafortide binds CXCR4 with high affinity (IC50 < 10nM). It blocks beta arrestin recruitment and Calcium flux with IC50s < 10nM. A high 1000-fold selectivity window was demonstrated in a large panel of receptors including CXCR7. Balixafortide potently inhibits pERK / pAKT signaling in the lymphoma lines Namalwa (IC50 < 200 nM) and Jurkat (IC50 < 400 nM). Balixafortide efficiently blocks SDF-1 dependent chemotaxis of MDA MB 231 breast cancer cells (IC50 < 20 nM), Namalwa and Jurkat cells (IC50 < 10 nM). Receptor occupancy wash-out studies with competitive antibody 12G5 revealed prolonged binding of Balixafortide to CXCR4. In addition, Balixafortide was optimized for favorable mouse and human ADME properties with balanced plasma protein binding, greater plasma and microsomal stability.
Conclusions
Balixafortide is a product of an extensive optimization process which started from polyphemusin and now represents a favorable balance between ADMET properties, potency and tolerability which allows high and frequent dosing of a CXCR4 antagonist in cancer patients.
Clinical trial identification
Legal entity responsible for the study
Polyphor Ltd.
Funding
Has not received any funding.
Editorial Acknowledgement
Disclosure
J. Zimmermann: Employee and shareholder: Polyphor Ltd. T. Remus, G. Lemercier, D. Barker, D. Obrecht, G. Douglas, G. Gambino: Employee: Polyphor Ltd.
Resources from the same session
2595 - Real-Life Utilization of Genomic testing for invasive Breast Cancer patients in Italy and France reduces Chemotherapy Recommendations
Presenter: Sandro Barni
Session: Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care
Resources:
Abstract
2343 - Benefit of adjuvant chemotherapy in hormone receptor-positive, HER2-negative, invasive lobular carcinoma of the breast
Presenter: Alexandre De Nonneville
Session: Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care
Resources:
Abstract
2990 - Baseline lymphocyte counts predict distant recurrence in early breast cancer
Presenter: Gun Min Kim
Session: Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care
Resources:
Abstract
4532 - A propensity score analysis exploring the impact of the addition of adjuvant chemotherapy (aCT) to hormone therapy (aHT) in a multi-center series of resected luminal early stage pure Invasive Lobular Breast Carcinoma (ILC).
Presenter: Luisa Carbognin
Session: Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care
Resources:
Abstract
2344 - Benefit of Adjuvant Systemic Therapies in HR+ HER2- pT1ab Node-Negative Breast Carcinomas
Presenter: Alexandre De Nonneville
Session: Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care
Resources:
Abstract
3525 - Anti-proliferative effect of oral metronomic vinorelbine in PAM50 Luminal/HER2-negative early breast cancer (SOLTI-1501 VENTANA): an open-label, randomized, three-arm, multicenter, window-of-opportunity study
Presenter: Aleix Prat
Session: Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care
Resources:
Abstract
3908 - Clinicopathologic significance of androgen receptor expression and discordant receptor status during progression in breast cancer
Presenter: Chan Heun Park
Session: Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care
Resources:
Abstract
4075 - The outcomes of early breast cancers utilizing the Oncotype Dx Recurrence score (RS) instead of Clinico-pathological (CP) factors for prognostic risk assessment: A Single Institution Experience
Presenter: Adhar Alsayed
Session: Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care
Resources:
Abstract
738 - Circulating tumor cells as a prognostic marker in non metastatic breast cancer patients.
Presenter: Summar Elmorshidy
Session: Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care
Resources:
Abstract
3151 - Molecular subtyping of breast cancer by dedicated breast PET
Presenter: Satoshi Sueoka
Session: Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care
Resources:
Abstract