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Antibody targeting of phosphatidylserine for detection and immunotherapy of cancer

Authors Zohar DN, Shoenfeld Y

Received 27 March 2018

Accepted for publication 7 April 2018

Published 22 June 2018 Volume 2018:7 Pages 51—53

DOI https://doi.org/10.2147/ITT.S169383

Checked for plagiarism Yes

Editor who approved publication: Professor Michael Shurin



Daniela Noa Zohar, Yehuda Shoenfeld
  
Zabludowitz Centre for Autoimmune Diseases, Sheba Medical Centre, Tel-Hashomer, Israel

Belzile et al introduce a novel therapeutic approach for cancer by antibody targeting of phosphatidylserine (PS).1 As is well known, antiphospholipid autoantibodies are associated with hypercoagulability disorders, particularly antiphospholipid syndrome (APS).2 While the hallmark autoantibodies of APS are anti-beta2 glycoprotein and anticardiolipin, over 30 other non-classic autoantibodies were reported in correlation with APS. Particular attention was dedicated to antiphosphatidylserine (aPS) – a remarkable autoantibody that was detected in 68–86% of APS patients.2 aPS is associated with thrombosis, thrombocytopenia and hemolytic anemia.2 Previously, we have described the pathogenicity of aPS on experimental mice models by induction of APS, both through passive transfer of purified human IgG aPS antibodies3 and active immunization, whereas immunized mice with IgG aPS produced high titers of mouse aPS. The results demonstrated a clinical picture of APS by prolonged activated partial thromboplastin time, thrombocytopenia and increased rates of fetal resorptions.4

View the review paper by Belzile and colleagues.

Dear editor

Belzile et al introduce a novel therapeutic approach for cancer by antibody targeting of phosphatidylserine (PS).1

As is well known, antiphospholipid autoantibodies are associated with hypercoagulability disorders, particularly antiphospholipid syndrome (APS).2

While the hallmark autoantibodies of APS are anti-beta2 glycoprotein and anti-cardiolipin, over 30 other non-classic autoantibodies were reported in correlation with APS. Particular attention was dedicated to antiphosphatidylserine (aPS) – a remarkable autoantibody that was detected in 68–86% of APS patients.2 aPS is associated with thrombosis, thrombocytopenia and hemolytic anemia.2 Previously, we have described the pathogenicity of aPS on experimental mice models by induction of APS, both through passive transfer of purified human IgG aPS antibodies3 and active immunization, whereas immunized mice with IgG aPS produced high titers of mouse aPS. The results demonstrated a clinical picture of APS by prolonged activated partial thromboplastin time, thrombocytopenia and increased rates of fetal resorptions.4

In another study that deals with the mechanism for fetal loss in APS, exposure of rat embryos and their yolk sacs to aPS led to an inhibition of the yolk sac growth and a higher apoptosis rate compared with the control group.5 With this knowledge, cancer immunotherapy by antibody targeting the PS1 raises questions regarding the development of thromboembolic events in patients who accept this therapy.

In general, antibody targeting of PS increases the risk of developing thromboembolic events as some individuals may have occult genetic predisposition which is unknown to the clinician when prescribing the medication. This risk is doubled in the target population for this therapy, as oncological patients have a higher tendency to develop hypercoagulability states, compared to healthy population.6

Thus, perhaps a specific follow-up is required for patients with a high risk for development of thromboembolic events in order to detect and treat these side effects in time. In addition, a prophylactic therapy with low-molecular-weight heparin or oral anticoagulants should be considered upon initiation of therapy with antibody targeting of PS.6

Disclosure

The authors report no conflicts of interest in this communication.

References

1.

Belzile O, Huang X, Gong J, et al. Antibody targeting of phosphatidylserine for the detection and immunotherapy of cancer. Immunotargets Ther. 2018;7:1–14

2.

Shoenfeld Y, Twig G, Katz U, Sherer Y. Autoantibody explosion in antiphospholipid syndrome. J Autoimmun. 2008;30(1–2):74–83.

3.

Blank M, Tincani A, Shoenfeld Y. Induction of experimental antiphospholipid syndrome in naive mice with purified IgG antiphosphatidylserine antibodies. J Rheumatol. 1994;21(1):100–104.

4.

Yodfat O, Blank M, Krause I, Shoenfeld Y. The pathogenic role of antiphosphatidylserine antibodies: active immunization with the antibodies leads to the induction of antiphospholipid syndrome. Clin Immunol Immunopathol. 1996;78:14–20.

5.

Blank M and Shoenfeld Y. Antiphosphatidylserine antibodies and reproductive failure. Lupus. 2004;13:661–665.

6.

Raskob G.E, van Es N, Verhamme P, Carrier M, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378:615–624.

Author’s reply

Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA

Correspondence: Rolf A Brekken Hamon Center for Therapeutic, Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA
Tel +1 214 648 5151
Email [email protected]

Dear editor

We appreciate the comments from Zohar and Shoenfeld and agree that antibody targeting of phosphatidylserine (PS) for cancer therapy should be evaluated carefully. Bavituximab, a chimeric antibody targeting PS via the bridging protein β2 glycoprotein 1 (β2GP1),1 has been in clinical testing since the mid-2000s. Phase I safety testing was reported by Gerber et al,2 and additional clinical studies testing bavituximab have also been reported.36 The general conclusion from the clinical studies to date is that bavituximab is well tolerated at doses up to 3 mg/kg weekly. A study worth considering in the context of antiphospholipid syndrome (APS) is that of Mineo et al,7 which demonstrated that the antibody 1N11 attenuates APS-related thrombosis. 1N11 is a fully human antibody that targets PS via B2GP1 and phenocopies the anti-cancer activity of bavituximab in preclinical models.8 Overall, the preclinical and clinical data generated thus far demonstrate that bavituximab is safe and does not promote hypercoagulability. The mechanism of action of bavituximab and 1N11 has not been elucidated completely but is an area of active research that will hopefully provide insight as to how targeting PS with these antibodies can stimulate immune activation without inducing hypercoagulability.

Disclosure

University of Texas Southwestern Medical Center, are collaborators of Peregrine and receive research funding from the company. The author reports no other conflicts of interest in this communication.

References

1.

Belzile O, Huang X, Gong J, et al. Antibody targeting of phosphatidylserine for the detection and immunotherapy of cancer. Immunotargets Ther. 2018;7:1–14

2.

Gerber DE, Stopeck AT, Wong L, et al. Phase I safety and pharmacokinetic study of bavituximab, a chimeric phosphatidylserine-targeting monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 2011;17(21):6888–6896.

3.

Gerber DE, Spigel DR, Giorgadze D, et al. Docetaxel combined with bavituximab in previously treated, advanced nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2016;17(3):169–176.

4.

Grilley-Olson JE, Weiss J, Ivanova A, et al. Phase Ib Study of bavituximab with carboplatin and pemetrexed in chemotherapy-naive advanced nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2018. Epub 2018 Mar 17.

5.

Grilley-Olson JE VL, Stinchcombe TE, Weiss J, Shan J, Vashishtha A et al., editor. A phase Ib study of bavituximab plus carboplatin and pemetrexed in chemotherapy naïve stage IV non-squamous non-small cell lung cancer. Chicago Multidisciplinary Symposium on Thoracic Oncology; 2014; Chicago, IL.

6.

Meyer J, Arriaga Y, Anandam J, et al. A Phase I clinical trial of the phosphatidylserine-targeting antibody bavituximab in combination with radiation therapy and capecitabine in the preoperative treatment of rectal adenocarcinoma. Am J Clin Oncol. 2017. Epub 2017 Jul 31.

7.

Mineo C, Lanier L, Jung E, et al. Identification of a monoclonal antibody that attenuates antiphospholipid syndrome-related pregnancy complications and thrombosis. PloS One. 2016;11(7):e0158757.

8.

Freimark BD, Gong J, Ye D, et al. Antibody-mediated phosphatidylserine blockade enhances the antitumor responses to CTLA-4 and PD-1 antibodies in melanoma. Cancer Immunol Res. 2016;4(6):531–540.

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