Iago Rodríguez-Lago ¹, Leticia Abecia ², Iratxe Seoane ², Juan Anguita ³, José Luis Cabriada ⁴Gastroenterol Hepatol. 2023 Jul 6:S0210-5705(23)00370-9. doi: 10.1016/j.gastrohep.2023.07.001.[Article in English, Spanish]

Objective: Primary non-response and secondary loss of response to anti-TNF agents are common in inflammatory bowel disease. Increasing drug concentrations are correlated to better clinical response and remission rates. Combination of granulocyte-monocyte apheresis (GMA) with anti-tumor necrosis factor (TNF) agents could be an option in these patients. The objective of our study was to perform an in vitro assay to determine if the GMA device can lead to infliximab (IFX) adsorption.

Patients and methods: A blood sample was obtained from a healthy control. It was incubated with three concentrations of IFX (3, 6, and 9μg/ml) at room temperature for 10min. At that time, 1ml was collected to determine the IFX concentration. Then, 10ml of each drug concentration was incubated with 5ml of cellulose acetate (CA) beads from the GMA device at 200rpm for 1h at 37°C to simulate physiological human conditions. A second sample of each concentration was collected and IFX levels were determined.

Results: No statistically significant differences were observed in the IFX levels in the blood samples before and after incubation with the CA beads (p=0.41) and after repeated measurements (p=0.31). Mean change was 3.8μg/ml.

Conclusions: The in vitro combination of GMA and IFX did not change the circulating levels of IFX at the three concentrations tested, suggesting that there is no interaction between the drug and the apheresis device in vitro and that they might be safely combined with each other.

An in vitro analysis of the interaction between infliximab and granulocyte-monocyte apheresis – PubMed (nih.gov)

An in vitro analysis of the interaction between infliximab and granulocyte–monocyte apheresis – ScienceDirect

Shoichi Nishise ^1 2, Yuji Takeda ³, Yasuhiko Abe ¹, Yu Sasaki ¹, Shinichi Saitoh ³, Hidetoshi Nara ³, Hironobu Asao ³, Yoshiyuki Ueno, Ther Apher Dial 2020 Oct 17.

These results indicated that physiological heating of the apheresis carrier augmented the anti-inflammatory reaction in vitro. Thus, heating during GMA may be a new approach for augmenting clinical efficacy.

https://pubmed.ncbi.nlm.nih.gov/33067913/

Shoichi Nishise ¹, Yuji Takeda ², Hidetoshi Nara ², Yasuhiko Abe ¹, Yu Sasaki ¹, Hironobu Asao ², Yoshiyuki Ueno ¹ , Ther Apher Dial. 2018 Jun;22(3):261-265.

These results suggest that independent of incubation temperature, sICAM-1 and sVCAM-1 are likely to adsorb CA beads. These molecules may be a new index for predicting the therapeutic effects of GMA.

https://pubmed.ncbi.nlm.nih.gov/29745046/

Ziwei Huang ¹, Vikram Singh Raghuwanshi ¹, Gil Garnier ¹Front Bioeng Biotechnol. 2017 Jul 17:5:41. doi: 10.3389/fbioe.2017.00041

The functionality and aging mechanism of antibodies physisorbed onto cellulosic films was investigated. Blood grouping antibodies immunoglobulin G (IgG) and immunoglobulin M (IgM) were adsorbed onto smooth cellulose acetate (CAF) and regenerated cellulose (RCF) films. Cellulose films and adsorbed IgG layers were characterized at the air and liquid interface by X-ray and neutron reflectivity (NR), respectively. Cellulose film 208 Å thick (in air) swell to 386 Å once equilibrated in water. IgG adsorbs from solution onto cellulose as a partial layer 62 Å thick. IgG and IgM antibodies were adsorbed onto cellulose and cellulose acetate films, air dried, and aged at room temperature for periods up to 20 days. Antibody functionality and surface hydrophobicity were measured everyday with the size of red blood cell (RBC) agglutinates (using RBC specific to IgG/IgM) and the water droplet contact angle, respectively. The functionality of the aged IgG/IgM decreases faster if physisorbed on cellulose than on cellulose acetate and correlates to surface hydrophobicity. IgG physisorbed on RCF or CAF age better and remain functional longer than physisorbed IgM. We found a correlation between antibody stability and hydrogen bond formation ability of the system, evaluated from antibody carbonyl concentration and cellulosic surface hydroxyl concentration. Antibody physisorbs on cellulose by weak dipole forces and hydrogen bonds. Strong hydrogen bonding contributes to the physisorption of antibody on cellulose into a non-functional configuration in which the molecule relaxes by rotation of hydophobic groups toward the air interface.

Functionality of Immunoglobulin G and Immunoglobulin M Antibody Physisorbed on Cellulosic Films – PubMed (nih.gov)

Functionality of Immunoglobulin G and Immunoglobulin M Antibody Physisorbed on Cellulosic Films – PMC (nih.gov)

Muhammad Ali Muzammil ¹, Fnu Fariha ², Tirath Patel ³, Rohab Sohail ⁴, Munesh Kumar ⁵, Ejaz Khan ⁶, Bushra Khanam ⁷, Satesh Kumar ⁸, Mahima Khatri ⁹, Giustino Varrassi ¹⁰, Prasanthi Vanga ¹¹2023 Jun 28;15(6):e41120. doi: 10.7759/cureus.41120.

The functionality and aging mechanism of antibodies physisorbed onto cellulosic films
was investigated. Blood grouping antibodies immunoglobulin G (IgG) and immunoglobulin M (IgM) were adsorbed onto smooth cellulose acetate (CAF) and regenerated
cellulose (RCF) films. Cellulose films and adsorbed IgG layers were characterized at the
air and liquid interface by X-ray and neutron reflectivity (NR), respectively. Cellulose film
208 Å thick (in air) swell to 386 Å once equilibrated in water. IgG adsorbs from solution
onto cellulose as a partial layer 62 Å thick. IgG and IgM antibodies were adsorbed onto
cellulose and cellulose acetate films, air dried, and aged at room temperature for periods
up to 20 days. Antibody functionality and surface hydrophobicity were measured everyday with the size of red blood cell (RBC) agglutinates (using RBC specific to IgG/IgM)
and the water droplet contact angle, respectively. The functionality of the aged IgG/IgM
decreases faster if physisorbed on cellulose than on cellulose acetate and correlates to
surface hydrophobicity. IgG physisorbed on RCF or CAF age better and remain functional longer than physisorbed IgM. We found a correlation between antibody stability
and hydrogen bond formation ability of the system, evaluated from antibody carbonyl
concentration and cellulosic surface hydroxyl concentration. Antibody physisorbs on cellulose by weak dipole forces and hydrogen bonds. Strong hydrogen bonding contributes
to the physisorption of antibody on cellulose into a non-functional configuration in which
the molecule relaxes by rotation of hydophobic groups toward the air interface.

Functionality of Immunoglobulin G and Immunoglobulin M Antibody Physisorbed on Cellulosic Films – PubMed (nih.gov)

Shuai Ma ¹, Qingqing Xu ¹, Bo Deng ¹, Yin Zheng ², Hongyan Tian ¹, Li Wang ³, Feng Ding ⁴ , Intensive Care Med Exp. 2017 Dec;5(1):18.

This study showed that selective granulocyte and monocyte adsorption with cellulose acetate beads might ameliorate cecal ligation and puncture (CLP)-induced sepsis and improve survival and organ function.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366986/pdf/40635_2017_Article_129.pdf

https://pubmed.ncbi.nlm.nih.gov/28342161/

Shoichi Nishise ¹, Yuji Takeda ², Yasuhiko Abe ¹, Yu Sasaki ¹, Hidetoshi Nara ², Hironobu Asao ², Yoshiyuki Ueno ¹ , Ther Apher Dial. 2017 Jun;21(3):248-254.

These results suggest that warming the column during GMA might increase GM adsorption to CA beads, thereby enhancing the clinical efficacy of GMA.

https://pubmed.ncbi.nlm.nih.gov/28661094/

Shoichi Nishise ¹, Yasuhiko Abe ¹, Eiki Nomura ², Takeshi Sato ¹, Yu Sasaki ¹, Daisuke Iwano ¹, Kazuya Yoshizawa ¹, Makoto Yagi ¹, Kazuhiro Sakuta ¹, Yoshiyuki Ueno ¹ , Ther Apher Dial. 2016 Aug;20(4):354-9.

 In conclusion, CA beads inhibited IL-23 release from adsorbed GMs. The biological effects of this decrease in IL-23 release during GM adsorption to CA beads need further clarification.

https://pubmed.ncbi.nlm.nih.gov/27523075/

Shoichi Nishise ¹, Yasuhiko Abe ¹, Eiki Nomura ¹, Takeshi Sato ¹, Yu Sasaki ¹, Daisuke Iwano ¹, Makoto Yagi ¹, Kazuhiro Sakuta ¹, Rika Shibuya ¹, Naoko Mizumoto ¹, Nana Kanno ¹, Yoshiyuki Ueno ¹ , Ther Apher Dial. 2015 Aug;19(4):330-5.

In conclusion, CA beads inhibited the release of TGF-β from adsorbed platelets. The biological effects of this reduction of TGF-β release during platelet adsorption to CA beads need further clarification.

https://pubmed.ncbi.nlm.nih.gov/26386220/

Shoichi Nishise ¹, Yasuhiko Abe, Eiki Nomura, Takeshi Sato, Yu Sasaki, Daisuke Iwano, Kazuya Yoshizawa, Makoto Yagi, Yuko Nishise, Yoshiyuki Ueno, Ther Apher Dial. 2014 Jun;18(3):252-7.

umor necrosis factor-α, (TNF)-α, a proinflammatory cytokine, is produced by activated granulocytes and monocytes (GMs) and implicated as a major factor in inflammatory bowel disease (IBD) pathogenesis. Reduction of TNF-α should improve IBD pathology. GM adsorptive apheresis (GMA) is an effective therapy for inflammatory disorders including IBD. GM adsorption to cellulose acetate (CA) beads induces anti-inflammatory cytokine release, although these effects on TNF-α release are not clarified. We hypothesized that GMA may inhibit TNF-α release. The aim of the present study was to clarify the effects of GM adsorption to CA beads on TNF-α release in vitro. Peripheral blood was incubated with and without CA beads and TNF-α was measured. For comparison, TNF-α was measured in another lipopolysaccharide (LPS)-containing peripheral blood sample incubated similarly. The amount of TNF-α in blood samples incubated with CA beads was significantly higher than in those incubated without beads, although it was significantly lower than TNF-α incubated with LPS-containing sample without beads. The amount of TNF-α after incubation with CA beads positively correlated with GM adsorption ratio. GM adsorption to CA beads induced a small amount of TNF-α release. This is the first report on TNF-α release induced via GM adsorption stimuli. The biological effects of TNF-α release during GM adsorption need to be clarified.

https://pubmed.ncbi.nlm.nih.gov/24965291/