
==== Front
Intern Med
Intern Med
Internal Medicine
0918-2918
1349-7235
The Japanese Society of Internal Medicine

38171874
10.2169/internalmedicine.2900-23
Original Article
Clinical Efficacy of Imdevimab/Casirivimab for Persistent Omicron SARS-CoV-2 Infection in Patients with Hematological Malignancies
Hagihara Masao 1
Hayashi Hiroyoshi 1
Nakashima Shiori 1
Imai Yui 1
Nakano Hirofumi 1
Uchida Tomoyuki 1
Inoue Morihiro 1
Sakai-Tagawa Yuko 2
Ito Mutsumi 2
Yamayoshi Seiya 23
Iwatsuki-Horimoto Kiyoko 2
Suzuki Yutaka 4
Kawaoka Yoshihiro 2356
1 Department of Hematology, Eiju General Hospital, Japan
2 Division of Virology, Institute of Medical Science, The University of Tokyo, Japan
3 The Research Center for Global Viral Disease, Research Institute, National Center for Global Health and Medicine, Japan
4 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Japan
5 Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), The University of Tokyo, Japan
6 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, USA
Correspondence to Dr.　Masao Hagihara, hagihara@eijuhp.com

2 1 2024
15 8 2024
63 16 22832287
11 9 2023
13 11 2023
Copyright © 2024 by The Japanese Society of Internal Medicine
https://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Objective

Prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been reported in immunocompromised patients, as they poorly develop antibodies against SARS-CoV-2. We conducted a clinical trial to determine the efficacy of Imdevimab/Casirivimab (Imde/Casiri), an anti-viral monoclonal antibody (mAb), for prolonged infection at our institution.

Methods

Nine patients with hematological malignancies (six with malignant lymphoma and three with multiple myeloma) in our institution presented with coronavirus disease 2019 caused by SARS-CoV-2 omicron variants (one, five, and one with BA.2, BA.5, and BF.7, respectively; two undetermined). Although not all nine patients developed severe disease, viral mRNA was detected in all patients after treatment with remdesivir or molnupiravir. Imde/casiri was infused 11-49 days after the disease onset.

Results

Within seven days of infusion, viral RNA was undetectable in five of the nine cases. Because all seven viruses isolated from patients whose viral RNA became undetectable showed low or no sensitivity to this monoclonal antibody cocktail, the disappearance of viral RNA in these cases may not be attributable to the antibody cocktail.

Conclusion

It may be worth considering the use of monoclonal antibodies that show some activity against these virus variants to treat persistent SARS-CoV-2 infection in immunocompromised patients.

COVID-19
hematological malignancies
persistent infection
Imdevimab/Casirivimab
mRNA
==== Body
pmcIntroduction

Patients with hematological disorders, especially those undergoing chemotherapy, are at particularly high risk of severe or fatal disease if they contract coronavirus disease 2019 (COVID-19) (1-3). One major reason for this is impaired immunity (4). To circumvent this drawback, vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is being conducted worldwide. Nevertheless, antibody responses to the COVID-19 mRNA vaccine are significantly diminished in patients with hematological malignancies, especially those treated with anti-CD20 monoclonal antibodies (mAbs) (5,6). Persistent infections in extremely immunocompromised patients are also concerning. We previously showed that patients with hematological diseases are less likely to develop antibodies against SARS-CoV-2 than are those with non-hematological diseases (7). Prolonged viral shedding in patients with B-cell depletion caused by anti-CD20mAb has been demonstrated, and prolonged COVID-19 pneumonia during anti-CD20mAb treatment has also been reported (8-10).

Several antiviral drugs and mAbs are currently approved for the treatment of COVID-19 patients who are at a risk of severe disease. In Japan, two mAb therapeutics are available for patients with non-severe COVID-19. Although sotrovimab has completely lost neutralizing activity against BA.2 and BA.5, Imdevimab/Casirivimab (Imde/Casiri) has retained some efficacy against some variants, albeit reduced compared with that against the ancestral strains (11).

Several cases of successful treatment of persistent SARS-CoV-2 infection using mAbs, including Imde/Casiri with antiviral agents, have been reported (12-14). Even though our country's guidelines for COVID-19 recommend an infusion of mAb to patients who develop symptoms within eight days and do not require oxygen for respiratory distress, combination therapies are often applied to those with sustained, relatively severe cases requiring oxygen support (13,14). Even if mAbs should have sensitivity against SARS-CoV-2 by an early period of Omicron predominance, there is no information regarding a clinical efficacy of Imde/Casiri in the ongoing mAb-resistant Omicron era.

Thus, we conducted a clinical trial of Imde/Casiri infusion after early treatment failure with conventional antiviral drugs.

Materials and Methods

From April 2022 to February 2023, during the sixth to seventh waves of the COVID-19 pandemic in Japan, patients with hematological malignancies who suffered from persistent SARS-CoV-2 infection even after antiviral drug treatment (remdesivir or molnupiravir) were enrolled. Patients who met these criteria [6 malignant with lymphoma (ML) and 3 with multiple myeloma (MM)] received Imde/Casiri infusion 11-49 days after the disease onset.

The SARS-CoV-2 diagnosis was confirmed by real-time reverse-transcription polymerase chain reaction testing of nasopharyngeal swab samples at our institution; the viral load is shown as the cycle threshold value. The SARS-CoV-2 anti-spike IgG titer at diagnosis was determined using a chemiluminescent microparticle immunoassay (SARS-CoV-2 IgG II Quant; Abbott Laboratories, Chicago, USA. COVID-19 severity ranged from asymptomatic to moderate-II based on the Clinical Guidelines (Ver. 9) for COVID-19 by the Japanese Ministry of Health, Labour and Welfare.

The in vitro 50% inhibitory concentration (IC50) values of Imde/Casiri were determined using a focus reduction neutralization test, as previously described (13). Serial dilutions of Imde/Casiri (starting concentration, 50,000 ng/mL) were mixed with 100-400 focus-forming units (FFUs) of virus/well and incubated for 1 h at 37°C. The antibody-virus mixture (50 μL) was then inoculated onto Vero E6-TMPRSS2-T2A-ACE2 cells in 96-well plates in triplicate. After a 1-h incubation at 37°C, 100 μL of 1.5% Methyl Cellulose 400 (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan) in the culture medium was added to each well. The cells were incubated for 14-18 h at 37°C and fixed with formalin. After formalin removal, the cells were immunostained with a mouse monoclonal antibody against SARS-CoV-2 nucleoprotein (N45; TAUNS Laboratories, Izunokuni, Japan), followed by horseradish peroxidase-labeled goat anti-mouse immunoglobulin (Jackson ImmunoResearch Laboratories, West Grove, USA). The infected cells were stained with TrueBlue Substrate (SeraCare Life Sciences, Milford, MA, USA) and washed with distilled water. After drying, the focus numbers were quantified using an ImmunoSpot S6 Analyzer, the ImmunoCapture software program, and the BioSpot software program (Cellular Technology, Cleveland, USA). The results are expressed as IC50 values, which were calculated using the GraphPad Prism software program (GraphPad Software, San Diego, USA).

For whole-genome sequencing, viral RNA was extracted using the MGIEasy Nucleic Acid Extraction Kit (MGI Tech, Shenzhen, China). The whole genomes of SARS-CoV-2 were analyzed using an Illumina COVIDSeq Test V4 and NovaSeq 6000 (Illumina, San Diego, USA) in 100-bp single-end mode. To determine the virus sequences, the reads were assembled using the CLC Genomics Workbench (version 23; QIAGEN N. V., Venlo, Netherlands) with the Wuhan/Hu-1/2019 sequence (GenBank accession no. MN908947) used as a reference.

This retrospective study was conducted in compliance with the ethical principles of the Declaration of Helsinki and was approved by the Institutional Ethics Committee of Eiju General Hospital and the Research Ethics Review Committee of the Institute of Medical Science of the University of Tokyo (approval numbers: 2019-71-0201).

Results

The baseline characteristics of the 9 patients are shown in Table, and their clinical course is shown in Figure. In all cases, at least two mRNA vaccines had been administered.

Table. Patient Characteristics and COVID-19 Outcomes.

Case	Age (years)	Sex	Underlying disease	Treatment	COVID-19	
Omicron variant	Severity (O2 requirement)	SARS-CoV-2 IgG at diagnosis (U/mL)	Ct value lowest/highest	Treatment (day of treatment from diagnosis)	IC50 of isolates against Imde/Casiri* (ng/mL)	Days from diagnosis to negative PCR	Days from Imde/Casiri to negative PCR	
1st	2nd	3rd	
1	78	F	ML	RCHOP	BA.2	Mild	<50	30/40	Rem (D8-12)	Sotro (D14)	Imde/Casiri (D49)	3,908	56	7	
2	76	F	ML	maintenance with O	BQ.1.14	Mild	<50	21/24	Rem (D4-10)	Imde/Casiri (D11)		>50,000	>60	>60	
3	62	F	ML (LPL)	Tir	BF.21	Mild	<50	28/40	Rem (D4-13)	Imde/Casiri (D15)		7,051	36	21	
4	63	F	ML	8M after OB	BA.5.1	Moderate-I	<50	26/40	Molnu (D1-5)	Imde/Casiri (D26)	Rem (D32-38)	>50,000	39	13	
5	82	F	ML	3M after RCHOP	BA.5.2	Moderate-II (1L/min)	<50	31/40	Rem (D2-11)	Imde/Casiri (D16)		31,446	19	3	
6	68	M	ML	8 M after OB	BA.5.2	Moderate-II (6L/min)	<50	19/40	Rem (D38-51)	Imde/Casiri (D45)		3,219	52	7	
7	84	M	MM	DLd	Unknown	Mild	202	26/39	Rem (D1-5)	Imde/Casiri (D35)		-	39	4	
8	76	F	MM	None	Unknown	Mild	891	29/40	Rem (D1-5)	Imde/Casiri (D14)		-	27	13	
9	97	F	MM	MP	BA.5.2	Moderate-II (2L/min)	100	31/40	Rem (D2-15)	Imde/Casiri (D23)		6,146	26	3	
F: Female, M: Male, ML: Malignant Lymphoma, LP: Lymphoplasmacytic Lymphoma, MM: Multiple Myeloma

RCHOP: Rituximab, Cyclophosphamide, Adriamycin, Vincristine, Prednisolone, O: Obinutumab, Tir: Tirabrutinib, OB: Obinutumab, Bendamustine, DLd: Daratumumab, Lenalidmide, dexamethasone, MP: Melphalan, Prednisolone, Rem: Remdesivir, Molnu: Molnupiravir, Sotro: Sotrovimab, Imde/Casiri: Imdevimab,Casirivimab

*invitro50% inhibitory concentration (IC50) of Imde/Casiri against viruses isolated from each patient

Figure. Clinical course of nine hematological patients with COVID-19. The clinical time courses are indicated by bars. Gray, infection with COVID-19; light gray, non-infection with COVID-19; orange, antiviral drug administration; yellow, antibody cocktail administration. DLD: Daratumumab, Lenalidmide, and Dexamethasone, F: Female, Imde/Casiri, Imdevimab and Casirivimab, LPL: Lymphoplasmacytic Lymphoma, M: Male, ML: Malignant Lymphoma, Molnu: Molnupiravir, MM: Multiple Myeloma, MP: Melphalan and Prednisolone, O: Obinutumab, OB: Obinutumab and Bendamustine, Rem: Remdesivir, RCHOP: Rituximab, Cyclophosphamide, Adriamycin, Vincristine, and Prednisolone, Sotro: Sotrovimab, Tir: Tirabrutinib, The in vitro 50% inhibitory concentration (IC50) of Imde/Casiri against viruses isolated from each patient is shown in ng/mL.

Case 1 was infected with SARS-CoV-2 in April 2022, and the viral isolate was determined to be BA.2. COVID-19 was diagnosed in other cases between December 2022 and February 2023, when BA.5 was the dominant variant. Of these, Cases 2, 3, and 4 were confirmed as BQ1.14, BF.21, and BA.5.1, respectively, and Cases 5, 6, and 9 were confirmed as BA.5.2. The details of the remaining two cases were undetermined. All but one of the six lymphoma cases (i.e. Cases 1, 2, and 4-6) had been treated with anti-CD20mAb; Case 3, which was lymphoplasmacytic lymphoma, was treated with the Bruton tyrosine kinase (BTK) inhibitor tirabrutinib. The MM cases (Cases 7 and 9) were treated with daratumumab, lenalidomide, dexamethasone, and melphalan prednisolone, whereas Case 8 was not under treatment. In all cases, the anti-SARS-CoV-2 IgG titers after COVID-19 were low (＜891 IU/mL; in 6 cases, the titers were below the limit of detection). Viral RNA was detected even after treatment with remdesivir or molnupiravir. Therefore, Imde/Casiri was infused in these patients 11-49 days after the onset.

Within 7 days of infusion, viral RNA was undetectable in five of the nine cases (Cases 1, 3, 5, 6, and 9). As viruses isolated from seven patients (Cases 1, 2-6, and 9) showed low or no sensitivity to this monoclonal antibody cocktail, the disappearance of viral RNA upon antibody treatment in these cases may not be due to the antibody cocktail. Therefore, these findings support the use of mAbs that show some activity against these viruses in addition to direct neutralization to treat persistent SARS-CoV-2 infection in immunocompromised patients.

Discussion

Although vaccination against COVID-19 is a promising strategy to decrease the rate of infection or progression to severe disease, breakthrough infections occur frequently, as shown in our cases. Imde/Casiri has been shown to reduce the viral load in outpatients with COVID-19 (15), particularly those in whom an adequate immune response was not induced (16). Furthermore, Imde/Casiri has reduced the risk of COVID-19-related hospitalizations or deaths among outpatients and ameliorated the rates of hospitalization for high-risk patients with mild-to-moderate COVID-19 (17). In solid organ transplant patients, Imde/Casiri arrested symptom progression and reduced the need for hospitalization (18). Therefore, most patients with hematological malignancies are suitable candidates for this therapeutic intervention, which was able to reduce mortality in those who were seronegative at baseline (19). However, these reports were published when the alpha and delta variants were dominant. Since the end of 2021, the omicron variant of SARS-CoV-2 has predominated globally and evolved into several distinct sublineages (20); the clinical effectiveness of Imde/Casiri in this variant has not yet been established.

In our case, remdesivir or molnupiravir was administered without successful viral elimination. Therefore, Imde/Casiri was infused, although we subsequently found that the isolates from these patients were not susceptible to this antibody cocktail (Table). Since the Imde/Casiri cocktail has antibody-dependent cellular cytotoxicity (ADCC) against omicron variants (11), ADCC activity may have contributed to virus elimination in our patients. Alternatively, viruses may have been eliminated by the body's defense mechanisms. Similar successful viral clearance has been reported in immunodeficiency-associated patients with relapsing or prolonged COVID-19 (13,21). Previously, we treated a case of malignant lymphoma with an anti-CD20mAb-containing regimen, in which SARS-CoV-2 viral shedding persisted for as long as 246 days after the disease onset (8). In the present case, the patient was vaccinated, and the level of anti-SARS-CoV-2 IgG increased to more than 10,000 AU/mL at approximately 3 months after the onset, with the viruses ultimately eliminated. Cellular immunity may also have contributed to the elimination of the virus in this case, as a marked increase in CD4 and CD8 lymphocytes was observed after vaccination. Therefore, we need to seek appropriate treatment options on a case-by-case basis, considering the patient's level of immunocompromise, antigenicity of the virus, and availability of effective vaccines and therapeutic antibodies.

Sotrovimab, another mAb against SARS-CoV-2, retains stronger ADCC activity against BA.2 and BA.5 than does Imde/Casiri (22) and has neutralizing activity against XBB, one of the current omicron subvariants (23). Therefore, the clinical efficacy of sotrovimab should be evaluated in future COVID-19 studies.

Informed consent was obtained from all participants included in the study.

The authors state that they have no Conflict of Interest (COI).

Financial Support

Yoshihiro Kawaoka received collaborative research funds from FUJIFILM Toyama Chemical Co. LTD, Shionogi & Co. LTD, Daiichi Sankyo Pharmaceutical, Otsuka Pharmaceutical, KM Biologics, Kyoritsu Seiyaku, Fuji Rebio, Tauns Laboratories, Inc., Matsubara Co. LTD, and a cofounder of FluGen.
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