Crotalidae polyvalent immune fab ovine (CroFab) as a model of hidden α Gal antigen
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4/12/2021
Crotalidae‐polyvalent immune fab
[ovine] (CroFab®) as a model of
hidden α‐Gal antigen
59th Annual Swineford Conference
BY: M AT T H E W ST RAESSER, M D
2 0 2 0 G R A D UATE O F U VA A L L E RGY A N D I M M U N O LOGY F E L LOWS H IP
E M P LOYED P H YS I C IA N AT C E N T R A L P E N N SY LVAN I A A S T H M A A N D A L L E RGY C A R E
Disclosures
I have no relevant disclosures
1
4/12/2021
FabAV as a model of hidden α‐Gal antigen
‐ Background
Crotalidae‐polyvalent immune fab [ovine] = CroFab® = FabAV
FabAV is FDA approved for venomous snake bite treatment of the
crotalus subfamily (new world pit vipers)
FabAV is synthesized by hyperimmunizing sheep against venom of
the following species:
Eastern diamond back rattlesnake
Western diamond back rattlesnake
Mojave rattlesnake
Cottonmouth
FabAV as a model of hidden α‐Gal antigen
‐ Background: Virginia venomous snakes
Endangered Species
https://www.virginiaherpetologicalsociety.com/reptiles/snakes/snakes_of_virginia.htm
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4/12/2021
FabAV as a model of hidden α‐Gal antigen
‐ Background
The polyvalent antibodies are isolated, enzyme treated and
extensively purified to Fab fragments
Drug carries a black box warning for hypersensitivity reactions: reported
5‐19%, including immediate hypersensitivity reactions
Warning for known hypersensitivity to sheep, papaya, papaya extracts, papain,
chymopapain, pineapple‐enzyme bromelain1
May cross‐react with dust mite and latex allergens
Pre‐marketing study demonstrated adverse reactions (any) in 12/42
subjects treated with FabAV
3/12 were severe allergic reactions1
CroFab® Package Insert.
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4/12/2021
FabAV as a model of hidden α‐Gal antigen
‐ Background
Post‐marketing analysis: 36/247 patients experienced adverse
reactions
11/36 reactions were deemed hypersensitivity reactions (11/247 = 4.45%)
However, Khobrani et al reported that allergic reactions to FabAV were noted in
19/1340 patients treated with FabAV in the Arizona Poison and Drug Information
Center Toxicall Database (equates to 1.4%)2
At UVA, Rizer et al published a case report of anaphylaxis to FabAV in a patient
with asymptomatic α‐Gal sensitization. First published report linking FabAV to a
possible α‐Gal related reaction3
1. FabAV Package Insert.
2. Khobrani et al. Critical Care Medicine. 2016 44(12).
3. Rizer et al. Journal of Clinical Toxicology. 2017.
FabAV as a model of hidden α‐Gal antigen
‐ Background
The presence of α‐Gal in antivenom was first reported by Fischer et al
However, FabAV was not evaluated and they lacked a confirmed α‐Gal
reaction case
BAT’s of various antivenoms (manufacturer)
• SAI: SAIMR polyvalent snake antivenom
• BHA: Snake venom antiserum I.P.
• CSL: Polyvalent snake antivenom
Australia‐Papua New Guinea
• BUT: Soro Antiscorpionico
• CET: cetuximab
• PK: pork kidney
Fischer et al. Allergy. 2016.
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FabAV as a model of hidden α‐Gal antigen
Retrospective chart review of all patients at UVA who received FabAV between 2011‐2020
Many patients presented with toxic envenomation (nausea, vomiting, flushing) and were
treated symptomatically with diphenhydramine, steroids
Additionally, many patients received diphenhydramine/methylprednisolone pretreatment in
anticipation for allergic reactions
4 allergic reactions were identified; all were severe, requiring epinephrine, diphenhydramine,
and/or methylprednisolone treatment
Number Male Female Median Age Average dose Reactions α‐Gal assessed
72 40 32 35 4.3 4 (5.6%) 1 (sIgE α‐Gal = 4.1)
Straesser and Keshavarz et al. JACI: In Practice. 2021.
FabAV as a model of hidden α‐Gal antigen
FabAV ImmunoCAP was generated using the biotin‐streptavidin technique
Ideal and pragmatic solid phase concentration was found to be 20
µg/ImmunoCAP
α‐Gal seropositive and seronegative controls available from prior IRB approved
studies
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4/12/2021
FabAV as a model of hidden α‐Gal antigen
‐ ImmunoCAP analysis
*Spearman coefficient, r
CroFab RFU
0.71, p
4/12/2021
Basophil Activation Test (BAT)
Conducted using commercially available Flow CAST® BAT kit through
Buhlmann Diagnostics Corporation
Basophil detection marker CCR3
Activation marker CD63
Two accepted methods to conduct BAT
Direct BAT: direct stimulation of subject basophils
Indirect BAT: passive transfer of subject’s serum to donor (non‐allergic)
basophils
https://buhlmannlabs.com/products‐solutions/cellular‐allergy/flow‐cast/
FabAV as a model of hidden α‐Gal antigen
‐ Direct BAT analysis
Basophil activation test results on a
subject with α‐Gal syndrome (sIgE
35.0 IU/mL), α‐Gal‐sensitized patient
with FabAV anaphylaxis, and a
negative control subject (non‐allergic).
1.4 mg/mL FabAV concentration
chosen as this approaches physiologic
concentrations. 4‐16 grams FabAV per
5L blood volume.
Straesser and Keshavarz et al. JACI: In Practice. 2021.
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4/12/2021
FabAV as a model of hidden α‐Gal antigen
‐ Indirect BAT analysis
(a) Subject prior to passive IgE transfer (b) Subject after passive IgE transfer
Indirect BAT using passive IgE transfer.
Diluent Negative control non‐reactive to
Negative control
FabAV and beef thyroglobulin prior to
passive serum transfer.
Anti‐FcεRI
Positive control
13.7% FabAV After passive serum transfer with a
(0.1 mg/mL) known α‐Gal subject (sIgE 35 IU/mL),
negative control now stimulates to
45.2%
Beef thyroglobulin FabAV and beef thyroglobulin.
(0.1 mg/mL)
FabAV as a model of hidden α‐Gal antigen
‐ Conclusion
ImmunoCAP, Western Blot, and BAT analyses confirm that α‐Gal antigen is
present on FabAV
Higher reaction rate to antivenom at UVA and case report suggest that α‐Gal is
functioning as a target for IgE‐mediated reactions
However, quantity of α‐Gal antigen present on FabAV does appear to be
substantially lower than quantity present on cetuximab, estimated to be ~50‐
100x lower on molar basis
This finding is consistent with Fischer et al report
Published JACI: In Practice. 2021, 9(2):1015‐1017.
Fischer et al. Allergy. 2016.
Straesser and Keshavarz et al. JACI: In Practice. 2021.
84/12/2021
Acknowledgements:
Acknowledgements:
Larry Borish Emily McGowan Thamiris Palacios
Thomas Platts‐Mills Peter Heymann Timothy Kyin
Monica Lawrence Elaine Etter Anna Smith
John Steinke Rung‐chi Li Jonathan Hemler
Julie Negri Monica Gupta Samantha Minnicozzi
Madison Ramsden Julia Sohn Judith Woodfolk
Jeffrey Wilson William Eschenbacher Jacob Eccles
Lisa Workman Alice Knoedler Lyndsey Muehling
Margaret Kim Robert Sullivan All clinical staff
Behnam Keshavarz DeVon Preston at Northridge/Battle
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