1. ATGs: how many??
ATG Fresenius: rabbit serum containing polyclonal antibodies against the ALL-T leukemia line Jurkat.
TMG Genzyme: rabbit serum containing polyclonal antibodies against human thymocytes.

2. Antibodies specificities
ATG/ALG CD mAb inhibitions
Source Fl-labeled CD mAb-50% inhibition point in μg/ml of ATG/ALG
CD2 CD3 CD4 CD5 CD7 CD8
ATG AM
(ATG horse Upjohn)
Merieux rabbit
Merieux horse
Fresenius >
MALG
(horse ATG Minnesota) Bourdage et al., Transplantation 1995;59:

3. ATG-F / TMG-G:
Different spectrum of specifities against co-stimulation molecules activity
Activities
anti CTLA ATG - F ++++
TMG - S ++
anti CD ATG - F +++
anti CD TMG - S +++
anti CD ATG - F ++++
TMG - S -
Pistillo et al., Transplantation 2000

4. ATG–F administration schedule (BO)
Total dose 15 mg/kg
3 mg/kg
CsA - MTX
Total dose 30 mg/kg
10 mg/kg
CsA - MTX

5. Prophylaxis of chronic GvHD with or without anti T-lymphocyte globulin (ATG-F) prior allogeneic peripheral stem cell transplantation from HLA-identical sibling after myeloablative conditioning in patients with acute leukemia: A randomised phase III study
Primary endpoint: reduction of cGVHD from 60% to 35%
Sample size: 60/arm
Study medication: ATG-Fresenius 10 mg/kg on days

6. Protocol Coordinator Germany: Nicolaus Kröger Hamburg
EUDRACT-Number (ATGfamily study) Sponsor: University Hospital Hamburg
Protocol Coordinator Germany: Nicolaus Kröger Hamburg
Protocol Coordinator Italy: Francesca Bonifazi Bologna
Scientific Committee: Nicolaus Kröger,
Axel R. Zander,
Frank Schulz-Kindermann Ernst Holler,
Hermann Einsele,
Jürgen Finke,
Rainer Schwerdtfeger,
Michael Schleuning
Gerhard Ehninger,
Martin Bornhäuser,
Hans-Jochem Kolb,
Hans-Jochem Kolb
Francesca Bonifazi,
Giuseppe Bandini,
Arnon Nagler,
Wolfang Bethke
Statistics: Dr. Hinke, Germany
Data Management: Andreas Voelp
C.R DataLog
Clinical monitoring Pharmalog/R. Dautermann 1

7. Levels of plasma ATG (active) and blood lymphocytes

8. ‘
mean channel value of fluorescence arbitrary units

9. Half time of Jurkat-reactive antibodies
8 patients after 30 mg/kg ATG-Fresenius days -3, -2, -1.

11. Preparative regimen ATG – G 800 cGy Tot. dose 7.5 mg 800 Gy
From Lowsky et al., 2005
CsA/MMF
ATG – G
800 cGy
Preparative regimen

12. ATG-G levels
From Lowsky et al., 2005

13. Intracellular interleukin-4
Comparison of Intracellular Cytokine Production.
From Lowsky et al., 2005

15. Effect of ATG prior to allogeneic stem cell transplantation
Before Tx
To facilitate engraftment
After Tx
To reduce risk of GvHD

16. GVHD after NMA Vs MA AlloSCT:
Skin
Morbidities involving the skin, liver, and gut after nonmyeloablative conditioning compared with myeloablative conditioning.
Liver
Gut
Figura 2
Overall
Acute
Chronic
Mielcarek et al. Blood 2003

18. From Sala-Torra et al., 2008

19. Linfomi.Ric GVHD ACUTA E CRONICA:
ATG VS NON ATG (BO)
Nr. pazienti

23. I and II treatment plans
ATG-G
- 4
- 1
10 mg/KG
200 Gy
FK / MTX
3/16 graft failure I
- 7
-10
ATG-G
10 mg/KG II
no graft failure
more infections
more relapse
450 Gy
FK / MTX
- 1
G-csf
From Toor et al., 2008

25. Hematopoietic Stem Cell Transplantation in a canine model
cATG-G
2-5 mg/kg
100 Gy
Csa /MMF
- 12
- 7
From Diaconescu et al., 2005

26. Dog. N°.
cATG-g (mg/kg)
Marrow Cells (million/kg)
Maximum Donor MNC Chimerism
(%)
Graft Rejection
Engraftment Duration (wk)
TNC
CD34
CD3
G200
3.5
263
4.2
17.8 5
Yes 8
G198 4
345
4.1
25.1 25 18
G166
206
7.5
6.9 11
G208
453
11.3
38.5 40 No
≥36
G252
175
6.6
13.2
From Diaconescu et al., 2005

28. Preparative regimen ATG – G 800 cGy Tot. dose 7.5 mg 800 Gy
From Lowsky et al., 2005
CsA/MMF
ATG – G
800 cGy
Preparative regimen

29. Lymphoid and myeloid engraftment
From Lowsky et al., 2005

30. T-cell engraftment
From Lowsky et al., 2005

31. Conclusioni
Utilizzo ATG non sarebbe indicato, in quanto riduce la GVHD, soprattutto cronica, diminuendo la GvL.
Utilizzo ATG indicato in quanto necessario per favorire l‘attecchimento, il chimerismo completo, elementi di primaria importanza ai fini del successo (eradicazione della malattia) del trapianto. La tossicità è minima. Gli ATG concorrono a realizzare dei condizionamenti “ridotti” evitando l’impiego di farmaci citotossici/immunosoppressivi.
Poiché il punto 2 è molto più importante del punto 1, gli ATG devono essere usati nei regimi “a intensità ridotta”.