In Brief: 1) ADCT-301, a CD25 targeting ADC from ADC Therapeutics utilising PBD payload and HuMax technology. 2) PCA062, a p-Cadherin targeting ADC from 3) We were interested to see the re-introduction of ImmunoGen’s IMGN-901 into clinical trials with two new phase II trials added this month, for leukemia and childhood cancers. In addition we have been adding a significant number of immunotoxins, including denileukin diftitox (ONTAK®), Moxetumomab pasudotox, LMB-2, naptumomab estafenatox, VB4-845, D2C7-IT and SS1P. Read June’s Digest in Full

2. Welcome
May has just flown by in a whirlwind of Immunotoxins and abstracts. We
have decided to send out this month’s digest a little early so that you can
read it on the plane to ASCO! Don’t worry if you aren’t going to ASCO– all
the new and exciting data will be added to World ADC Trials Intelligence as
soon as possible, with a round up next month.
New Clinical Trials for May
New compounds that have recently initiated their first phase I trials and have
been added to the trials intelligence database:
• ADCT-301, a CD25 targeting ADC from ADC Therapeutics utilising PBD
payload and HuMax technology.
• PCA062, a p-Cadherin targeting ADC from Novartis.
• We were interested to see the re-introduction of Immunogen’s IMGN-901
into clinical trials with 2 new phase 2 trials added this month, for leukemia
and childhood cancers. A previous trial was terminated in 2013 due to
concerns over infection rates and infection-related deaths as well as a lack
of PFS benefit in patients with small cell lung cancer.

3. Focus on Immunotoxins
1
We have added more than 70 trials this month, most of these are Immunotoxins
(ITs). There are a variety of different toxin based payloads that the immunotoxins
are utilising and are reviewed in Alewine C., et al., 2015. Many of the early ITs
generated very rapid and strong neutralising antibodies to both target and toxin,
preventing repeated cycles of treatment which impeded effective responses (e.g.
LMB-1 , RFT5-dgA and RFB4-SMPT-dgA).
More recently, attempts to reduce the immune response to treatment without
altering the clinical response has been the focus of several trials. Pre-treatment
with cyclophosphamide, cyclosporine A or rituximab proved to be not effective at
preventing the development of neutralising antibodies, but using a combination of
pentostatin and cyclophosphamide (as in GvHD) has been shown to delay the
neutralising antibodies to immunotoxins (e.g. SS1P).

4. Focus on Immunotoxins
2
The use of a toxin rather than a chemotherapeutic agent as the payload may allow
the combination of chemotherapy and IT without overlapping toxicities.
Alternatively, they may prove effective in chemo-refractory tumors. In addition, ITs
can kill non-dividing cells. However, this capacity to target non-dividing cells is also
likely responsible for many of the off target toxicities, particularly vascular leak
syndrome, a frequently reported dose limiting toxicity.
Like ADCs there are many ITs in clinical development, but the only IT to be licenced
currently is denileukin diftitox (Ontak®) which is indicated for use in chronic T cell
leukemia, and is currently showing efficacy for other conditions such as B cell non-
Hodgkin Lymphoma and chronic lymphocytic leukemia, but not for melanoma.
In the pipeline are several other agents of interest (Table 1), with the same targets
as the ADCs, including CD22(Moxetumomab pasudotox), CD25 (LMB-2), 5T4
(naptumomab estafenatox), EpCAM (VB4-845), EGFR (D2C7-IT) and mesothelin
(SS1P).

5. Table 1: Immunotoxins in active
clinical testing
Sponsor Drug Name Phase Target Target Moiety Payload
National Cancer Institute
(NCI), Medimmune LLC
CAT-8015, Moxetumomab
Pasudotox, GCR-8015, High
affinity BL22 (HA22)
3 CD22
Moxetumomab, Fv
Portion
Pseudomonas Exotoxin-A (PE38),
BL22 Immunotoxin
Aeterna Zentaris Zoptarelin doxorubicin, AEZS-108 3 LHRH D-Lys6-LHRH PE
Insys
Cintredekin besudotox, IL13-
PE38QQR
3 IL13R IL13 PE38QQR
Eisai Ontak, E777, denileukin diftitox 3 CD25 IL2 Diptheria Toxin
Active Biotech AB
Naptumomab Estafenatox,
Anyara, ABR-217620, 5T4FabV18-
SEA/E-120
2, 3 5T4
Naptumomab, Fab
fragment
Staphylococcal Enterotoxin A & E
(SEA/E-120)
Angimmune LLC
A-dmDT390-bisFv(UCHT1),
Resimmune
2 CD3 bisFv(UCHT1) Diptheria Toxin - dmDT390
National Cancer Institute (NCI) LMB-2, Anti-Tac(Fv)-PE38 2 CD25 Tac
Pseudomonas Aeruginosa
exotoxin (PE38)
Viventia Biotech VB4-845: Proxinium 2
Epithelial cell adhesion
molecule (EpCAM)
EpCAM targetting
fragment
Truncated form of Pseudomonas
exotoxin A
Viventia Biotech VB4-845: Vicinium 2
Epithelial cell adhesion
molecule (EpCAM)
EpCAM targetting
fragment
Truncated form of Pseudomonas
exotoxin A
National Cancer Institute (NCI) SS1P, SS1 (dsFv)-PE38 1, 2 Mesothelin (MSLN) Unknown
Pseudomonas Aeruginosa
exotoxin (PE38)
Masonic Cancer Center DT2219 1 CD19, CD22 HD37, RFB4 Diptheria Toxin - dmDT390
Darell D. Bigner, Duke
University Medical Center
D2C7-(scdsFv)-PE38KDEL, D2C7 1 EGFRvIII and wt PE
Oslo University Hospital MOC31PE, ImmunoPeCa 1
Epithelial cell adhesion
molecule (EpCAM)
PE
Alfred Einstein College of
Medicine of Yershiva
University
Combotox 1 CD19, CD22 HD37, RFB4(dsFv) deglycosylated ricin A (dgA)
Molecular Templates MT-3724 1 CD20 scFv Fragment Shiga-like toxin A (SLTA)
Viventia Biotech VB6-845 1
Epithelial cell adhesion
molecule (EpCAM)
Fab fragment DeBouganin

6. Table 2: Immunotoxin compounds that
have been discontinued
Sponsor Drug Name Phase Target Target Moiety Payload
Teva Pharmaceutical
Industries
TP38 2
Epidermal growth
factor receptor
(EGFR)
TGF-alpha
Pseudomonas Aeruginosa
exotoxin (PE38)
Simmons Cancer Center RFT5-dgA 2 CD25 RFT5 deglycosylated ricin A (dgA)
National Cancer Institute
(NCI)
LMB-1 2 Lewis Y antigen B3
Pseudomonas Aeruginosa
exotoxin (PE38)
Duke University Medical
Center
LMB-7 1 Lewis Y antigen scFv of B3
Pseudomonas Aeruginosa
exotoxin (PE38)
M.D. Anderson Cancer
Center
HuM-195/rGel 1 CD33 Hum195 recombinant Gelonin (rGel)
Darell D. Bigner, Duke
University Medical Center
MR1-1 1 Unknown Unknown Unknown
Medimmune LLC BL22, CAT3888 1 CD22 RFB4(dsFv)
Pseudomonas Aeruginosa
exotoxin (PE38)
National Cancer Institute
(NCI)
LMB-9 1 Lewis Y antigen dsFv of B3
Pseudomonas Aeruginosa
exotoxin (PE38)
National Cancer Institute
(NCI)
IgG RFB4 SMPT 1 CD22 RFB4 deglycosylated ricin A (dgA)

7. Focus on Immunotoxins
3
The future of ITs looks promising with Zoptarelin doxorubicin, Cintredekin
besudotox, Moxetumomab pasudotox and Naptumomab estafenatox all currently
in phase III trials . As you would expect, we will be adding novel date an
compounds to the trials intelligence database as soon as we hear it.

8. Things to look out for in June on
World ADC Trials Intelligence
ASCO, ASCO, ASCO! We will be updating the trials intelligence database on a daily
basis during ASCO with all new relevant information, and will continue adding data
as it comes in throughout June.
If you are presenting any new data or would like your posters added to the
database then please do email them to me.
Have a great month, and don’t forget, you can email me any time for any specific
queries you have regarding the database or ADCs in general
Heather
Contact the World ADC Research Team on:
research@hansonwade.com