STRUCTURAL ASPECTS OF FUSION PROTEINS DETERMINING THE LEVEL OF COMMERCIAL SUCCESS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 42

instead designed to bind to target recepto rs and thereby
block another disease-re lated ligand from d oing so. Biogen
Idec/ Astel las' Amevive (R) (alefacept ) is the only marketed
signal-bl ocking ligand half-life FP, formed of a ligand
fragment fuse d to IgG Fc that prevents the co-s timulatory
molecu le intera ction with the target receptor. It is approved
for the treatme nt o f plaq ue psorias is. However, the produc t
has disappoi nted in the market due to the super ior efficacy
and safe ty offered by TNF inhib itors and failure to gain
EU approval.

groups , the FPs are desi gned to exploit certai n targets
that are disp roportionat ely assoc iated with cells causing
the disease .
Ontak gain ed FDA approval in 1999 for the treatme nt of
adult patient s with recurre nt or persistent cutaneous T-cell
lymphom a (CTCL) expressing the CD25 com ponent of the
IL-2 recepto r. It is current ly the only marketed targeted
toxin. To date, Ont ak has failed to achieve annual globa l
sales of over $100 milli on—pr imarily due to a small
approved patient popul ation, acute hyper sensitivity
reactions, and a lack of indi cation expansion [21] . 2,3
CTCL accounts for only 2.2% of total lymphom a case s in
the Uni ted States. 4 As a tec hnology, such FPs are positi oned
to compet e with conjugat ed immu notoxins (immunoc onju-
gates/ Ab-drug conjugates) , such as Pfizer's Mylotarg 1
(gemt uzumab ozogami cin), which was granted accele rated
FDA approval in 2000 for the treat ment of patients aged 6 0
or over with CD33

3.1.6 FPs Of fer a Wide Range of Cell Death
Mecha nisms (3a-7b)

Disorders i nvolving malfunctioning cells can potentially
be treated in a number of wa ys. Where associated with
disease s ym ptoms or the survival and proliferation of
disease-related cells, individual proteins represent poten-
t i a l c a n d i d a t e s f o r m a n i p u l a t i o n . A l t e r n a t ivel y, p r o b l e m -
a t i c c e l l s c a n b e k i l l e d o ff. S t u d i e s h ave i d e n t i fie d
numerous antigens that are a ssociated with cells involved
in c anc er and o the r dis e as es . T hes e prov ide a r ic h sourc e of
targets that can be employed by a ntibodies or ot he r m ol -
e c u l e s t h a t s e l e c t ivel y b i n d t o t h e m .
Out o f the 43 total FPs , 20 relat e to cell deat h mec ha-
nisms. Of these, 16 are in development for cancer indica-
tions, with the remainder treating infectiou s dise ases and to a
lesser extent, autoimm une and urol ogy (benign prostat ic
hyperpla sia) disorders (see therapy area discussi on in Cha p-
ter 2). Th e cell death products span eigh t differ ent partner
combina tions with the largest tw o bein g ligands (IL-2 or
TNF) fused to Abs and micro bial toxins fused to non-Abs
(Figure 3.2: 4b and 3a). A further approach consi sts o f
vaccine FPs that efficient ly deliver antigen s direct ly to
the immu ne system (5a and 5b). Sim ilarly, bispeci fic anti-
body construc ts have been designed to actively recruit the
immune response machin ery (7b).

recurrent acute myeloid leukem ia who
were not consider ed candidates for other chemot herapy.
However, the product was withd rawn from the market in
June 2010 after further trials showed it to offer no clinical
benefit but an increas ed fatality rate. Seat tle Genetics '
conjug ated Ab, Adcetr is TM (brentux imab vedotin) gain ed
FDA approval in August 2011.
I n i t i a l t a rg e t e d t o x i n d evel o p m e n t a t t e m p t s f o c u s e d o n
chemo-labeled antibodies, or standard chemotherapy
agents conjugated to mAbs. These small molecule t oxin
approaches offered only limited potency, a nd so, more
efficient agents w ere em pl oyed, including the a ttachm ent
or fusion to enzymatic peptides that required only one copy
to kill a cell. Safet y concerns ex ist r egardi ng the a dminis-
trat ion o f h ighly p otent t oxins. Im portant ly, the toxin a nd
targeting c om ponent must contain minim al or no
sequences that bind to targ ets i n healthy tissue. The
toxicity and fatalities caused by M ylotarg are thought to
r e s u l t f r o m u n i n t e n d e d d e l iver y t o C D 3 3

þ

cells i n the l ive r
[ 2 2 ] . A s i d e f r o m d e l iver y t o h e a l t h y c e l l s ex p r e s s i n g t h e
ri ght target, toxici ty si de effe ct s w ith targeted toxi ns can
also arise f rom nonspecific uptake by cells or indirect
ex posure to the released toxin.
In many cases, the toxin is desi gned to be internalize d via
recepto r-med iated endocytosis of the linked d elivery com -
ponent . The therape utic profile of a produc t will be affected
by factor s such as the accessi bility of targets, target half-lif e
and the intern alizatio n half-life of the complex following

þ

3.1.6.1 Targeted Toxins (3a a nd 3b) Cytot oxic agents
historica lly used for the treatme nt of cancer, for example,
typicall y have low specifi city for tum ors, causing problem -
atic side effects. In “magic bullet” appro aches , cytotoxics
can be targeted to partic ular area s of the body or cell types,
resulting in a mor e conce ntrated dose at desired sites. This
allows highe r overall d oses or mor e pote nt agents to be used,
increasing efficacy, as well as reduc ing doses in othe r areas
of the body for an improved side effect profil e. Of the six
targeted toxin FPs, four use non-A b delivery, includi ng the
most advanced , Eisa i's Ontak 1 (denil eukin dif titox) which
is on the market and Neo Pharm's cintredekin besudo tox in
Phase III. Several of thes e non-A b FPs use interleuk ins to
deliver the micro bial toxin to loca tions expressing interleu-
kin recepto rs, while the tw o antibody -delivered FPs (recom -
binant immu notoxin) target cel l-surface antigen s. In both

2 http://www.evaluatepharma.com/Universal/View.aspx?type ¼ Entity&
entityType ¼ Product&id ¼ 35272&lType ¼ modData&componentID ¼ 1002
3 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/EnforcementActivitiesbyFDA/WarningLettersandNoticeof
ViolationLetterstoPharmaceuticalCompanies/ucm053642.pdf?utm_
campaign ¼ Google2&utm_ source ¼ fdaSearch&utm_medium ¼ website&
utm_term ¼ ucm053642.pdf&utm_content ¼ 1
4 http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4191B1_03_
Ligand-Ontak.pdf