TUMOR-TARGETED SUPERANTIGENS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 353

24

TUMOR-TARGETED SUPERANTIGENS

G UNNAR H EDLUND ,Go RAN F ORSBERG ,T HORE N EDERMAN ,A NETTE S UNDSTEDT ,
L EIF D AHLBERG ,M IKAEL T IENSUU , AND M ATS N ILSSON

Active Biotech AB, Lund, Sweden

24.1 Introduction: tumor-targeted superantigens—a unique
concept of cancer treatment
24.2 Structure and production of tumor-targeted superantigens
24.3 Tumor-targeted superantigens are powerful targeted immune
activators and useful for all types of malignancies
24.4 Increasing the therapeutic window and exposure by the
creation of a novel TTS fusion protein with minimal MHC
class II affinity; naptumomab estafenatox
24.5 Clinical experience with TTS therapeutic fusion proteins
24.6 Combining TTS with cytostatic and immunomodulating
anticancer drugs
24.7 Conclusions
References

knowledge regarding T-cell activation by the SAg staphylo-
coccal enterotoxin A (SEA) was lined out at the Wallenberg
laboratory in Lund, Sweden, where it was shown that SEA
binds to MHC class II expressing accessory cells and
activates both CD4 þ and CD8 þ T cells [4,5]. Subsequently,
the binding sites between SEA (Figure 24.1) and MHC
class II and the T-cell receptor (TCR) containing certain
V b sequences were identified [6-10]. The capacity of SEA
to associate with MHC class II and activate T cells was
further elucidated, and it was demonstrated that MHC
class II expressing cells were killed by cytotoxic T lympho-
cytes (CTLs) when targeted by SEA [11-14].
A tumor-specific SAg can be created by fusing the SAg to
the Fab moiety of a tumor reactive monoclonal antibody
(mAb). Fab-SAg fusion proteins have been successfully
used to cure mice with established experimental tumors
(for references see 24.3). The therapeutic effect was associ-
ated with a massive infiltration throughout the tumor of T
cells that actively produced tumoricidal cytokines such as
tumor necrosis factor (TNF)- a and interferon (IFN)- g . The
therapeutic efficacy is most likely related to the dual mech-
anism of tumor cell killing: direct lysis of tumor cells
expressing the antigen recognized by the antibody moiety
of the fusion protein and secretion of cytokines eliminating
antigen-negative tumor cell variants (Figure 24.2). The
induction of multiple antitumor mechanisms is considered
clinically important because it addresses the problem of
tumor cell heterogeneity inevitably found in all human
tumors. The inflammatory response induced in the tumor
also facilitates uptake of the fusion proteins, thereby over-
coming the poor penetration of macromolecules in a tumor.
The TTS therapeutic proteins are typically used in cycles of
4-5 daily intravenous injections. In the first phase of a cycle,

24.1 INTRODUCTION: TUMOR-TARGETED
SUPERANTIGENS—A UNIQUE CONCEPT OF
CANCER TREATMENT

The tumor-targeted superantigen (TTS) concept uses a
unique approach to target large numbers of T cells to tumors
[1-3]. T lymphocytes are very effective in eliminating virus-
infected cells, allogeneic transplants, and some experimen-
tal tumors. However, in humans, tumor-specific T cells occur
in low numbers and are insufficient to interfere with an
established growing tumor. In TTS, bacterial superantigens
(SAgs), the most potent activators of human T cells known
today, are used to activate and target large numbers of T cells
to the tumor. SAgs bind to major histocompatibility complex
(MHC) class II molecules and activate large numbers of
cytotoxic and helper T lymphocytes. The fundamental