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90 CHAPTER 4 Immunotherapy

FIGURE 4.11 Bystander killing.

e) Lysosomal degradation of ADC in noncleavable payloads
f) Release of payloads causing disruption of microtubule or DNA break and finally
g) Cell apoptosis
Note: permeable membrane causing bystander killing in antigen negative cells as
a result of drug release in its micro environment.
Although ADCs have the ability to expand the therapeutic window through its
ability in antigen selection and usage of toxic agents [58,60,61], as well as increas-
ing the safety by decreasing the toxic agent exposure with normal tissues, scientists
are faced with obstacles and failures due to the usage of weak chemotherapy agents,
linkers with instability and problems with antigen recognition, slow rates of antibody
penetration from plasma to target tissue which causes low amount of ADCs to reach
tumors. Further investigation revealed that after 24 h of injection, only 0.01% of
administrated dose was reached to tumor cells [60-62].
The vital factors in ADCs manufacturing include: decreasing the immunogenic-
ity, expanding the circulation span, boosting the antigen targeting specificity, and
diminishing the normal cell injuries [63].
To satisfy all these factors it is essential to study the chemical properties of the
linkers, the payload and antibody, the tumor antigen selection and the bio proper-
ties of the target cell surface [62,64]. ADCs are composed of three divergent parts:
the antibody, the cytotoxic part (drug) and the linker. All these parts and the antigen
selection are illustrated in this chapter.

4.5.1 Antigens

Some crucial factors that lead to a better ADCs response include:
1) The targeted antigen should be expressed in a great amount with minimal
heterogeneity, the nonhomogenous tumor antigen expression may cause the