Therapeutic Antibodies and Immunologic Conjugates
Summary of Key Points
• Because of their tumor selectivity, monoclonal antibodies offer exceptional opportunities for targeted therapy.
• When naked, monoclonal antibodies can kill tumors by receptor blockade and by actively inducing apoptosis.
• Tumor cytotoxicity is mediated through white cells by activating antibody-dependent cell-mediated cytotoxicity, and in the presence of serum, by complement-mediated cytotoxicity.
• Bispecific or multifunctional constructs can greatly enhance the antitumor effect of antibodies.
• Antibodies can deliver effector molecules in the form of drug conjugates, radioimmunoconjugates, immunocytokines, immunotoxins, immunoenzymes, immunoliposomes, and retargeted killer cells.
• Naked antibodies generally do not have overlapping toxicity profiles with chemotherapy and radiation therapies, and dose-limiting toxicities of immunoconjugates vary depending on the cytotoxic moiety (e.g., myelosuppression in radioimmunoconjugates) being used.
• Antibodies are likely to be most beneficial at the time of minimal residual disease, especially when used in conjunction with standard therapy.
• The following antibodies are licensed by the Food and Drug Administration and are in use for the cancers listed (target molecule in bold):
Alemtuzumab (Campath): B-chronic lymphocytic leukemia (CD52)
Bevacizumab (Avastin): colorectal cancer (VEGF)
Cetuximab (Erbitux): colorectal cancer, head and neck cancer (EGFR)
Ibritumomab (Zevalin): non-Hodgkin lymphoma (Yttrium-90, CD20)
Rituximab (Rituxan): non-Hodgkin lymphoma (CD20)
Trastuzumab (Herceptin): breast cancer (HER2)
Ipilimumab (Yervoy): melanoma (CTLA4)
• In the coming decade, other monoclonal antibodies currently in various phases of clinical trial, as well as those approved for nononcologic indications, may be added to the list. The prospects for further innovation in this established cancer treatment modality are highly favorable.
1. Improving the efficacy of antibody-based therapeutics is an active area of research. Monoclonal antibodies (MAbs) can be engineered to reduce immunogenicity, enhance its binding to human FcR, and prolong its serum half-life. Based on your understanding of the steps taken to improve the efficacy of antibody-based therapies, which of the following statements is most likely to be true?
A Increasing antigen-binding affinity through reengineering of an MAb will not increase antitumor response.
B Humanizing MAb reduces immunogenicity through joining antigen combining variable domains of a human MAb to the human constant domain.
C Defucosylation of the Fc region of an MAb can greatly improve its antibody-dependent cell-mediated cytotoxicity (ADCC) properties.
D Point mutations of the Fc region of an MAb have little effect on effector functions, including ADCC and complement-mediated cytotoxicity (CMC).
2. Antibody drug conjugate (ADC) for selective delivery of drugs to a tumor has had limited clinical success until recently. Which of the following is least likely to be a limitation of this modality?
3. MAbs have the potential to target and ablate tumors by radioimmunotherapy. Based on the previous discussion, which radioactive particles have the ideal cytotoxic profile with the least bystander effect, while allowing for radioimaging and dosimetry?
4. MAbs can mediate highly effective tumoricidal functions both in vitro and in vivo. These functions include signaling through receptor binding, ADCC, and CMC mediated by antitumor antibodies. MAb can also enhance tumor cytotoxicity by activating lymphocytes or removing their inhibitory signals. In which of the following situations would you least expect heightened antitumor effects as a result?
A Treatment with antibodies to CD137
B Treatment with anti-CTLA4 antibodies
5. Immunotherapy of solid tumors poses many challenges for antibody development. Which of the following would be considered the least likely limitation of immunotherapy for solid tumors?
1. Answer: C. Defucosylation of the Fc region can theoretically and in practice enhance effector function of monoclonal antibodies. Likewise, increasing antigen-binding affinity and introduction of certain point mutations in the Fc region may also increase ADCC and CMC. Although humanization does reduce immunogenicity, it involves grafting complementarity-determining regions from a mouse MAb (not human MAb) onto the backbone or a human IgG.
2. Answer: D. Short transit time of the ligand in multistep targeting actually leads to improvement in the therapeutic ratio without sacrificing the percent injected dose per gram in the tumor. Short transit time is not a limitation, whereas all the other choices are limitations.
3. Answer: E. Alpha particles have a short path length but extremely high linear energy transfer for killing cells. Gamma particle emitters, being so much lighter, travel much farther and can be easily detected by a gamma camera; thus it is also ideal for radioimaging and dosimetry.
4. Answer: D. Although increasing the CMC potency of an antibody can theoretically increase its antitumor activity, human tumors express anticomplement surface proteins and remain relatively resistant to killing by CMC, unless these braking proteins are turned off. Removing inhibitory signaling of immune cells in immunocompetent patients has proven effective.
5. Answer: A. Cytokine release, immunogenicity, and cross-reactivity are all limitations encountered during the clinical development of antitumor antibodies. Myelosuppression is rare except when radioisotopes or drugs are conjugated to the antibody. Myelosuppression is not a general limitation of antibody technology.
