LICR Targeted Therapies

Targeted Antibody Therapies

Targeted antibodies have emerged as an important therapeutic modality for treating cancer. Although results from clinical trials with antibodies do show some efficacy, the widely-predicted success of several targeted antibodies has failed to fully materialize thus far. LICR believes that the full potential of this type of therapy will only be realized by more comprehensive study.

LICR First in Man Antibody Investigation

LICR utilizes its own clinical investigation model to efficiently and comprehensively evaluate the potential of a mAb for clinical development. The objective is to acquire as much information as possible in a single clinical trial about the mAb’s safety, immunogenicity, targeting, pharmacokinetics and anti-tumor activity.

  • Safety: The health and welfare of patients following antibody transfusions are key concerns of all clinical trials. All adverse events experienced by patients while on study are reported to the central LICR Office of Clinical Trials Management and assessed for relationship to the therapy.
  • Immunogenecity: Blood samples are tested for the presence of secondary antibodies - human anti-human antibodies (HAHA), or human anti-chimeric antibodies (HACA) - that indicate the mAb is immunogenic. HAHA and HACA build up over time, and are thus most effectively monitored using a multiple infusion and testing strategy such as that employed by LICR.
  • Targeting: Utilization of a trace-labeled mAb enables the visualization of tumor targeting and distribution to normal tissues, and the duration of mAb binding (see figure at right). In addition, the rate of clearance of a second injection of trace-labelled mAb after completing a course of antibody treatment provides another way to assess immunogenicity. More rapid clearance indicates that the mAb has elicited an immune reaction and is therefore unlikely to be of clinical value.
  • Pharmacokinetics: The mAb protein concentration in blood is used to calculate half-life, body clearance, volume of distribution and other pharmacokinetic parameters, which will be used to establish dose and delivery.
  • Tumor Response: The tumor response to mAb treatment is evaluated in accordance with the accepted standards of clinical practice and patient care.

Clinical Development

To optimize targeting and therapeutic efficiency, preclinical and clinical investigations are addressing the many variables involved in evolving successful antibody-based therapies:

  • Antibody Variants : The LICR Antibody Targeting Program is assessing the therapeutic potential of chimeric, humanized, and scFv antibodies. The smaller scFv constructs may be better suited to the delivery of particular isotopes/toxins to certain tumors. In addition, antibody-cytokine fusion proteins have been constructed as a way to deliver inflammatory or immunomodulatory cytokines, eg tumor necrosis factor (TNF) to the tumor site.
  • Isotopes/Toxins: LICR is assessing several different radioisotopes for their potential for RIT, or for diagnostic imaging using PET and SPECT. Different isotopes have different physical properties making them better suited to therapy or diagnostic imaging depending on the half-life of the mAb and the radioisotope. The therapeutic potential of selected drugs and toxins is also being investigated.
  • Antibody Fate: The first objective of LICR’s Antibody Targeting Program is to identify antibodies with high selectivity for tumor cells, no immunogenicity, and excellent tumor targeting characteristics in humans. Much attention is now being focused on the fate of the different antibodies in the LICR portfolio after they bind to the tumor cell surface. Some antibodies remain on the cell surface for extended periods, others are promptly taken up by the cell, in a process called internalization, and directed to various cellular compartments. Understanding the fate of the antibody after localization to the tumor will help define the optimal therapeutic strategies for different antibodies and antibody constructs.

Antibody Table

LICR Antibodies in Clinical Discovery
  Ongoing or completed clinical trials.
Antibody Target Tumor mAb mAb + CT RIT RIT + CT PET
Humanized A33 Colonocyte differentiation antigen Colorectal X X X X X
Chimeric G250 Carbonic anhydrase IX Renal Cell Carcinoma X X X   X
Humanized F19 FAPα in stroma (connecting tissue around tumors) Breast, Colorectal, Non small cell, Head and Neck X   X    
Chimeric KW2871 GD3 ganglioside Melanoma X        
Humanized 3S193 LewisY blood group antigen Breast, Colorectal, Small cell lung, Ovarian X        
Humanized LK26 Folate binding protein Ovarian X        
Chimeric 806 Overexpressed EGFR and Δ2-7 EGFR   X        
LICR Antibodies in Clinical Discovery
MX35 Unknown target antigen Ovarian          
A34 Differentiation antigen Gastric          
Lewisb Lewisb blood group antigen Gastric          
Legend: mAb = monoclonal antibody; CT = chemotherapy; RIT = radiotherapy; PET = positron emission tomography