NONTECHNICAL RESEARCH PLAN
nycornell.org
Objectives:
Define the toxicity and maximal tolerated dose (MTD) of humanized monoclonal
antibody (mAb) huJ591 in patients with prostate cancer who have recurrent and/or
metastatic prostate cancer (Pca). .....
Background: Prostate cancer is the most commonly diagnosed and 2nd most common cause of cancer
deaths in American males. In 1998, 185,000 new cases were diagnosed and 37,000 died of this disease (1).
It accounts for 40% of all cancers diagnosed in men. A male born in the U.S. in 1990 has approximately a 1 in
8 likelihood of being diagnosed with clinically apparent prostate cancer in his lifetime. Even prior to the recent
increase in incidence, prostate cancer was the most prevalent cancer in men (2, NEJM).
There is currently no curative treatment for prostate cancer once it has metastasized (spread beyond
the prostate). Currently, systemic therapy is limited to various forms of androgen (male hormone) deprivation.
While most patients will demonstrate initial clinical improvement, virtually inevitably, androgen-independent
cells develop. The median time to development of androgen-independence is 9-30 months from the time of
initiating hormonal treatment (3). Once this occurs, there is no effective standard therapy and the median
duration of survival is 18-24 months (3). Endocrine therapy is thus palliative, not curative. Cytotoxic
chemotherapy is poorly tolerated in this age group and generally considered ineffective and/or impractical.
No chemotherapeutic regimen has been demonstrated a survival benefit.
Rationale:
Monoclonal antibodies (mAbs) are undergoing investigation in many tumor types because of their
ability to specifically target tumor sites while sparing normal tissues. MAbs are now FDA-approved in
several clinical settings: transplantation, cardiovascular disease, inflammatory bowel disease, rheumatoid
arthritis, infectious disease and cancer. In the latter setting (cancer), mAbs are approved in Europe for the
adjuvant treatment of colon cancer (and in multi-center pivotal trials in the U.S.) and approved in the U.S. for
treatment of non-Hodgkins’ lymphoma and breast cancer. Two additional mAbs, a radiolabeled mAb for
treatment of lymphoma and a drug-conjugated mAb for treatment of leukemia, are currently under review by
the FDA for possible approval.
In general, the attributes and strengths of mAbs are particularly well-suited to the demands of prostate
cancer therapy:
1) mAbs can specifically and precisely target tumor sites while sparing normal tissues. The ability to
spare normal tissue and the resulting toxicity is particularly important in this generally elderly population.
2) Prostate cancer metastases predominantly involve the bone marrow and lymph nodes--sites which
receive very high levels of administered antibody.
3) cancers similar to Pca have been successfully treated with mAbs. (Lymphoma and breast cancer
both have a predilection for bone marrow and lymph nodes.)
4) Individual tumor sites tend to be small volume sites, ideally suited for both antibody delivery and
access. At the time of PSA relapse, patients have a very low disease burden, typically years from becoming
manifest on imaging studies.
5) the availability of clinical parameters such as serum prostate specific antigen (PSA) and
pathological features of a patient's cancer such as stage, Gleason score, extracapsular, seminal vesicle or
perineural invasion, positive margins, etc. provides the clinician with appropriate indications for mAb therapy
in an adjuvant setting where such therapy is likely to be of the greatest benefit.
6) The ability to rapidly define biochemical response to treatment using PSA as a surrogate marker.
Given the theoretical advantages of mAbs in this disease, it is compelling to evaluate this approach.
PSMA/ mAb anti-PSMA:
Prostate specific membrane antigen (PSMA) is the single most well-established, highly restricted prostate epithelial
cell membrane antigen (4-11).
The PSMA gene has been cloned, sequenced (5), and mapped to chromosome 11 (6). In contrast to other
highly restricted prostate-related antigens such as prostate specific antigen (PSA), prostatic acid
phosphatase (PAP) and prostate secretory protein (PSP), all of which are secretory proteins, PSMA is
anchored to the cell membrane. Among reasons for significant interest in PSMA is that it is ideal for in vivo
prostate-specific targeting strategies. In addition to its prostate specificity (4,5,7,8), PSMA is expressed by
virtually all PCa (9, 15), expression is further increased in higher grade cancers and in metastatic disease (9)
and in hormone-refractory PCa (8-10).
Initial validation of PSMA as an in vivo target has been borne out by imaging trials with mAb
7E11/CYT-356 (17-20), marketed as ProstaScint. Molecular mapping, however, indicates that mAb
7E11/CYT-356/ ProstaScint targets a portion of the PSMA molecule that is in the cell’s interior and not
exposed on the outer cell surface (21,22). In living cells, this interior binding site is not accessible to antibody
(14,21,22). Successful imaging with ProstaScint relates to targeting of dead/dying cells within tumor sites
(22-24). It has been noted (22-24) that a mAb to the extracellular domain of PSMA would provide benefits
including improved localization in patients and enhanced imaging and therapy. At Weill Medical College, Liu
et al have reported the development of 4 IgG mAbs to the external domain of PSMA (PSMAext; ref 24).
These antibodies to PSMAext demonstrate high affinity binding to PCa cells in tissue culture, on
tissue sections and in animal models. Furthermore, unlike ProstaScint, these mAbs can bind to viable cells
(24) as the target binding site is present on the exterior of the cell.
Clinical grade mouse (murine) antibody was produced and began clinical trials at NYPH-WMC in
October, 1998 (see below). In parallel, using genetic engineering techniques, these mouse antibodies have
been “deimmunized” by replacing murine sequences with human sequences (25). This results in a
non-immunogenic antibody, which can be administered to patients on multiple occasions over long time
periods without inducing an immune response. Furthermore, the deimmunized mAb additionally has been
engineered to possess the additional effect of inducing ADCC with human effector cells. Pre-clinical cell
culture and animal studies with mAbs to PSMAext have demonstrated substantial anti-tumor effect (). snip<>
DONT MISS this on proteins:
Message 14479446
Jim |
