Full Text HL-97-002
 
HUMAN ANTI-HIV MONOCLONAL ANTIBODIES IN IMMUNOTHERAPY OF HIV
 
NIH GUIDE, Volume 25, Number 43, December 13, 1996
 
RFA:  HL-97-002
 
National Heart, Lung, and Blood Institute
 
P.T.  34

Keywords: 
  Monoclonal Antibodies 
  Immunotherapy 
  AIDS 

 
Letter of Intent Receipt Date:  March 17, 1997
Application Receipt Date:  April 18, 1997
 
THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  THIS RFA
INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS
THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS
RFA.
 
PURPOSE
 
The Transfusion Medicine Scientific Research Group, Division of Blood
Diseases and Resources, National Heart, Lung, and Blood Institute
(NHLBI), announces the availability of a Request for Applications
(RFA) on the above subject. The purpose of this initiative is to
encourage the conduct of basic and applied research on the
development of human anti-HIV monoclonal antibodies (mAb), the
establishment of effective in vitro neutralization test systems or
other assay systems for the evaluation of candidate mAb preparations
prior to their use in in vivo studies, and the creation of animal
model systems to evaluate their effectiveness as passive
immunotherapy for prevention and treatment of HIV infection.  The
goal of this program is to produce sufficient quantities of  mAb
preparations, perhaps formulated as mixtures of mAbs or in
combination with other products, for evaluation of their safety and
efficacy in clinical trials.
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000",
a PHS-led national activity for setting priority areas.  This RFA,
Human anti-HIV Monoclonal Antibodies in Immunotherapy of HIV, is
related to the priority areas of HIV infection, and immunization and
infectious diseases.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0 or
Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of state or local
governments, and eligible agencies of the Federal government.  Awards
in response to this RFA will be made to foreign institutions only for
research of very unusual merit, need, and promise, and in accordance
with PHS policy governing such awards.  Minority individuals, women,
and persons with disabiities are encouraged to apply.  Newly
independent investigators, who may wish to consult with a program
representative, (see "INQUIRIES" section) are encouraged to apply.
 
MECHANISM OF SUPPORT
 
This RFA will use the NIH individual research project grant (R01)
mechanism of support.  Specific application instructions have been
modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining
efforts being examined by the NIH.  The MODULAR GRANT concept
establishes specific modules in which direct costs may be requested
as well as a maximum level for requested budgets.  Only limited
budgetary information is required under this approach.  The
JUST-IN-TIME concept allows applicants to submit certain information
only when there is a possibility for an award.  It is anticipated
that these changes will reduce the administrative burden for the
applicants, reviewers, and Institute staff.
 
For this RFA, funds must be requested in $25,000 direct cost modules.
A maximum of eight modules ($200,000 direct costs) per year may be
requested.  Any necessary escalation must be included within the
number of modules being requested.  Only limited budget information
will be required and any budget adjustments made by the Initial
Review Group will be in modules of $25,000.  Instructions for
completing the Biographical Sketch have also been modified. In
addition, Other Support information and the application Checklist
page are not required as part of the initial application.  If there
is a possibility for an award, necessary budget, Other Support and
Checklist information will be requested by NHLBI staff following the
initial review.  The APPLICATION PROCEDURES section of this RFA
provides specific details of modifications to standard PHS 398
application kit instructions. Applicants, who will plan and execute
their own research programs, are requested to furnish their own
estimates of the time required to achieve the objectives of the
proposed research project.  Up to 5 years of support may be
requested.  At the end of the official award period, renewal
applications may be submitted for peer review and competition for
support through the regular grant program of the NHLBI.  It is
anticipated that support for this program will begin in September
1997.  Administrative adjustments in project period or amount of
support may be required at the time of the award.  Since a variety of
approaches would represent valid responses to this RFA, it is
anticipated that there will be a range of costs among individual
grants awarded.  All current policies and requirements that govern
the research grant programs of the NIH will apply to grants awarded
in connection with this RFA.
 
FUNDS AVAILABLE
 
It is anticipated that for fiscal year 1997, the first year of
support for this initiative, $3,000,000 total costs will be
available.  The award of grants pursuant to this RFA is contingent
upon receipt of such funds for this purpose.  It is anticipated that
approximately ten to twelve new grants will be awarded under this
program.  Applicants may request up to five years of support.  The
specific number to be funded will, however, depend on the merit and
scope of the applications received and on the availability of funds.
Direct costs will be awarded in modules of $25,000, less any overlap
or other necessary administrative adjustments. Facilities and
Administrative costs (indirect costs) will be awarded based on the
negotiated rates.   If collaborative arrangements involve
subcontracts with other institutions, Ms. Jane R. Davis of the NHLBI
Grants Operations Branch (telephone: (301) 435-0166), should be
consulted regarding procedures to be followed.
 
RESEARCH OBJECTIVES
 
Background
 
Passive immunotherapy in the prevention of viral diseases prior to or
shortly after exposure is a well-accepted procedure and is utilized
in preventing infection with hepatitis B, measles, and
varicella-zoster, among other viruses.  Passive immunity may also
play an important role in the treatment or prevention of human
immunodeficiency virus (HIV) infection as suggested by a number of
clinical trials utilizing antibody preparations derived from
HIV-infected plasma donors.  The reagents thus far utilized in animal
as well as in human studies fall into one of the following
categories:
 
1.  Polyclonal antibodies: These antibody products are obtained by
plasmapheresing clinically healthy asymptomatic donors who have been
found to have high titer anti-p24 antibody and who are p24 antigen
negative.  Plasma pools are inactivated by a solvent-detergent
procedure before fractionation with the cold alcohol Cohn-Oncley
process. The final product is a monomeric, unfragmented, and
undenatured IgG.  Currently, the NHLBI is supporting the preparation
of an immunoglobulin with high titers of anti-HIV antibodies, which
is under evaluation in  Phase III clinical trials.  One trial
involves the use of this HIV-specific immunoglobulin (HIVIG) to
prevent the vertical transmission of the virus from HIV-infected
pregnant women to their offspring.  In a pilot study, the clinical
usefulness of HIVIG is being evaluated in children already infected
with HIV.  It is unknown whether or not HIVIG or other products of
this type contain adequate levels of protective antibodies to be
effective either prophylactically or therapeutically.  One of the
drawbacks in the use of HIVIG is that large quantities of the product
are needed for adult patients and the supply is quite limited.
 
2.  Monoclonal antibodies:   With the development of human mAb, the
potential for passive immunization has been enhanced, as antibodies
with negligible antigenicity and defined specificity can be
administered in relatively small amounts to individuals infected with
or at high risk for a particular infectious agent.  Several anti-HIV
mAbs have been produced but few have been shown to neutralize primary
HIV isolates.  Human mAbs offer the advantages that they can be
produced in large quantities without need for plasma donors and the
viral inactivation procedures currently used to treat plasma obtained
from such donors.  A potential problem with mAb preparations is that
they possess very specific neutralization properties, and may only
bind to a specific epitope of the HIV surface protein failing to
neutralize viral infectivity.  Thus, mixtures of several mAbs may be
required in order to achieve the broad neutralizing effect needed to
be clinically effective.  Such a cocktail would offer the advantages
of a greater range of activity against variants of HIV, and the use
of appropriately selected mAbs might lead to more effective
neutralization due to synergistic interaction between antibodies.
 
3.  Immunoadhesin (CD4-IgG): This is a genetically engineered
molecule containing two to four CD4 moieties associated with the
heavy and/or light chains of IgG replacing the immunoglobulin
variable domains.  One of the advantages that a preparation of this
type offers is its broad neutralizing capacity for both laboratory
and primary isolates of HIV.  Its half-life is significantly shorter
than that of IgG, but a half-life of a few days may be adequate in a
prophylactic setting.  Moreover, CD4-IgG can act in synergy with
human anti-HIV mAbs.  Ongoing studies and the availability of this
product will determine the utility of this immunoadhesin.
 
Most of the clinical studies conducted thus far involving the use of
immune plasma or HIVIG, have shown that both products are well
tolerated.  However, the number of patients in the studies who
received these products is generally small, and are primarily adult
males. Furthermore, most of the studies have been open label and the
definition of clinical response to therapy differed among studies.
Nevertheless, most studies have suggested some clinical benefit,
either in terms of time to development of opportunistic infections or
a decrease in their number as well as a trend towards increased
survival.  A number of the studies have shown a decrease in plasma
HIV; some showed a decline in p24 antigen; some demonstrated a
reduction in plasma HIV RNA; and in some studies , CD4 cell count
rose.
 
A serious obstacle to the development of these reagents for passive
immunization is the lack of a reliable in vitro assay to evaluate
their effectiveness.  Most assays depend on the infection of
mitogen-stimulated peripheral blood mononuclear cells (PBMC) and the
ability of mAbs, HIVIG, etc, to inhibit infection.  Results, however,
are difficult to interpret due to variations in both methods among
laboratories and between experiments within the same laboratory.  It
is as yet unclear why there is so much variation in sensitivity to
neutralization.  These variations are at least partially due to the
use of different PBMC donors, different sensitivity of primary
isolates, and differences in assay conditions.  Additionally, the
criteria for determining an acceptable antiviral activity or antibody
level are problematic because it is not currently known what level of
antibody titer or neutralizing antibody activity is likely to prevent
transmission of HIV.  It is postulated, however, that the infusion of
a candidate antibody product should result in antibody levels and
neutralizing activity that are at least as high as those found in
HIV-infected individuals.  Ultimately, the in vitro criteria for such
products will have to be determined from the correlation between the
in vitro antiviral characteristics of these preparations and their
efficacy in clinical trials.  Perhaps the best method for evaluating
the effects of passive immunotherapy is the severe combined immune
deficiency (SCID) mouse model.  This model has been successfully used
in the evaluation of HIVIG for pre- and post-exposure to HIV.  The
SCID mouse model has the potential of becoming the "gold standard"
for the evaluation of candidate antibody preparations.  Correlation
between this in vivo system  and a reliable, standardized  in vitro
antiviral activity would then form the basis for a product advancing
to clinical trials.
 
In summary, this initiative would support research leading to the
development and evaluation of mAbs that can be used for passive
immunization in the prevention and/or treatment of HIV infection in
man.  Research areas that are encouraged by this solicitation include
assessments of in vitro assays for evaluating candidate mAbs and
validating in vivo studies, characterization of the protective effect
of the candidate mAbs, evaluation of the SCID mouse model, and
preparation of sufficient amounts of the product to determine its
safety in Phase I clinical trials.  The candidate products  could be
mixtures of mAbs, or mixtures of mAbs with polyclonal antibodies,
immunoadhesins, or other potentially effective products for passive
immunotherapy.
 
SPECIAL REQUIREMENTS
 
Upon initiation of the program, the NHLBI will sponsor annual
meetings to encourage the exchange of information among investigators
who participate in this program.  Travel funds for a one day meeting
each year, most likely to be held in Bethesda, Maryland, should be
included in the modules. Applicants should also include a statement
in the applications indicating their willingness to participate in
such meetings.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of research.  This new policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.
All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research", which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.
 
Investigators may obtain copies from these sources or from the
program staff or contact person listed below.  Program staff may also
provide additional relevant information concerning the policy.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by March 17, 1997, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.  Such letters are requested
only for the purpose of providing an indication of the number and
scope of applications to be received; therefore, their receipt is
usually not acknowledged.  A letter of intent is not binding, and it
will not enter into the review of any application subsequently
submitted, nor is it a necessary requirement for the application.  A
faxed letter of intent may be used in place of a posted one.
 
This letter of intent is to be mailed or FAXed to:
 
Dr. C. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email:  james_scheirer@nih.gov
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the research grant application
form PHS 398 (rev. 5/95).  Applications kits are available at most
institutional offices of sponsored research and may be obtained from
the Grants Information Office, Office of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714,
email:  ASKNIH@odrockm1.od.nih.gov.  Use the conventional format for
research grant applications and ensure that the points identified in
the section on REVIEW CONSIDERATIONS are fulfilled.
 
BUDGET INSTRUCTIONS
 
The total direct costs must be requested in accordance with the
program guidelines and the modifications made to the standard PHS 398
application instructions described below:
 
DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD
Do not complete Form Page 4 of the PHS 398 (rev 5/95).  It is not
required nor will it be accepted at the time of application.
 
BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT
 
Do not complete the categorical budget tables on Form page 5 of the
PHS 398 (rev. 5/95). Only the requested total direct costs line for
each year must be completed based on the number of $25,000 modules
being requested.  Applicants may not request a change in the amount
of each module.  A maximum of eight modules ($200,000) direct costs
per year may be requested and each applicant may request up to five
years of support for this RFA.  Direct cost budgets will usually
remain constant throughout the life of the project (i.e., the same
number of modules requested for all budget periods).  Any necessary
escalation should be considered when determining the number of
modules to be requested. However, in the event that the number of
modules requested must change in any future year due to the nature of
the research proposed, appropriate justification must be provided.
Total Direct Costs for the entire Proposed Project Period should be
shown in the box provided.
 
BUDGET JUSTIFICATION
 
- Budget justifications should be provided under "Justifications" on
Form Page 5 of the PHS 398.
 
- List the names, role on the project and proposed percent effort for
all project personnel (salaried or unsalaried) and provide a
narrative justification for each person based on his/her role on the
project.
 
- Identify all consultants by name and organizational affiliation and
describe the services to be performed.
 
- Provide a general narrative justification for individual categories
(equipment, supplies, etc.) required to complete the work proposed.
More detailed justifications should be provided for high cost items.
Any large one-time purchases, such as large equipment requests, must
be accommodated within these limits.
 
CONSORTIUM/CONTRACTUAL COSTS - If collaborations or subcontracts are
involved that require transfer of funds from the grantee to other
institutions, it is necessary to establish formal subcontract
agreements with each collaborating institution.  A letter of intent
from each collaborating institution should be submitted with the
application.  Only the percentage of the consortium/contractual TOTAL
COSTS (direct and indirect) relative to the total DIRECT COSTS of the
overall project needs to be stated at this time. The following
example should be used to indicate the percentage cost of the
consortium, "The consortium agreement represents 27 percent of
overall $200,000 direct costs requested in the first year."  A budget
justification for the consortium should be provided as described in
the "Budget Justification" section above (no Form Page 5 required for
the consortium).  Indicate whether the consortium will be in place
for the entire project period and identify any future year changes in
the percentage relative to the parent grant.
 
If there is a possibility for an award, the applicant will be
requested to identify actual direct and indirect costs for all years
of the consortium.  Total subcontract costs need not be calculated in
$25,000 modules.  However, when subcontract funds are added to the
parent grant budget, the total direct cost amount must be included in
the number of $25,000 modules requested.
 
BIOGRAPHICAL SKETCH - A biographical sketch is required for all key
personnel, following the modified instructions below.  Do not exceed
the two-page limit for each person.
 
- Complete the educational block at the top of the form page;
- List current position(s) and those previous positions directly
relevant to the application;
- List selected peer-reviewed publications directly relevant to the
proposed project, with full citation;
- The applicant has the option to provide information on research
projects completed and/or research grants participated in during the
last five years that are relevant to the proposed project.
 
OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page
7).  Selected other support information relevant to the proposed
research may be included in the Biographical Sketch as indicated
above.  Complete Other Support information will be requested by NHLBI
staff if there is a possibility for an award.
 
CHECKLIST - No "Checklist" page is required as part of the initial
application.  A completed Checklist will be requested by NHLBI staff
if there is a possibility for an award.
 
The applicant should provide the name and phone number of the
individual to contact concerning fiscal and administrative issues if
additional information is necessary following the initial review.
Sample budgets and justification page will be provided upon request
or following the submission of a letter of intent.  Applications not
conforming to these instructions will be considered unresponsive to
this RFA and will be returned without further review.
 
Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or principal investigator could be included
with the application.
 
The RFA label available in the PHS 398 application kit must be
affixed to the bottom of the face page of the original copy of the
application.  Failure to use this label could result in delayed
processing of the application such that it may not reach the review
committee in time for review  In addition, the RFA title (HUMAN
ANTI-HIV MONOCLONAL ANTIBODIES IN IMMUNOTHERAPY OF HIV) and number
(HL-97-002) must be typed on line 2 of the face page of the
application form and the YES box must be marked.
 
Send or deliver the completed application and three signed, exact
photocopies of it to the following, making sure that the original
application with the RFA label attached is on top:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier/overnight service)
 
Send an additional two copies of the application to the Chief, Review
Branch, at the address listed under LETTER OF INTENT.  It is
important to send these two copies at the same time as the original
and three copies are sent to the Division of Research Grants.
Otherwise the NHLBI cannot guarantee that the application will be
reviewed in competition for this RFA.
 
Applications must be received by April 18, 1997.  If an application
is received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this RFA that is essentially
the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The DRG will not accept
any application that is essentially the same as one already reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.
 
Although this is a National Heart, Lung, and Blood Institute Request
for Grant Applications, the National Institute of Allergy and
Infectious Diseases (NIAID) also has an interest in the subject
matter of this RFA.  Therefore, the NIAID may be given a secondary
institute assignment, if appropriate.
 
REVIEW CONSIDERATIONS
 
Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness by the NHLBI.  Incomplete and/or non-
responsive applications will be returned to the applicant without
further consideration.  Applications that are complete and responsive
to the RFA will be evaluated for scientific and technical merit by an
view, a process may be used by the initial review group in which
applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications
received in response to the RFA.  Applications judged to be
competitive will be discussed and be assigned a priority score.
Applications determined to be non-competitive will be withdrawn from
further consideration and the principal investigator/program director
and the official signing for the applicant organization will be
notified.
 
The criteria used in the evaluation of scientific merit of each
application will be similar to those used in the review of
traditional research-project grant applications, including novelty,
originality, and feasibility of the approach; the training experience
and research competence of the investigator(s); the adequacy of the
experimental design; the suitability of the facilities; and the
appropriateness of the requested budget to the work proposed.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
 
The personnel category will be reviewed for appropriate staffing
based on the requested percent effort.  The direct costs budget
request will be reviewed for consistency with the proposed methods
and specific aims.  Any budgetary adjustments recommended by the
reviewers will be in $25,000 modules.  The duration of support will
be reviewed to determine if it is appropriate to ensure successful
completion of the requested scope of the project.
 
AWARD CRITERIA
 
The anticipated date of award is September 1997.  Funding decisions
will be made on the basis of scientific and technical merit as
determined by peer review, program needs and balance, and the
availability of funds.
 
Awards in response to this RFA will be made to foreign institutions
only for research of very unusual merit, need, and promise, and in
accordance with PHS policy governing such awards.
 
Designated funding levels are subject to change at any time prior to
award, due to unforeseen budgetary, administrative and/or scientific
developments.
 
INQUIRIES
 
Inquiries concerning this RFA are encouraged.  Potential applicants
may request a copy of sample budget pages.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Inquiries regarding programmatic issues may be directed to:
 
Dr. Luiz H. Barbosa
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10146
Bethesda, MD  20892-7950
Telephone:  (301) 435-0075
FAX:  (301) 480-0868
Email:  lb30o@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Ms. Jane R. Davis
Section Grants Management Officer
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0166
FAX:  (301) 480-3310
Email:  jane_davis@nih.gov
 
AUTHORITY AND REGULATIONS
 
The programs of the Division of Blood Diseases and Resources, NHLBI,
are described in the Catalog of Federal Domestic Assistance No.
93.839.  Awards will be made under the authority of the Public Health
Service Act, Section 301 (42 USC 241) and administered under PHS
grant policies and Federal regulations, most specifically 42 CFR Part
52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.
 
The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the
American people.
 
.

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